Fiend and friend in the renin angiotensin system_ An

Biomedicine & Pharmacotherapy 110 (2019) 764–774

Contents lists available at ScienceDirect

Biomedicine & Pharmacotherapy journal homepage: www.elsevier.com/locate/biopha

Review

Fiend and friend in the renin angiotensin system: An insight on acute kidney injury Nisha Sharmaa, Hans-Joachim Andersb, Anil Bhanudas Gaikwada, a b

T

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Laboratory of Molecular Pharmacology, Department of Pharmacy, Birla Institute of Technology and Science, Pilani, Pilani Campus, Rajasthan 333 031, India Division of Nephrology, Department of Internal Medicine IV, University Hospital of the Ludwig Maximilians University Munich, 80336 Munich, Germany

A R T I C LE I N FO

A B S T R A C T

Keywords: Acute kidney injury Renin angiotensin system Conventional RAS Non-conventional RAS

Besides assisting the maintenance of blood pressure and sodium homeostasis, the renin-angiotensin system (RAS) plays a pivotal role in pathogenesis of acute kidney injury (AKI). The RAS is equipped with two arms i) the pressor arm composed of Angiotensin II (Ang II)/Angiotensin converting enzyme (ACE)/Angiotensin II type 1 receptor (AT1R) also called conventional RAS, and ii) the depressor arm consisting of Angiotensin (1-7) (Ang 17)/Angiotensin converting enzyme 2 (ACE2)/MasR known as non-conventional RAS. Activation of conventional RAS triggers oxidative stress, inflammatory, hypertrophic, apoptotic, and pro-fibrotic signaling cascades which promote AKI. The preclinical and clinical studies have reported beneficial as well as deleterious effects of RAS blockage either by angiotensin receptor blocker or ACE inhibitor in AKI. On the contrary, the depressor arm opposes the conventional RAS, has beneficial effects on the kidney but has been less explored in pathogenesis of AKI. This review focuses on significance of RAS in pathogenesis of AKI and provides better understanding of novel and possible therapeutic approaches to combat AKI.

1. Introduction The renin-angiotensin system (RAS) is one of the crucial regulatory systems for blood pressure and fluid balance. As RAS has a Janus face, it is classified in its two major axes: conventional and non-conventional axis. The principal effector of its conventional axis, angiotensin II (Ang II) is released by local and systemic RAS activation and in renal vasoconstriction as well as inflammation and tubular damage led to angiotensin II type1 receptor (AT1R) activation [1–3]. On the other hand, the non-conventional or protective axis of RAS, which exert its vasodilatative effects in various tissues (heart, kidney, lung, blood vessels) [2,4,5]. Hyperactivity of renal RAS has been linked with several kidney diseases, like nephropathies, renal artery stenosis and acute kidney injury (AKI) [6,7]. AKI is known to result from ischemia/reperfusion (I/ R) injuries occurring due to hypovolemia, septic shock, renal transplantation or cardiovascular surgery [8,9]. Epidemiological data on AKI collected from almost 50 million patients suggested that incidence and mortality of AKI in hospitalized adult patients is 21.6% and 23.9%, respectively [10]. The treatment regime followed for AKI involves angiotensin converting enzyme inhibitors (ACEi) and angiotensin II type 1 receptor blockers (ARB) which acts on conventional axis [11]. Apart from it, in basic research the upregulation of non-conventional axis components like angiotensin converting enzyme 2 (ACE2), mas ⁎

receptor (MasR) also have shown promising effect in experimental AKI [12,13]. Other components like angiotensin II type 2 receptor (AT2R), angiotensin (1-7) [Ang (1-7)], angiotensin (1-9) [Ang (1-9)] and alamandine are discussed thoroughly to provide promising ideas regarding their use under this fatal ailment [2,4,14–16]. Therefore, these scrutinizes the character of RAS components as a novel therapeutic strategy and summarize the reports that explored the concert of RAS components in progression and development of AKI. We highlight the current milieu of research on RAS and discuss the existing and emerging therapies targeting RAS in AKI. 2. Phases of acute kidney injury AKI has been designated with different terms depending upon the affected part of kidney tissue and the main categories are pre-renal, intrinsic and post-renal [17]. Amongst, intrinsic AKI is quite challenging to assess because four different structures (interstitium, tubules, glomeruli, intra kidney blood vessels) are involved in injury. Acute tubular necrosis (ATN) is the term used to nominate AKI, results from the damage to the tubular cells [18]. In clinical aspects, AKI is characterized by four phases: initiation, extension, maintenance, and recovery phases (Fig. 1). The initiation phase is ushered by drastic fall in renal blood flow followed by grievous depletion of ATP levels. This

Corresponding author at: Department of Pharmacy, Birla Institute of Technology and Science, Pilani, Pilani Campus, Pilani 333 031, Rajasthan, India. E-mail address: [email protected] (A.B. Gaikwad).

https://doi.org/10.1016/j.biopha.2018.12.018 Received 1 September 2018; Received in revised form 5 December 2018; Accepted 5 December 2018 0753-3322/ © 2018 The Authors. Published by Elsevier Masson SAS. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/BY-NC-ND/4.0/).


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Fig. 1. Link between clinical phases and cellular phases of AKI represented by alteration in GFR. AKI is typically characterized in four phases: initiation, extension, maintenance and recovery. Ischemic insult to renal tissue led to abruptly reduced renal blood flow, tubular obstruction and decrease in ATP levels. It further activates inflammatory cascade along with apoptosis and necrosis that causes loss of cellular integrity. In maintenance phase, GFR levels starts improving as cellular repair process get initiated leading to cell proliferation. Recovery phase is manifested by regain of cellular integrity and normalized organ function.

several other peptides that are equally significant. Therefore, another axis of RAS referred to as the non-conventional RAS. ACE2 is the key enzyme of non-conventional RAS by cleaving Ang I and Ang II into Ang (1-9) and Ang (1-7), respectively. Both of these peptides exert opposite effects to Ang II [31,32]. Ang II is further cleaved into angiotensin III [Ang (III)] and angiotensin IV [Ang (IV)], that act through AT1R and angiotensin II type 4 receptor (AT4R). Ang IV regulates cognitive, learning memory and regulates glucose uptake [33,34]. A schematic representation of the RAS components is shown in Fig. 2.

leads to severe dysfunction of renal cells [19]. These conditions are imitated by experimental kidney IR injury models, demonstrating structural and functional changes in tubular cells [20–22]. These alterations disrupt the normal functioning of renal epithelial and vascular cells. Cell necrosis in the early initiation phase leads to the release of cytokines and other inflammatory mediators [23,24]. The extension phase is characterized by sustained necroinflammation at the corticomedullary junction of kidney. To compensate function loss, the proximal tubular cells of outer cortex enter endocycles to increase their functional capacity by undergoing polyploidization and hypertrophy [25]. Moreover, glomerular filtration rate (GFR) used to gradually fall due to continuous corticomedullary injury [26]. Therefore, this phase could be considered as the better therapeutic target option for the treatment of AKI. The maintenance phase is sorted by cellular repair, migration, and programmed cell death along with progenitor proliferation in order to endeavor clonal regeneration of denudated tubular segments to regain tubular integrity [25,27]. This phase is also known as the reorganization phase in which due to tubular cell endocycle and progenitor-driven regeneration of necrotic S3 segments GFR recovers, although the extent to which recovery is possible depends the amount irreversibly lost nephrons in which regeneration failed. Therefore, irreversible nephron loss is common upon acute tubular necrosis and accounts for the high frequency of chronic kidney disease (CKD) after an AKI episode.

4. Conventional RAS 4.1. Angiotensinogen AGT is the parent polypeptide from which all other angiotensin peptides are formed. Structurally, human AGT is made up of 485 amino acids, involving a 33 amino-acid signal peptide. The 10 amino acid sequences on N-terminal are cleaved by renin into Ang I, which acts as the source for a range of active angiotensin peptides. AGT has been reported to play crucial roles in cardiovascular and renal disorders including AKI [35–37]. One study conducted by a group of scientists have explore the role of activated protein C on the altered expressions of different components of RAS including AGT in lipopolysaccharide induced AKI [38]. The pathogenesis involves endotoxemia, disturbed hemodynamics and increased production of nitric oxide (NO) along with renal vasoconstriction. There was an increased protein and mRNA levels of AGT and ACE but suppressed ACE2 levels which were interestingly reversed by activated protein C treatment. There are numerous biomarkers reported for the early diagnosis of AKI [39–47]. Amongst all, urinary angiotensinogen (uAGT) has also joined the biomarkers’ category that could serve in early diagnosis of AKI. It is highly stable in urine and helps in providing more appropriate information regarding RAS activity [48]. Further, a fine compilation of several studies carried out by Sheeba et al. have represented AGT as a biomarker for AKI [37]. AGT is the parent polypeptide that generates other RAS peptides, therefore its significance as of urinary biomarker make it more

3. RAS components It is acknowledged that altered levels of RAS components exerts prime roles in several pathophysiological conditions [28]. Renin (also known as angiotensinogenase) is a key enzyme of the RAS that is selectively produced inside the juxtaglomerular apparatus in each nephron. Renin converts angiotensinogen (AGT) to Ang I, which is further hewed by ACE into Ang II [29]. Ang II (major product) mediates its physiological roles via two receptors: AT1R and AT2R [30]. Ang II serves to be the major downstream molecule of conventional axis of RAS, however the substantial research done onto RAS has identified 765


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Fig. 2. RAS components and their respective receptors. AT1R exerts deteriorative effect on the tissues which are inhibited by AT2R. MrgD wields beneficial roles similar to that of MasR like vasodilatory, anti-fibrotic, anti-hypertensive. AT4R has its role in cognitive, learning and in glucose uptake as well.

diseases [65–69]. A strong link between ACE and disease exists for AKI [70,71]. Kidney ischemia has shown to alter the balance of the RAS axis [72]. Increased Ace expression contributes to activation of numerous pathological pathways such as release of ROS, oxidative stress, inflammation, fibrosis, and apoptosis which are attenuated by procuring ACEi. One report has proved the mechanistic approach of captopril sovereign to ATP-dependent potassium channels in curbing I/R renal injury [73]. Increased ACE levels are associated with elevated biochemical markers of excretory kidney function (cystatin C and creatinine) and intrarenal injury [interleukin-6 (IL-6), TGF-β, interleukin-10 (IL-10), Ang II] in I/R rats [74]. The ACEi captopril attenuated kidney injury, kidney inflammatory, intrarenal NO release and amassing of Ang II at initial phase of reperfusion [74]. Apart from captopril’s ACE inhibiting activity, it also possess an anti-oxidant property via its thiol moiety [75]. Thus, in a comparative study performed to treat kidney IR injury, it inhibits ROS and lipid peroxidation by reducing urea, creatinine and NGAL levels in the IR kidney [76]. Interestingly, Ace is set to play a major role in conversion of the active forms of bradykinin and kallidin to their inactive forms. Whereas ACEi has shown beneficial effects (partly via kinins) in ischemic AKI [77]. However, there are conflicting reports for bradykinin use in I/R. Indeed, exogenous bradykinin can aggravate injury, while depletion in endogenous bradykinin led to worsening of AKI [77,78]. Furthermore, bradykinin also exerts its action by increasing NO levels and phospholipase A2-derived products in ischemic AKI [79]. Because ACEi is known to reduce glomerular perfusion pressure, clinical reports have shown controversial effects of ACEi on the progression of AKI in patients undergoing cardiac surgery [80]. So, it is difficult to conclude the role of ACEi on worsening or alleviating AKI and further studies are needed to clarify this contentious mechanism.

convenient in regulating the severity of AKI. 4.2. Renin Renin, a specific endopeptidase, which is synthesized as an inactive proenzyme said to govern the rate limiting step in the generation of RAS metabolites. The synthesis and secretion of renin is regulated by sympathetic nervous system, blood pressure, extracellular fluid, and prostaglandins. It generally cleaves AGT to Ang I that increases blood pressure along with renal sodium retention [49,50]. Preclinical studies depicted that renin binds to its receptor and activate mitogen-active protein kinase p44/42 and transforming growth factor beta (TGF- β) led to increased kidney hypertrophy, and fibrosis [50]. Moreover, aliskiren belongs to a novel class of renin inhibitors [51]. Aliskiren has a therapeutic potential in hypertension, diabetes, myocardial infarction, and CKD [52–54]. Apart from these studies, aliskerin also has protective effects in animal models of unilateral ureteral obstruction and CKD [55–58]. Interestingly, it has also shown promising effect in experimental and human AKI [59–61]. Hammad et al. reported the effect of aliskiren before, after, and during AKI in an animal model of renal I/R [60]. Further, another study evaluated its role in AKI by electron microscopy and molecular studies [62]. Aliskiren reduced the induction of iNOS, interleukin-1β (IL-1β), Ang II, and NF-kB. It decreased serum creatinine and blood urea nitrogen (BUN) levels along with improved morphological changes. Thus, above mentioned reports have proven renoprotective role of aliskiren in AKI. Therefore, direct renin inhibition appears to be effective in attenuating AKI observed with clinical and preclinical conditions. 4.3. Angiotensin converting enzyme

4.4. Angiotensin II

ACE is a dicarboxypeptidase enzyme cleaving 2 amino acids from the c-terminus of the inactive precursor Ang I to produce the vasoactive peptide Ang II [63]. Ace has two large homologous domains: N and C domains, which showed difference in the binding properties for ACEi [64]. Further, ACE has different genetic variants at plasma and tissue levels. These variants of ACE gene have been associated with various vulnerabilities to hypertension, diabetes, cardiovascular, and kidney

Ang II, an octapeptide hormone, is the active product of RAS generated by the cleavage of Ang I. It is produced systemically and locally through “renal” and “tissue” RAS, respectively. Ang II controls renal blood flow and helps in maintaining homeostasis [81], and also exerts deleterious effects such as differentiation, proliferation, regeneration, 766


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allowed the progression of research on the function of this receptor [96,97]. The AT1R is composed of 359 amino acids (40 kDa) and belongs to the seven membered G protein-coupled receptor superfamily [98]. AT1R signaling contributes to blood pressure regulation, vasoconstriction, cardiac contractility, renal tubular sodium absorption, and cell proliferation. It also tends to effectuate detrimental effects by activating numerous pathological pathways such as inflammation, oxidative stress, endothelial dysfunction, cardiovascular and renal diseases [99–103] (Fig. 2). Indeed, the AT1R inhibitor losartan has anti-inflammatory activity by detaining tumor necrosis factor-α (TNF-α), IL1β, IL-6 and avert leucocytes infiltration and thus granting renoprotection against I/R injury [104,105]. Moreover, Mehrotra. P et al., confirmed the effect of a high salt diet and the role of AT1R activity on CD4 T cell activation and their latent effects on the development of CKD post-AKI [106]. In general, Ang II signals get intensified post-AKI and high salt diet amplifies Ang II-induced tissue damage [26]. These authors found an elevated number of activated T-cells along with IL-17 expressions acting as essential mediators of inflammation and fibrosis. The association of activated T cells and AT1R activity in AKI progression to CKD is supported by De Miguel et al., that revealed the elevated intrarenal Ang II levels within renal lymphocytes compared to whole kidney tissue [107], signifying the influence of local rather than systemic RAS activity that actually might contribute in salt-induced lymphocyte activation. Losartan treatment increased renal blood flow, a process inhibiting pro-fibrotic factors such as TGF-β and post-AKI fibrosis [106]. Furthermore, one more interesting finding suggested the potential of AT1R antagonism in the prevention for transition of ischemia insults induced renal injury to CKD by suppressing different maladaptive mechanisms [108]. At three days post-AKI was accompanied by renal dysfunction, tubular atrophy, and inflammation, which almost recovered in losartan-treated rats. Rats kept for 9 months upon AKI developed CKD, which was characterized by proteinuria, kidney hypertrophy, glomerulosclerosis, tubular atrophy, and interstitial fibrosis. This process was associated with elevated expression levels of vascular endothelial growth factor (VEGF) and of hypoxia inducible factor-1α [108]. Hence, AT1R blockade prior to ischemia might help in averting AKI to CKD transition via ameliorating early renal blood flow recovery, reduced inflammation, and amplified HIF-1α activity (Fig. 3). We can conclude that induction and activity of the AT1R has a prominent role in the pathogenesis of AKI and the use AT1R blockers have

oxidative stress [82,83], and apoptosis [84]. It acts as a heady intrarenal vasoconstrictor and GFR regulator, along with it stimulates hypertrophy and promotes mitogenesis in proximal tubule cells by binding to apical or basolateral receptors [85–88]. Furthermore, the different hemodynamic and tubular growth responses exerted by Ang II are supposed to be mediated via receptor; AT1R. So, the activation of RAS along with elevated Ang II levels emerged as the major risk factors for AKI [89,90]. A study by Alicia et al. had revealed the differential actions of renal I/R injury on the intrarenal RAS. AKI was associated with a significant elevation of inrenal levels of Ang II, while tissue Ang I or Ang(1-7) remained unchanged. The raised Ang II levels may be a direct consequence of induced cortical renin activity. These changes were shortlived providing a mechanism for decrease in Ang II-induced vasoconstriction following ischemia. In addition, Ang II also triggers aldosterone production in the adrenal gland, and its role has been evaluated for the development and progression of kidney injury [91,92]. Gupta et al. revealed the effect of activated protein C on local RAS in lipopolysaccharide induced endotoxemia model of AKI [38]. In this, lipopolysaccharide leads to upregulation of deteriorative RAS components, including Ang II. Furthermore, they speculate on the decrease in Ang II synthesis, which may participate in improving kidney functions (Table 1). Apart from its conventional role in renal sodium and electrolyte transport, Ang II tends to increase kidney tissue injury independently of blood pressure and renal hemodynamics [93]. Therefore, in some studies the effects of the mineralocorticoid antagonist spironolactone on Ang II and aldosterone levels was evaluated against AKI [94]; out of which one has focused on administration of spironolactone before or after AKI and found that this intervention attenuates the development of CKD upon AKI [95]. However, CKD is the common problem in AKI survivors. A marked reduction of Ang II and aldosterone levels along with decreased inflammatory and fibrotic markers has been reported with spironolactone treatment even before or after ischemia, specifying the promising role of spironolactone as a preventive measure for AKIinduced CKD [95] (Fig. 3). 4.5. Angiotensin II type 1 receptor In the year 1991, the cloning of the AT1R was completed, which

Table 1 Effect of different components of conventional axis of RAS on preclinical and clinical models. AKI models

Effect on RAS components

Associated consequences

LPS-induced AKI in rats

↑ Intrarenal AGT, ACE, Ang II and ↓ ACE2 expression

Patients of AKI linked with acute decompensated heart failure Tourniquet-induced AKI in mouse hindlimb I/ R model Bilateral I/R rat model

↑ uAGT, Ang II levels

↑ BUN levels & NO production endotoxemia, blight hemodynamics [38] ↑ uAGT/creatinine concentration [48]

Unilateral I/R rat model Unilateral I/R rat model Gender related study on bilateral renal I/R model Unilateral I/R rat model followed by 5 weeks reperfusion I/R renal injury followed by 9 month reperfusion Knock out bilateral I/R mouse model Left nephrectomy I/R rat model Folic acid nephropathy

↑ Intrarenal ACE, Ang II and ↓ ACE2, Ang (1-7) expression Early (24 h) enhance in Ang II levels, ↓ mRNA levels of AGT and proximal tubular AT1R followed by later (120 h) ↑ in AT1R expression ↑ Urinary Ang I, Ang (1-7), tissue Ang II at 24 h ↓ AT1R density ↑ AT1R expression ↑ Intrarenal AT2R:AT1R ratio in females than males ↑ AT1R expression ↑ AT1R expression ↓ ↑ ↓ ↑

MasR Intrarenal Ang II, ACE, MasR and ↓ Ang (1-7) levels renin, AT1R, ACE2 mRNA levels AT1R and AT2R expressions

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↑ Cystatin C, creatinine levels ↑ inflammatory signals and tubular necrosis [90] ↑ Serum BUN, creatinine levels [89]

↑ Serum BUN, creatinine levels [194] ↑ TNF-α, IL-1β, IL-6 & elevated leucocytes infiltration; reversed by losartan treatment [104] Female rats shown positive response to losartan therapy [195] ↑ Activated T cells and AT1R activity in AKI progress into CKD and reversed by losartan therapy [106] Renal hypertrophy, glomerulo-sclerosis, tubular structural injury & tubulointerstitial fibrosis [108] Leukocyte activation, ↑ inflammatory cascades [13] Activation of ACE2-Ang (1-7)-Mas axis [4] ↓ Bcl2/Bax ratio [174]


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Fig. 3. Pathways involved in AKI to CKD conversion. AKI leads to increase in nitric oxide, Na+retention, decrease in HIF-1 and VEGF through AT1R. It also increase inflammatory cytokines like IL-4, IL-17, IFN-γ, oxidative stress and fibrotic markers (TGF-β, p-smad3, collagen-I and fibronectin) which together precipitates chronic kidney disease (CKD). CKD described as aberrations of kidney structure or function, present for more than three months. These effects have been reversed by losartan and spironolactone treatment.

activation after AKI underlies the plausible cause for development of CKD [106,108]. To give an insight towards clinical application of RAS inhibitors under these conditions, large population cohort studies has been conducted. One study was carried on cardiac surgery-associated AKI patients. By multivariate Cox regression analyses, it was demonstrated that RAS inhibition reduces the risk of ensuing CKD in cardiac surgery-associated AKI [124]. Recently, Gayat et al. reported a prospective cohort with an enrollment of 1551 intensive care unit patients (out of which 611 had AKI), prescribed with RAS blockers at the time of hospital discharge. Such patients showed a 52% decrease in mortality rate within 1 year [125]. Another study analyzing a outcomes of 46,253 patients revealed that ARB/ACEi use might be helpful in improving post-discharge (post-acute phase of AKI) consequences in patients with AKI [126]. Thus, all these retrospective cohort studies create a valid rationale for randomized controlled trial to ultimately answer the question whether RAS inhibition could improve AKI outcomes.

revealed their promising role in curbing long term outcomes of AKI (Table 1).

5. Renin-angiotensin system inhibition in acute kidney injury ACEi and ARBs both cause vasodilation of the renal efferent arterioles and result in reduction of glomerular filtration pressure. During hypovolemia, the reduced efferent vascular tone lowers GFR and ultimately promoting AKI [109]. However, the concern that use of ARB/ ACEi leads to the precipitation of AKI is poorly substantiated. In randomized controlled trials, the incidence of AKI upon the use of ARB/ ACEi compared to placebo are poorly explained due to uncertain definitions and lack of kidney-related severe outcomes [110]. Moreover, few clinical studies have been conducted to compare the incidence of AKI using ARB/ACEi along with prescribed diuretics, non-steroidal anti-inflammatory drugs and in ARB/ACEi alone therapy [111–115]. Nevertheless, such studies have not been conducted in a population cohort using individual data. However, several randomized trials reported an outstanding confirmation on escalated risk of AKI linked with paired ARB/ACEi prescription as compared to mono-therapy which led to a limited consumption of their combined dosage form [116,117]. Despite the lack of clear evidence, several guidelines recommend to withhold ARB/ACEi usage under acute complications (sepsis, hypovolemia/hypotension) [118,119]. In a large population-based cohort study conducted on individual patient basis, the effect of ARB/ACEi and their associated AKI complications has been evaluated. ARB/ACEi treatments where associated with showed little extent of AKI risk, however patient-related comorbidities (hypertension, diabetes mellitus, cardiac failure, cardiac arrhythmia and ischaemic heart disease) showed a greater impact on the frequency of AKI [11]. Moreover, supporting evidences has shown that AKI and CKD are seems to be an unified syndrome [120]. Kidney functions has to be repeatedly monitored, even though patients have reported normalized functions after AKI [121]. The maladaptive repair, focal tubular atrophy, continuing inflammation and intrarenal RAS activation results a nefarious series in kidney function repair for CKD progression. During AKI, tubular necrosis occur which initiates repairing under recovery phase of AKI. The inadequate tubular epithelium regeneration led to nephron loss and elevated GFR [122]. Intrarenal RAS activation seems to be the possible cause for altered GFR [123]. In animal studies, intrarenal RAS

6. Non-conventional RAS in AKI: a counterregulatory RAS pathway 6.1. Angiotensin converting enzyme 2 ACE2 is a monocarboxypeptidase, the only identified homologue of ACE, and has a 42% sequence homology with the N- and C-terminal domains of somatic ACE [127–130]. It is a negative regulator of RAS as it degrades Ang II to Ang (1-7) [63]. ACE2 is highly expressed within the kidneys in tubular epithelial cells, in glomerular epithelial cells, and in the renal vasculature. ACE2 activity has reported to get altered in numerous types of kidney injury [131–134]. Recently, several studies revealed the role of ACE2 in different animal models of AKI. Gupta et al., have found the efficacy of activated protein C as an anti-inflammatory agent, which can hold back lipopolysaccharide-induced AKI by significantly upregulating the mRNA levels of ACE2 in renal tissue [38]. Da Silveira et al. [4] examined the renal profile of ACE2, including Ang (1-7) and the MasR in renal I/R injury. Rats were subjected to left nephrectomy and ischemia (45 min) followed by reperfusion (2 h or 4 h) in the right kidney. Renal ACE2 activity was diminished along with reduced levels of Ang (1-7) and increased levels of MasR further illustrating the complexity and importance of ACE2-Ang (1-7)-MasR 768


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participation of Ang (1-7) in kidney inflammation and fibrosis [142–144]. To understand the interplay between Ang (1-7) and MasR, Esteban et al. employed animal models of unilateral ureteral obstruction and I/R injury. They delineated the effect of Ang (1-7) on inflammatory cascades via MasR. When MasR-deficient mice were infused with the Ang (1-7), they showed a decreased inflammatory response compared to wild type mice. The major findings of this study demonstrates new avenue for other inflammatory diseases [14]. Furthermore, Da Silveria et al. explored the ACE2/MasR/Ang (1-7) axis in postischemic AKI. The upregulation of Ang (1-7) and MasR levels had checked by biochemical assays, immunohistochemical and western blot analysis. Elevated expressions of MasR and Ang(1-7) had confirmed their connectum and prospective in the pathogenesis of AKI [4] (Table 1). Peptide Ang (1-7) analogues mimic Ang (1-7) activity, e.g. CGEN856 or the cyclic structural Ang (1-7) analogue (Pancyte) and their activity has been tested in vivo for cardiovascular disorders such as cardiac arrhythmias and pulmonary hypertension [145,146]. Due to poor oral bioavailability, Ang (1-7) has been encapsulated with hydroxyl-propyl β-cyclodextrin, which can attenuate cardiac complications and improve type 2 diabetes in rat model [147,148]. Although, these available analogues have not yet been explored in AKI. Moreover, Ang (1-7) play a crucial role in potentiating blood cell reconstitution after toxic myelosuppression. [149,150]. With such reports effect of Ang (1-7) on HLA-I+ and CD34+ cells (progenitor cells) was evaluated where it arouses the proliferation and differentiation of stem cells. The progenitor cells are defined by their limited self-renewal ability and give rise to a specific type of mature cells. Hence, they said to play a significant role in tissue regeneration [151]. Due to its regenerative ability, they were also explored in kidney tissue where they have given significant outcomes [151]. Ang (1-7) could be explored as a stimulator of progenitor cells proliferation and differentiation also in kidney regeneration upon AKI as previously shown for other drugs. Thus, a lot of work is yet to be done to fully explore the role of Ang (1-7) in AKI.

alliance in AKI. An altered ratio of ACE/ACE2 results could affect disease outcomes by escalating oxidative stress. Moreover, Yang et al. have demonstrated the effect of imbalanced ACE/ACE2 in tourniquet-induced kidney injury. Diminished ACE2 levels promulgate the disease along with increased free radicals and suppressed anti-oxidant levels [90]. Recently, Soler et al. studied circulating ACE2 activity in kidney transplant patients and found that the enzymatic activity of ACE2 correlated with graft function, glycosylated hemoglobin, and liver function tests [135]. Thus, serum ACE2 levels could be a non-invasive marker of the function of RAS in kidney transplant patients. In addition, urinary ACE2 activity and ACE2 protein got augmented in transplant recipients, moreover the co-existance of diabetes has shown a major association with urinary ACE2 levels and thus served as a biomarker in such patients [136]. These findings might be helpful to exert a special importance for a variety of clinical relevance. Apart from the research onACE2 regulation some therapeutic regimens have also been studied in the AKI context. Malek et al. established the functional role of ACE2 using diminazene aceturate (DIZE) in gender-based I/R kidney injury [12]. When given to male rats the ACE2 activator markedly reduced markers of kidney and liver dysfunction, while no such effect was noted in female rats. DIZE could elicit antioxidant effects and increased nitrite levels in the male kidney [12] however, biochemical and oxidative stress parameters did not conclude much about the action of DIZE. So, more studies are required to explore the mechanisms underlying these renoprotective effects of ACE2. Thus, these findings suggest that ACE2 has a potential role in the pathogenesis of AKI (Fig. 4). 6.2. Angiotensin (1-7) Ang (1-7) is an active 7-amino acid peptide (Asp-Arg-Val-Tyr-IleHis-Pro) generated by the hydrolysis of Ang II via ACE2 activity [128,137]. Ang (1-7) has reported to exert its action via MasR [138,139] and also act via AT2R [131,140]. Though, the ACE2/Ang (17)/MasR axis has emerged as a novel pathway in AKI, its molecular effects are still unclear. Ang (1-7) is said to counterregulates various harmful effects of Ang II by releasing the vasodilatory mediators NO, prostaglandin E2, and bradykinins [141]. Studies has suggested the

Fig. 4. Role of non-conventional axis [ACE2/Ang (1-7)/ MasR axis] on the progression of AKI. AKI results in decreased ACE2, Ang (1-7), MasR expressions results in increased free radicals formation, oxidative stress, and elevated creatinine, nitric oxide and MDA levels. The treatment with MasR agonist and ACE2 activator alleviate these effects and improves AKI condition.

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characterized by AT2R overexpression and apoptosis in tubular cells [2]. Thus, AT2R re-expression along with AT1R suggests the crucial role of this receptor in AKI. Initially, peptide AT2R agonists such as CGP42112 A or LP2 were discovered but possess no oral bioavailability and low specificity for AT2R. The first non-peptide, specific AT2R agonist, Compound 21; showed better oral availability [175] and is currently tested in hypertension, heart failure, stroke, and diabetic nephropathy [176–180]. Hence, AT2R expression and its activation by specific agonists remain largely to be explored in AKI.

6.3. Mas receptor The Mas oncogene acts as a receptor for Ang (1-7) [139,143]. Pharmacologically, Mas belongs to the class of G-protein-coupled receptors. It is made of 325 amino-acids and is highly expressed in brain and testis and less in other tissues, such as lung, spleen, heart, kidney, tongue, and skeletal muscle [152,153]. In the kidney tissue, the major pathway of Mas signaling is the ACE2/Ang (1-7)/Mas axis. Promising approaches to exploite MasR stimulation include the development of peptide analogues or a non-peptide Mas receptor agonists in order to mimic Ang (1-7) activity [154]. So far, MasR remains to be explored in the AKI context. Recently, a study evaluated the activity of MasR along with other RAS peptides in a model of postischemic AKI. Interestingly, MasR expression was found elevated, possibly due to activation of defensive pathways coping with the kidney insult [4]. Moreover, study conducted on MasR gene knockout mice using AVE0991, a MasR agonist verified its reno-protective effect in I/R injury. It attenuated glomerular and tubulointerstitial damage and improved kidney injury in association with decreased leucocyte infiltration and chemokine (CXCL1) production [13] (Fig. 4). Reversal of all histopathological and biochemical parameters has further proven the renoprotective activity of MasR. Indeed, MasR signaling suppresses numerous oxidative stress factors and inflammatory cascades. An overall enhancement of MasR stimulation increased endogenous Ang (1-7) levels by ACE2 activation. Thus, this approach actually leads to the simultaneous upsurge in Ang II deprivation along with diminution of AT1R stimulation. Furthermore, this novel target and its related therapeutic strategies support the concept that the ACE2/Ang (1-7)/MasR axis contributes to in renal I/R injury although the precise nature of signaling pathways awaits further investigation.

6.5. Angiotensin (1-9) Ang (1-9) is a crucial member of the RAS having nine amino acids in its structure [181]. Ang (1-9) is produced from Ang I by the action of ACE2, carboxypeptidase A or cathepsin A [182,183]. It is reported to be widely expressed in platelets, heart, and kidney [5,184–187]. Systemic levels of Ang (1-9) are detectable at 2–6 fmol/ml in healthy individuals, but these levels increase during disease condition [188]. Moreover, Ang (1-9) exerts its protective effects in experimental hypertension and cardiovascular remodeling [15]. Recently, one study performed using deoxycorticosterone acetate hypertensive rat model, to demonstrate the anti-inflammatory activity of Ang (1-9) via AT2R on cardiac and kidney inflammation and fibrosis [186]. Intravenous administration of Ang (19) has lessened macrophage infiltration in kidney parenchyma and diminished tubular-interstitial fibrosis by attenuating collagen deposition. Henceforth, this explanation prompted the conclusion that Ang (19) has kidney protective effect and might be evaluated under AKI settings. 6.6. Alamandine

6.4. Angiotensin II type 2 receptor

Recently, alamandine [Ala1-Ang-(1-7)] was revealed as another previously unknown endogenous peptide of RAS. This heptapeptide is produced either by decarboxylation of the N-terminal aspartate residue of Ang (1-7) or ACE2-mediated hydrolysis of Ang II [189]. Although, alamandine and Ang (1-7) act via different receptors, there biological actions are quite similar [190]. Alike Ang (1-7), alamandine binds specifically to a G-protein coupled receptor, i.e. MrgD (Mas-related genes) [191–193] (Fig. 2). Lautner et al. conducted a preclinical study to characterize alamandine and its function in rat heart [16]. They revealed that alamandine is produced from heart and also present in blood. Further, study was continued to evaluate its efficacy in hypertensive and fibrotic heart rat models, where it produces a long term antihypertensive and antifibrotic effects in rat heart [16]. Thus, it is an interesting area of further research and could be explored in AKI condition.

The AT2R is a G-protein coupled receptors coupled to Gαi2 and Gαi3 proteins [155]. The expression of the AT2R declines during development and is found only in some organs after birth but is overexpressed in pathological states [156]. Structurally, human, rat and mouse AT2R encodes for a 363 amino acid protein. The AT2R possesses five possible N-glycosylation sites, which impart for different molecular weights (68–113 kDa). The presence of two characteristic disulfide bonds present in AT2R structure differs from the respective AT1R [157]. In addition to it, Carey presented an in-depth work on RAS (especially AT2R) [158–160]. He introduced a compiled report on the role of AT2R in maintaining blood pressure and kidney function [161]. AT2R mediates its action by inducing the release of kinins (bradykinin, kallikrein), cGMP, and NO levels [162] which facilitates the natriuresis and lowering BP along with vasodilatory, anti-inflammatory, anti-oxidative stress responses (offsets the actions of AT1R) [163–166] (Fig. 2). It is now widely recognized that AT2R has opposite actions compared to AT1R. In the cardiovascular system, AT2R has also been reported to exert its role in cardioprotection via offsetting various effects of AT1R [167]. Moreover, the AT2R activation results in an equipoise of blood pressure elevated by AT1R signaling [168]. In cardiomyocytes; the activation of AT2R leads to inhibit the autophagy signaling referred by AT1R [169]. Apart from it, AT2R also exerts its pivotal role in insulin signaling [170–172]. Recently, Munoz et al. have identified that the inhibition of AT2R with PD123319 (AT2R antagonist) has increased adiponectin, MCP-1, TNF-α, and other cytokines level in adipose tissue [173]. Although, the importance and efficacy of this receptor is not much explored in the pathophysiology of AKI, data from few studies are presented in this section. Folic acid nephropathy is one of the typical models of toxic AKI. Folic acid induced kidney injury elevated the mRNA levels of c-myc (transcription factor) and Bcl2 family proteins which are reported as cell death markers in tubular epithelium [174] and further results in decreased Bcl2/Bax ratio that favored cell death. Further, Ruiz-Ortega et al. observed that folic acid nephropathy was

7. Conclusion After decades of RAS research it remains an area of active research and unexpected discoveries averting an ever increasing complexity. Recent advances in understanding the cellular and molecular basis of RAS in AKI have identified the contribution of redox imbalance, inflammatory cascades and apoptotic signaling pathways. In clinical settings, treatment regimen (ARB/ACEi) given to prevent the detrimental effects of conventional axis in AKI has shown to be associated with aggravation of AKI risk to a lesser extent, though individual linked co-morbidities have a meticulous control with AKI occurrence. In addition, this regimen may prevent subsequent complications of AKI in those that survive the acute phase, e.g. AKI to CKD transition. Apart from clinical studies, these drugs have also proven their beneficial effects in experimental studies. On the other hand, the emerging reports received from non-conventional RAS exposed the new arena for subsiding AKI under clinical and preclinical studies. Rigorous research carried out on both axes of RAS over the past few decades, carried new insights for the potential use of RAS activators/inhibitors in AKI. 770


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Components like Ang (1-7), AT2R, and MasR evolved. In addition Ang (1-9) and alamandine are the latest members, not yet explored in the AKI context. Thus, analogs or activators of above mentioned components might arise as a better therapy for AKI. Despite the comprehensive range of new possible beneficial targets for AKI, drug monotherapies: Ang (1-7) as regenerative compound, alamandine analogs, AT2R and MasR agonists, and combination therapy such as, AT1R antagonists and AT2R agonists; AT1R antagonists and ACE2 activators could provide an advanced therapeutic armament to combat AKI.

[20] A. Zuk, J.V. Bonventre, Acute kidney injury, Annu. Rev. Med. 67 (2016) 293–307. [21] S. Dube, T. Matam, J. Yen, H.E. Mang, P.C. Dagher, T. Hato, T.A. Sutton, Endothelial STAT3 modulates protective mechanisms in a mouse ischemia-reperfusion model of acute kidney injury, J Immunol. Res. 2017 (2017) 1–9. [22] W.M. Raup-Konsavage, Y. Wang, W.W. Wang, D. Feliers, H. Ruan, W.B. Reeves, Neutrophil peptidyl arginine deiminase-4 has a pivotal role in ischemia/reperfusion-induced acute kidney injury, Kidney Int. 93 (2) (2018) 365–374. [23] S.A. Lee, S. Noel, M. Sadasivam, A.R. Hamad, H. Rabb, Role of immune cells in acute kidney injury and repair, Nephron 137 (4) (2017) 282–286. [24] D. Lee, S. Faubel, C. Edelstein, Cytokines in acute kidney injury (AKI), Clin. Nephrol. 76 (3) (2011) 165–173. [25] E. Lazzeri, M.L. Angelotti, A. Peired, C. Conte, J.A. Marschner, L. Maggi, B. Mazzinghi, D. Lombardi, M.E. Melica, S. Nardi, Endocycle-related tubular cell hypertrophy and progenitor proliferation recover renal function after acute kidney injury, Nat. Commun. 9 (1) (2018) 1–18. [26] D.P. Basile, E.C. Leonard, A.G. Beal, D. Schleuter, J. Friedrich, Persistent oxidative stress following renal ischemia-reperfusion injury increases ANG II hemodynamic and fibrotic activity, Am. J. Physiol. Ren. Physiol. 302 (11) (2012) 1494–1502. [27] L. Bird, D. Walker, Pathophysiology of acute kidney injury, Comp. Anim. 20 (3) (2015) 142–147. [28] H. Kobori, M. Nangaku, L.G. Navar, A. Nishiyama, The intrarenal renin-angiotensin system: from physiology to the pathobiology of hypertension and kidney disease, Pharmacol. Rev. 59 (3) (2007) 251–287. [29] K.E. Bernstein, P.P. Sayeski, T. Doan, P. Farmer, M.S. Ali, Signal transduction pathways of angiotensin II in the kidney, The Renin-Angiotensin System and Progression of Renal Diseases, Karger Publishers, 2001, pp. 16–33. [30] M. Kanasaki, T. Nagai, M. Kitada, D. Koya, K. Kanasaki, Elevation of the antifibrotic peptide N-acetyl-seryl-aspartyl-lysyl-proline: a blood pressure-independent beneficial effect of angiotensin I-converting enzyme inhibitors, Fibrogenesis Tissue Repair. 4 (1) (2011) 25. [31] M. Bader, ACE2, angiotensin-(1-7), and mas: the other side of the coin, Pflugers Arch.: Eur. J. Physiol. 465 (1) (2013) 79–85. [32] H. Xia, E. Lazartigues, Angiotensin-converting enzyme 2: central regulator for cardiovascular function, Curr. Hypertens. Rep. 12 (3) (2010) 170–175. [33] J.J. Braszko, A. Walesiuk, P. Wielgat, Cognitive effects attributed to angiotensin II may result from its conversion to angiotensin IV, J. Renin Angiotensin Aldosterone Syst. 7 (3) (2006) 168–174. [34] A.L. Albiston, S. Diwakarla, R.N. Fernando, S.J. Mountford, H.R. Yeatman, B. Morgan, V. Pham, J.K. Holien, M.W. Parker, P.E. Thompson, Identification and development of specific inhibitors for insulin-regulated aminopeptidase as a new class of cognitive enhancers, Br. J. Pharmacol. 164 (1) (2011) 37–47. [35] M.S. ElAlfy, F.S.E. Ebeid, T.M. Kamal, D.S. Eissa, E.A.R. Ismail, S.H. Mohamed, Angiotensinogen M235T gene polymorphism is a genetic determinant of cerebrovascular and cardiopulmonary morbidity in adolescents with sickle disease, J. Stroke Cerebrovasc. Dis. (2018). [36] B. Zhou, M. Wen, L. Mi, C.-J. Hu, Y. Zhang, J.-T. Wang, L. Tang, Associations between angiotensinogen M235T polymorphisms and the risk of diabetic nephropathy: a meta-analysis, Diab. Res. Clin. Pract. 142 (2018) 26–36. [37] S.H. Ba Aqeel, A. Sanchez, D. Batlle, Angiotensinogen as a biomarker of acute kidney injury, Clin. Kidney J. 10 (6) (2017) 759–768. [38] A. Gupta, G.J. Rhodes, D.T. Berg, B. Gerlitz, B.A. Molitoris, B.W. Grinnell, Activated protein C ameliorates LPS-induced acute kidney injury and downregulates renal INOS and angiotensin 2, Am. J. Physiol. Ren. Physiol. 293 (1) (2007) 245–254. [39] X. Shao, L. Tian, W. Xu, Z. Zhang, C. Wang, C. Qi, Z. Ni, S. Mou, Diagnostic value of urinary kidney injury molecule 1 for acute kidney injury: a meta-analysis, PLoS One 9 (1) (2014) 389–391. [40] J. Mishra, Q. Ma, A. Prada, M. Mitsnefes, K. Zahedi, J. Yang, J. Barasch, P. Devarajan, Identification of neutrophil gelatinase-associated lipocalin as a novel early urinary biomarker for ischemic renal injury, J. Am. Soc. Nephrol. 14 (10) (2003) 2534–2543. [41] C.R. Parikh, A. Jani, V.Y. Melnikov, S. Faubel, C.L. Edelstein, Urinary interleukin18 is a marker of human acute tubular necrosis1, Am. J. Kidney Dis. 43 (3) (2004) 405–414. [42] S. Herget-Rosenthal, G. Marggraf, J. Hüsing, F. Goring, F. Pietruck, O. Janssen, T. Philipp, A. Kribben, Early detection of acute renal failure by serum cystatin C, Kidney Int. 66 (3) (2004) 1115–1122. [43] D. Portilla, C. Dent, T. Sugaya, K. Nagothu, I. Kundi, P. Moore, E. Noiri, P. Devarajan, Liver fatty acid-binding protein as a biomarker of acute kidney injury after cardiac surgery, Kidney Int. 73 (4) (2008) 465–472. [44] K. Kashani, A. Al-Khafaji, T. Ardiles, A. Artigas, S.M. Bagshaw, M. Bell, A. Bihorac, R. Birkhahn, C.M. Cely, L.S. Chawla, Discovery and validation of cell cycle arrest biomarkers in human acute kidney injury, Crit. Care 17 (1) (2013) 1–12. [45] J.L. Alge, N. Karakala, B.A. Neely, M.G. Janech, J.A. Tumlin, L.S. Chawla, A.D. Shaw, J.M. Arthur, S. Investigators, Urinary angiotensinogen and risk of severe AKI, Clin. J. Am. Soc. Nephrol. 8 (2) (2013) 184–193. [46] K. Kashani, A. Al-Khafaji, T. Ardiles, A. Artigas, S.M. Bagshaw, M. Bell, A. Bihorac, R. Birkhahn, C.M. Cely, L.S. Chawla, D.L. Davison, T. Feldkamp, L.G. Forni, M.N. Gong, K.J. Gunnerson, M. Haase, J. Hackett, P.M. Honore, E.A. Hoste, O. Joannes-Boyau, M. Joannidis, P. Kim, J.L. Koyner, D.T. Laskowitz, M.E. Lissauer, G. Marx, P.A. McCullough, S. Mullaney, M. Ostermann, T. Rimmele, N.I. Shapiro, A.D. Shaw, J. Shi, A.M. Sprague, J.L. Vincent, C. Vinsonneau, L. Wagner, M.G. Walker, R.G. Wilkerson, K. Zacharowski, J.A. Kellum, Discovery and validation of cell cycle arrest biomarkers in human acute kidney injury, Crit. Care (Lond., Engl.) 17 (1) (2013) 1–12. [47] A. Bihorac, L.S. Chawla, A.D. Shaw, A. Al-Khafaji, D.L. Davison, G.E. Demuth,

Conflict of interest The authors declare that this article content has no conflict of interest. Acknowledgements A.B.G sincerely acknowledges the financial support obtained from SERB/ECR/2017/000317 for his research work. HJA was supported by the Deutsche Forschungsgemeinschaft (AN372/23-1 and 24-1). References [1] T.H. Kwon, J. Nielsen, Y.H. Kim, M.A. Knepper, J. Frokiær, S. Nielsen, Regulation of sodium transporters in the thick ascending limb of rat kidney: response to angiotensin II, Am. J. Physiol. Ren. Physiol. 285 (1) (2003) 152–165. [2] M. Ruiz-Ortega, V. Esteban, Y. Suzuki, M. Ruperez, S. Mezzano, L. Ardiles, P. Justo, A. Ortiz, J. Egido, Renal expression of angiotensin type 2 (AT2) receptors during kidney damage, Kidney Int. 64 (2003) S21–S26. [3] M. Malek, M. Nematbakhsh, Renal ischemia/reperfusion injury; from pathophysiology to treatment, J. Ren. Inj. Prev. 4 (2) (2015) 20–27. [4] K.D. da Silveira, K.S.P. Bosco, L.R. Diniz, A.K. Carmona, G.D. Cassali, O. BrunaRomero, L.P. de Sousa, M.M. Teixeira, R.A. Santos, A.C.S. e Silva, ACE2-angiotensin-(1-7)–mas axis in renal ischaemia/reperfusion injury in rats, Clin. Sci. 119 (9) (2010) 385–394. [5] M.P. Ocaranza, J.E. Jalil, Protective role of the ACE2/Ang-(1-9) axis in cardiovascular remodeling, Int. J. Hypertens. 2012 (2012) 1–12. [6] V. Raizada, B. Skipper, W. Luo, J. Griffith, Intracardiac and intrarenal renin-angiotensin systems: mechanisms of cardiovascular and renal effects, J. Investig. Med. 55 (7) (2007) 341–359. [7] R. Bellomo, J.A. Kellum, C. Ronco, Acute kidney injury, Lancet 380 (9843) (2012) 756–766. [8] B.A. Molitoris, T.A. Sutton, Endothelial injury and dysfunction: role in the extension phase of acute renal failure, Kidney Int. 66 (2) (2004) 496–499. [9] A.M. Versteilen, I.J. Korstjens, R.J. Musters, A.J. Groeneveld, P. Sipkema, Rho kinase regulates renal blood flow by modulating eNOS activity in ischemia-reperfusion of the rat kidney, Am. J. Physiol. Ren. Physiol. 291 (3) (2006) F606–F611. [10] P. Susantitaphong, D.N. Cruz, J. Cerda, M. Abulfaraj, F. Alqahtani, I. Koulouridis, B.L. Jaber, World incidence of AKI: a meta-analysis, Clin. J. Am. Soc. Nephrol. 8 (9) (2013) 1482–1493. [11] K.E. Mansfield, D. Nitsch, L. Smeeth, K. Bhaskaran, L.A. Tomlinson, Prescription of renin-angiotensin system blockers and risk of acute kidney injury: a populationbased cohort study, BMJ Open 6 (12) (2016) e012690. [12] M. Malek, M. Nematbakhsh, The preventive effects of diminazene aceturate in renal ischemia/reperfusion injury in male and female rats, Adv. Prev. Med. 2014 (2014) 1–10. [13] L.C. Barroso, K.D. Silveira, C.X. Lima, V. Borges, M. Bader, M. Rachid, R.A.S. Santos, D.G. Souza, A.C. Simoes e Silva, M.M. Teixeira, Renoprotective effects of AVE0991, a nonpeptide mas receptor agonist, in experimental acute renal injury, Int. J. Hypertens. 2012 (2012) 1–8. [14] V. Esteban, S. Heringer-Walther, A. Sterner-Kock, R. de Bruin, S. van den Engel, Y. Wang, S. Mezzano, J. Egido, H.P. Schultheiss, M. Ruiz-Ortega, T. Walther, Angiotensin-(1-7) and the g protein-coupled receptor MAS are key players in renal inflammation, PLoS One 4 (4) (2009) e5406. [15] M.P. Ocaranza, J. Moya, V. Barrientos, R. Alzamora, D. Hevia, C. Morales, M. Pinto, N. Escudero, L. García, U. Novoa, Angiotensin-(1-9) reverses experimental hypertension and cardiovascular damage by inhibition of the angiotensin converting enzyme/Ang II axis, J. Hypertens. 32 (4) (2014) 771–783. [16] R.Q. Lautner, D.C. Villela, R.A. Fraga-Silva, N. Silva, T. Verano-Braga, F. CostaFraga, J. Jankowski, V. Jankowski, F. Sousa, A. Alzamora, Discovery and characterization of alamandine novelty and significance: a novel component of the renin-angiotensin system, Circ. Res. 112 (8) (2013) 1104–1111. [17] K. Makris, L. Spanou, Acute kidney injury: definition, pathophysiology and clinical phenotypes, Clin. Biochem. Rev. 37 (2) (2016) 85–98. [18] R. Alobaidi, R.K. Basu, S.L. Goldstein, S.M. Bagshaw, Sepsis-Associated Acute Kidney Injury, Seminars in Nephrology, Elsevier, 2015, pp. 2–11. [19] P. Devarajan, Update on mechanisms of ischemic acute kidney injury, J. Am. Soc. Nephrol. 17 (6) (2006) 1503–1520.

771


N. Sharma et al.

[48]

[49] [50] [51]

[52] [53]

[54]

[55]

[56]

[57]

[58]

[59]

[60] [61] [62]

[63]

[64]

[65] [66] [67]

[68]

[69]

[70]

[71] [72]

[73]

ATP dependent potassium channels, Iran Biomed. J. 12 (4) (2008) 241–245. [74] S. Efrati, S. Berman, R.A. Hamad, Y. Siman-Tov, E. Ilgiyaev, I. Maslyakov, J. Weissgarten, Effect of captopril treatment on recuperation from ischemia/reperfusion-induced acute renal injury, Nephrol. Dial. Transpl. 27 (1) (2011) 136–145. [75] A.A. Fouad, I. Jresat, Captopril and telmisartan treatments attenuate cadmiuminduced testicular toxicity in rats, Fund. Clin. Pharmacol. 27 (2) (2013) 152–160. [76] C. Kocak, F.E. Kocak, R. Akcilar, Z. Bayat, B. Aras, M.H. Metineren, M. Yucel, H. Simsek, Effects of captopril, telmisartan and bardoxolone methyl (CDDO-Me) in ischemia-reperfusion-induced acute kidney injury in rats: an experimental comparative study, Clin. Exp. Pharmacol. Physiol. 43 (2) (2016) 230–241. [77] W.-C. Chiang, C.-T. Chien, W.-W. Lin, S.-L. Lin, Y.-M. Chen, C.-F. Lai, K.-D. Wu, J. Chao, T.-J. Tsai, Early activation of bradykinin B2 receptor aggravates reactive oxygen species generation and renal damage in ischemia/reperfusion injury, Free Radic. Biol. Med. 41 (8) (2006) 1304–1314. [78] M. Kakoki, R.W. McGarrah, H.-S. Kim, O. Smithies, Bradykinin B1 and B2 receptors both have protective roles in renal ischemia/reperfusion injury, Proc. Natl. Acad. Sci. U. S. A. 104 (18) (2007) 7576–7581. [79] M.S. Paller, J.C. Manivel, M. Patten, M. Barry, Prostaglandins protect kidneys against ischemic and toxic injury by a cellular effect, Kidney Int. 42 (6) (1992) 1345–1354. [80] M. Meersch, C. Schmidt, A. Hoffmeier, H. Van Aken, C. Wempe, J. Gerss, A. Zarbock, Prevention of cardiac surgery-associated AKI by implementing the KDIGO guidelines in high risk patients identified by biomarkers: the PrevAKI randomized controlled trial, Intensive Care Med. 43 (11) (2017) 1551–1561. [81] M. De Gasparo, K. Catt, T. Inagami, J. Wright, T. Unger, International union of pharmacology. XXIII. The angiotensin II receptors, Pharmacol. Rev. 52 (3) (2000) 415–472. [82] B. Lopez, M.G. Salom, B. Arregui, F. Valero, F.J. Fenoy, Role of superoxide in modulating the renal effects of angiotensin II, Hypertension 42 (6) (2003) 1150–1156. [83] S.M. Kim, Y.G. Kim, K.H. Jeong, S.H. Lee, T.W. Lee, C.G. Ihm, J.Y. Moon, Angiotensin II-induced mitochondrial Nox4 is a major endogenous source of oxidative stress in kidney tubular cells, PLoS One 7 (7) (2012) 60–70. [84] X.J. Zou, L. Yang, S.L. Yao, Endoplasmic reticulum stress and C/EBP homologous protein-induced Bax translocation are involved in angiotensin II-induced apoptosis in cultured neonatal rat cardiomyocytes, Exp. Biol. Med. 237 (11) (2012) 1341–1349. [85] R. Yacoub, K.N. Campbell, Inhibition of RAS in diabetic nephropathy, Int. J. Nephrol. Renovasc. Dis. 8 (2015) 29–40. [86] Y. Isobe-Sasaki, M. Fukuda, Y. Ogiyama, R. Sato, T. Miura, D. Fuwa, M. Mizuno, T. Matsuoka, H. Shibata, H. Ito, Sodium balance, circadian BP rhythm, heart rate variability, and intrarenal renin-angiotensin-aldosterone and dopaminergic systems in acute phase of ARB therapy, Physiol. Rep. 5 (11) (2017) 1–13. [87] J.C. Jha, C. Banal, B.S. Chow, M.E. Cooper, K. Jandeleit-Dahm, Diabetes and kidney disease: role of oxidative stress, Antioxid. Redox Signal. 25 (12) (2016) 657–684. [88] Y. Isaka, Epidermal growth factor as a prognostic biomarker in chronic kidney diseases, Ann. Trans. Med. 4 (Suppl. 1) (2016) 1–4. [89] J. Kontogiannis, K.D. Burns, Role of AT1 angiotensin II receptors in renal ischemic injury, Am. J. Physiol. Ren. Physiol. 274 (1) (1998) 79–90. [90] Xh. Yang, Yh. Wang, Jj. Wang, Yc. Liu, W. Deng, C. Qin, Jl. Gao, Ly. Zhang, Role of angiotensin-converting enzyme (ACE and ACE2) imbalance on tourniquet-induced remote kidney injury in a mouse hindlimb ischemia-reperfusion model, Peptides 36 (1) (2012) 60–70. [91] A. Chrysostomou, E. Pedagogos, L. MacGregor, G.J. Becker, Double-blind, placebocontrolled study on the effect of the aldosterone receptor antagonist spironolactone in patients who have persistent proteinuria and are on long-term angiotensin-converting enzyme inhibitor therapy, with or without an angiotensin II receptor blocker, Clin. J. Am. Soc. Nephrol. 1 (2) (2006) 256–262. [92] X. Zhou, H. Ono, Y. Ono, E.D. Frohlich, Aldosterone antagonism ameliorates proteinuria and nephrosclerosis independent of glomerular dynamics in L-NAME/ SHR model, Am. J. Nephrol. 24 (2) (2004) 242–249. [93] K. Rafiq, H. Hitomi, D. Nakano, A. Nishiyama, Pathophysiological roles of aldosterone and mineralocorticoid receptor in the kidney, J. Pharmacol. Sci. 115 (1) (2011) 1–7. [94] K. Sanchez-Pozos, J. Barrera-Chimal, J. Garzon-Muvdi, R. Perez-Villalva, R. Rodriguez-Romo, C. Cruz, G. Gamba, N.A. Bobadilla, Recovery from ischemic acute kidney injury by spironolactone administration, Nephrol. Dial. Transplant. 27 (8) (2012) 3160–3169. [95] J. Barrera Chimal, R. Perez Villalva, R. Rodriguez-Romo, J. Reyna, N. Uribe, G. Gamba, N.A. Bobadilla, Spironolactone prevents chronic kidney disease caused by ischemic acute kidney injury, Kidney Int. 83 (1) (2013) 93–103. [96] T. Murphy, R.W. Alexander, K.K. Griendling, M.S. Runge, K.E. Bernstein, Isolation of a cDNA encoding the vascular type-1 angiotensin II receptor, Nature 351 (6323) (1991) 233–236. [97] K. Sasaki, Y. Yamano, S. Bardhan, N. Iwai, J.J. Murray, M. Hasegawa, Y. Matsudat, Cloning and expression of a complementary DNA encoding a bovine adrenal angiotensin II type-1 receptor, Nature 351 (6323) (1991) 230–233. [98] S. Higuchi, H. Ohtsu, H. Suzuki, H. Shirai, G.D. Frank, S. Eguchi, Angiotensin II signal transduction through the AT1 receptor: novel insights into mechanisms and pathophysiology, Clin. Sci. 112 (8) (2007) 417–428. [99] K.K. Griendling, D. Sorescu, M. Ushio-Fukai, NAD (P) H oxidase: role in cardiovascular biology and disease, Circ. Res. 86 (5) (2000) 494–501. [100] N. Kim, Y. Jung, M. Nam, M.S. Kang, M.K. Lee, Y. Cho, E.K. Choi, G.S. Hwang, H.S. Kim, Angiotensin II affects inflammation mechanisms via AMPK-related

R. Fitzgerald, M.N. Gong, D.D. Graham, K. Gunnerson, M. Heung, S. Jortani, E. Kleerup, J.L. Koyner, K. Krell, J. Letourneau, M. Lissauer, J. Miner, H.B. Nguyen, L.M. Ortega, W.H. Self, R. Sellman, J. Shi, J. Straseski, J.E. Szalados, S.T. Wilber, M.G. Walker, J. Wilson, R. Wunderink, J. Zimmerman, J.A. Kellum, Validation of cell-cycle arrest biomarkers for acute kidney injury using clinical adjudication, Am. J. Respir. Crit. Care Med. 189 (8) (2014) 932–939. H. Kobori, L.M. Harrison-Bernard, L.G. Navar, Urinary excretion of angiotensinogen reflects intrarenal angiotensinogen production, Kidney Int. 61 (2) (2002) 579–585. P.B. Persson, Renin: origin, secretion and synthesis, J. Physiol. 552 (2003) 667–671. M.K.S. Wong, Subchapter 29A - renin, in: Y. Takei, H. Ando, K. Tsutsui (Eds.), Handbook of Hormones, Academic Press, San Diego, 2016pp. 255-e29A-2. K. Allikmets, Aliskiren—an orally active renin inhibitor. Review of pharmacology, pharmacodynamics, kinetics, and clinical potential in the treatment of hypertension, Vasc. Health Risk. Manag. 3 (6) (2007) 809–815. A. Hassanin, H.A. Malek, Effect of renin inhibition on adipokines in diabetic rats, Pak. J. Pharm. Sci. 27 (4) (2014). C. Bavishi, S. Bangalore, F.H. Messerli, Renin angiotensin aldosterone system inhibitors in hypertension: is there evidence for benefit independent of blood pressure reduction? Prog. Cardiovasc. Dis. 59 (3) (2016) 253–261. S.D. Solomon, S. Hee Shin, A. Shah, H. Skali, A. Desai, L. Kober, A.P. Maggioni, J.L. Rouleau, R.Y. Kelly, A. Hester, Effect of the direct renin inhibitor aliskiren on left ventricular remodelling following myocardial infarction with systolic dysfunction, Eur. Heart J. 32 (10) (2011) 1227–1234. K.-T. Woo, H.-L. Choong, K.-S. Wong, H.-K. Tan, M. Foo, F.-C. Stephanie, E.J. Lee, V. Anantharaman, G.S. Lee, C.-M. Chan, A retrospective Aliskiren and Losartan study in non-diabetic chronic kidney disease, World J. Nephrol. 2 (4) (2013) 129. D.E. Choi, J.Y. Jeong, B.J. Lim, Y.-K. Chang, K.-R. Na, Y.-T. Shin, K.W. Lee, Aliskiren ameliorates renal inflammation and fibrosis induced by unilateral ureteral obstruction in mice, J. Urol. 186 (2) (2011) 694–701. T. Moriyama, Y. Tsuruta, C. Kojima, M. Itabashi, H. Sugiura, T. Takei, T. Ogawa, K. Uchida, K. Tsuchiya, K. Nitta, Beneficial effect of aliskiren combined with olmesartan in reducing urinary protein excretion in patients with chronic kidney disease, Int. Urol. Nephrol. 44 (3) (2012) 841–845. S. Lizakowski, L. Tylicki, M. Renke, P. Rutkowski, Z. Heleniak, M. SławińskaMorawska, E. Aleksandrowicz, W. Łysiak-Szydłowska, B. Rutkowski, Effect of aliskiren on proteinuria in non-diabetic chronic kidney disease: a double-blind, crossover, randomised, controlled trial, Int. Urol. Nephrol. 44 (6) (2012) 1763–1770. Z. Harel, C. Gilbert, R. Wald, C. Bell, J. Perl, D. Juurlink, J. Beyene, P.S. Shah, The effect of combination treatment with aliskiren and blockers of the renin-angiotensin system on hyperkalaemia and acute kidney injury: systematic review and meta-analysis, BMJ 344 (2012) e42. F. Hammad, S. Al-Salam, L. Lubbad, 609 renoprotective effects of aliskiren following ischemia reperfusion injury, Eur. Urol. Suppl. 12 (1) (2013) e609. M. Azizi, J. Menard, Renin inhibitors and cardiovascular and renal protection: an endless quest? Cardiovasc. Drug Ther. 27 (2) (2013) 145–153. T. Ziypak, Z. Halici, E. Alkan, E. Akpinar, B. Polat, S. Adanur, E. Cadirci, I. Ferah, Y. Bayir, E. Karakus, Renoprotective effect of aliskiren on renal ischemia/reperfusion injury in rats: electron microscopy and molecular study, Ren. Fail. 37 (2) (2015) 343–354. P. Corvol, M. Eyries, F. Soubrier, Peptidyl-dipeptidase A/angiotensin I-converting enzyme, second edition, Handbook of Proteolytic Enzymes vol. 1, Elsevier, 2004, pp. 332–346. L. Wei, E. Clauser, F. Alhenc-Gelas, P. Corvol, The two homologous domains of human angiotensin I-converting enzyme interact differently with competitive inhibitors, J. Biol. Chem. 267 (19) (1992) 13398–13405. F. Sayed-Tabatabaei, B. Oostra, A. Isaacs, C. Van Duijn, J. Witteman, ACE polymorphisms, Cir. Res. 98 (9) (2006) 1123–1133. N. Takahashi, O. Smithies, Human genetics, animal models and computer simulations for studying hypertension, Trends Genet. 20 (3) (2004) 136–145. B. Rigat, C. Hubert, F. Alhenc-Gelas, F. Cambien, P. Corvol, F. Soubrier, An insertion/deletion polymorphism in the angiotensin I-converting enzyme gene accounting for half the variance of serum enzyme levels, J. Clin. Invest. 86 (4) (1990) 1343–1346. M. Marre, P. Bernadet, Y. Gallois, F. Savagner, T.-T. Guyene, M. Hallab, F. Cambien, P. Passa, F. Alhenc-Gelas, Relationships between angiotensin I converting enzyme gene polymorphism, plasma levels, and diabetic retinal and renal complications, Diabetes 43 (3) (1994) 384–388. M. Marre, X. Jeunemaitre, Y. Gallois, M. Rodier, G. Chatellier, C. Sert, L. Dusselier, Z. Kahal, L. Chaillous, S. Halimi, Contribution of genetic polymorphism in the renin-angiotensin system to the development of renal complications in insulindependent diabetes: Genetique de la Nephropathie Diabetique (GENEDIAB) study group, J. Clin. Invest. 99 (7) (1997) 1585–1595. H.R. Pazoki‐Toroudi, A. Hesami, S. Vahidi, F. Sahebjam, B. Seifi, B. Djahanguiri, The preventive effect of captopril or enalapril on reperfusion injury of the kidney of rats is independent of angiotensin II AT1 receptors, Fundam. Clin. Pharmacol. 17 (5) (2003) 595–598. L.M. Vilander, M.A. Kaunisto, V. Pettilä, Genetic predisposition to acute kidney injury-a systematic review, BMC Nephrol. 16 (1) (2015) 197. F.E. Mackie, D.J. Campbell, T.W. Meyer, Intrarenal angiotensin and bradykinin peptide levels in the remnant kidney model of renal insufficiency, Kidney Int. 59 (4) (2001) 1458–1465. R. Habibey, M. Ajami, A. Hesami, H. Pazoki-Toroudi, The mechanism of preventive effect of captopril on renal ischemia reperfusion injury is independent of

772


N. Sharma et al.

signalling pathways in HL-1 atrial myocytes, Sci. Rep. 7 (1) (2017) 1–12. [101] M. Macia Heras, N. Del Castillo Rodriguez, J. Navarro Gonzalez, The renin-angiotensin-aldosterone system in renal and cardiovascular disease and the effects of its pharmacological blockade, J. Diabetes Metab. 3 (171) (2012) 1–24. [102] R. Scalia, Y. Gong, B. Berzins, B. Freund, D. Feather, G. Landesberg, G. Mishra, A novel role for calpain in the endothelial dysfunction induced by activation of angiotensin II type 1 receptor SignalingNovelty and significance, Circ. Res. 108 (9) (2011) 1102–1111. [103] R.M. Touyz, E.L. Schiffrin, Signal transduction mechanisms mediating the physiological and pathophysiological actions of angiotensin II in vascular smooth muscle cells, Pharmacol. Rev. 52 (4) (2000) 639–672. [104] S.M. Molinas, C. Cortés-González, Y. González-Bobadilla, L.A. Monasterolo, C. Cruz, M.M. Elías, N.A. Bobadilla, L. Trumper, Effects of losartan pretreatment in an experimental model of ischemic acute kidney injury, Nephron Exp. Nephrol. 112 (1) (2009) e10–e19. [105] N. Srisawat, F.E. Sileanu, R. Murugan, R. Bellomo, P. Calzavacca, R. Cartin-Ceba, D. Cruz, J. Finn, E.A. Hoste, K. Kashani, Variation in risk and mortality of acute kidney injury in critically ill patients: a multicenter study, Am. J. Nephrol. 41 (1) (2015) 81–88. [106] P. Mehrotra, J.B. Patel, C.M. Ivancic, J.A. Collett, D.P. Basile, Th-17 cell activation in response to high salt following acute kidney injury is associated with progressive fibrosis and attenuated by AT-1R antagonism, Kidney Int. 88 (4) (2015) 776–784. [107] C. De Miguel, S. Das, H. Lund, D.L. Mattson, T lymphocytes mediate hypertension and kidney damage in Dahl salt-sensitive rats, Am. J. Physiol. Regul. Integr. Comp. Physiol. 298 (4) (2010) 1136–1142. [108] R. Rodriguez Romo, K. Benitez, J. Barrera Chimal, R. Perez Villalva, A. Gomez, D. Aguilar Leon, J.F. Rangel Santiago, S. Huerta, G. Gamba, N. Uribe, AT1 receptor antagonism before ischemia prevents the transition of acute kidney injury to chronic kidney disease, Kidney Int. 89 (2) (2016) 363–373. [109] A.C. Schoolwerth, D.A. Sica, B.J. Ballermann, C.S. Wilcox, Renal considerations in angiotensin converting enzyme inhibitor therapy: a statement for healthcare professionals from the Council on the Kidney in Cardiovascular Disease and the Council for High Blood Pressure Research of the American Heart Association, Circulation 104 (16) (2001) 1985–1991. [110] S.C. Palmer, D. Mavridis, E. Navarese, J.C. Craig, M. Tonelli, G. Salanti, N. Wiebe, M. Ruospo, D.C. Wheeler, G.F. Strippoli, Comparative efficacy and safety of blood pressure-lowering agents in adults with diabetes and kidney disease: a network meta-analysis, Lancet 385 (9982) (2015) 2047–2056. [111] F. Lapi, L. Azoulay, H. Yin, S.J. Nessim, S. Suissa, Concurrent use of diuretics, angiotensin converting enzyme inhibitors, and angiotensin receptor blockers with non-steroidal anti-inflammatory drugs and risk of acute kidney injury: nested casecontrol study, BMJ 346 (2013) 1–11. [112] T. Dreischulte, D.R. Morales, S. Bell, B. Guthrie, Combined use of nonsteroidal anti-inflammatory drugs with diuretics and/or renin-angiotensin system inhibitors in the community increases the risk of acute kidney injury, Kidney Int. 88 (2) (2015) 396–403. [113] K.K. Loboz, G.M. Shenfield, Drug combinations and impaired renal function-the ‘triple whammy’, Br. J. Clin. Pharmacol. 59 (2) (2005) 239–243. [114] M. Plataki, K. Kashani, J. Cabello-Garza, F. Maldonado, R. Kashyap, D.J. Kor, O. Gajic, R. Cartin-Ceba, Predictors of acute kidney injury in septic shock patients: an observational cohort study, Clin. J. Am. Soc. Nephrol. 6 (7) (2011) 1744–1751. [115] M. Chaumont, A. Pourcelet, M. van Nuffelen, J. Racapé, M. Leeman, J.M. Hougardy, Acute kidney injury in elderly patients with chronic kidney disease: do angiotensin-converting enzyme inhibitors carry a risk? J. Clin. Hypertens. 18 (6) (2016) 514–521. [116] L.F. Fried, N. Emanuele, J.H. Zhang, M. Brophy, T.A. Conner, W. Duckworth, D.J. Leehey, P.A. McCullough, T. O’connor, P.M. Palevsky, Combined angiotensin inhibition for the treatment of diabetic nephropathy, N. Engl. J. Med. 369 (20) (2013) 1892–1903. [117] J.F. Mann, R.E. Schmieder, M. McQueen, L. Dyal, H. Schumacher, J. Pogue, X. Wang, A. Maggioni, A. Budaj, S. Chaithiraphan, Renal outcomes with telmisartan, ramipril, or both, in people at high vascular risk (the ONTARGET study): a multicentre, randomised, double-blind, controlled trial, Lancet 372 (9638) (2008) 547–553. [118] M. Bosomworth, B. Christie, A. Davies, J. Dhesi, R. Dowdle, C. Gibbins, I. Gonzalez, S. Harding, D. Lamont, G. Murphy, RCPE UK consensus conference statement management of acute kidney injury: the role of fluids, e-alerts and biomarkers, J. R. Coll. Phys. Edinb. 43 (2013) 38–42. [119] Acute Kidney Injury: Prevention, Detection and Management Up to the Point of Renal Replacement Therapy, National Institute for Health and Care Excellence, National Clinical Guideline Centre, London, 2013. [120] L.S. Chawla, P.W. Eggers, R.A. Star, P.L. Kimmel, Acute kidney injury and chronic kidney disease as interconnected syndromes, N. Engl. J. Med. 371 (1) (2014) 58–66. [121] C.F. Lai, V.C. Wu, T.M. Huang, Y.C. Yeh, K.C. Wang, Y.Y. Han, Y.F. Lin, Y.J. Jhuang, C.T. Chao, C.C. Shiao, P.R. Tsai, F.C. Hu, N.K. Chou, W.J. Ko, K.D. Wu, Kidney function decline after a non-dialysis-requiring acute kidney injury is associated with higher long-term mortality in critically ill survivors, Crit. Care (Lond., Engl.) 16 (4) (2012) R123. [122] M.A. Venkatachalam, K.A. Griffin, R. Lan, H. Geng, P. Saikumar, A.K. Bidani, Acute kidney injury: a springboard for progression in chronic kidney disease, Am. J. Physiol. Ren. Physiol. 298 (5) (2010) F1078–F1094. [123] C.Y. Hsu, R.K. Hsu, J. Yang, J.D. Ordonez, S. Zheng, A.S. Go, Elevated BP after AKI, JASN 27 (3) (2016) 914–923. [124] Y.H. Chou, T.M. Huang, S.Y. Pan, C.H. Chang, C.F. Lai, V.C. Wu, M.S. Wu,

[125]

[126]

[127]

[128]

[129]

[130]

[131]

[132]

[133] [134]

[135]

[136]

[137]

[138]

[139]

[140]

[141]

[142]

[143]

[144] [145]

[146]

773

K.D. Wu, T.S. Chu, S.L. Lin, Renin-angiotensin system inhibitor is associated with lower risk of ensuing chronic kidney disease after functional recovery from acute kidney injury, Sci. Rep. 7 (2017) 46518. E. Gayat, A. Hollinger, A. Cariou, N. Deye, A. Vieillard-Baron, S. Jaber, B.G. Chousterman, Q. Lu, P.F. Laterre, X. Monnet, Impact of angiotensin-converting enzyme inhibitors or receptor blockers on post-ICU discharge outcome in patients with acute kidney injury, Intensive Care Med. (2018) 1–8. S. Brar, F. Ye, M.T. James, B. Hemmelgarn, S. Klarenbach, N. Pannu, Association of angiotensin-converting enzyme inhibitor or angiotensin receptor blocker use with outcomes after acute kidney injury, JAMA Intern. Med. 178 (12) (2018) 1681–1690. M.A. Crackower, R. Sarao, G.Y. Oudit, C. Yagil, I. Kozieradzki, S.E. Scanga, A.J. Oliveira-dos-Santos, J. da Costa, L. Zhang, Y. Pei, J. Scholey, C.M. Ferrario, A.S. Manoukian, M.C. Chappell, P.H. Backx, Y. Yagil, J.M. Penninger, Angiotensinconverting enzyme 2 is an essential regulator of heart function, Nature 417 (6891) (2002) 822–828. M. Donoghue, F. Hsieh, E. Baronas, K. Godbout, M. Gosselin, N. Stagliano, M. Donovan, B. Woolf, K. Robison, R. Jeyaseelan, R.E. Breitbart, S. Acton, A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1-9, Circ. Res. 87 (5) (2000) 1–9. A.J. Turner, S.R. Tipnis, J.L. Guy, G.I. Rice, N.M. Hooper, ACEH/ACE2 is a novel mammalian metallocarboxypeptidase and a homologue of angiotensin-converting enzyme insensitive to ACE inhibitors, Can. J. Physiol. Pharmacol. 80 (4) (2002) 346–353. M. Donoghue, H. Wakimoto, C.T. Maguire, S. Acton, P. Hales, N. Stagliano, V. Fairchild-Huntress, J. Xu, J.N. Lorenz, V. Kadambi, C.I. Berul, R.E. Breitbart, Heart block, ventricular tachycardia, and sudden death in ACE2 transgenic mice with downregulated connexins, J. Mol. Cell. Cardiol. 35 (9) (2003) 1043–1053. S.K. Goru, A. Kadakol, V. Malek, A. Pandey, N. Sharma, A.B. Gaikwad, Diminazene aceturate prevents nephropathy by increasing glomerular ACE2 and AT2 receptor expression in a rat model of type1 diabetes, Br. J. Pharmacol. 174 (18) (2017) 3118–3130. Q. Lv, Q. Yang, Y. Cui, J. Yang, G. Wu, M. Liu, Z. Ning, S. Cao, G. Dong, J. Hu, Effects of taurine on ACE, ACE2 and HSP70 expression of hypothalamic-pituitaryadrenal axis in stress-induced hypertensive rats, Adv. Exp. Med. Biol. 975 (Pt. 2) (2017) 871–886. M.J. Ross, M. Nangaku, ACE2 as therapy for glomerular disease: the devil is in the detail, Kidney Int. 91 (6) (2017) 1269–1271. E.H. Bae, F. Fang, V.R. Williams, A. Konvalinka, X. Zhou, V.B. Patel, X. Song, R. John, G.Y. Oudit, Y. Pei, J.W. Scholey, Murine recombinant angiotensin-converting enzyme 2 attenuates kidney injury in experimental Alport syndrome, Kidney Int. 91 (6) (2017) 1347–1361. M.J. Soler, M. Riera, M. Crespo, M. Mir, E. Marquez, M.J. Pascual, J.M. Puig, J. Pascual, Circulating angiotensin-converting enzyme 2 activity in kidney transplantation: a longitudinal pilot study, Nephron Clin. Pract. 121 (3–4) (2012) c144–c150. F. Xiao, S. Hiremath, G. Knoll, J. Zimpelmann, K. Srivaratharajah, D. Jadhav, D. Fergusson, C.R. Kennedy, K.D. Burns, Increased urinary angiotensin-converting enzyme 2 in renal transplant patients with diabetes, PLoS One 7 (5) (2012) e37649. C. Vickers, P. Hales, V. Kaushik, L. Dick, J. Gavin, J. Tang, K. Godbout, T. Parsons, E. Baronas, F. Hsieh, S. Acton, M. Patane, A. Nichols, P. Tummino, Hydrolysis of biological peptides by human angiotensin-converting enzyme-related carboxypeptidase, J. Biol. Chem. 277 (17) (2002) 14838–14843. P. Xu, A.C. Costa-Goncalves, M. Todiras, L.A. Rabelo, W.O. Sampaio, M.M. Moura, S. Sousa Santos, F.C. Luft, M. Bader, V. Gross, Endothelial dysfunction and elevated blood pressure in MAS gene-deleted mice, Hypertension 51 (2) (2008) 574–580. R.A. Santos, A.C. Simoes e Silva, C. Maric, D.M. Silva, R.P. Machado, I. de Buhr, S. Heringer-Walther, S.V. Pinheiro, M.T. Lopes, M. Bader, E.P. Mendes, V.S. Lemos, M.J. Campagnole-Santos, H.P. Schultheiss, R. Speth, T. Walther, Angiotensin-(1-7) is an endogenous ligand for the G protein-coupled receptor mas, Proc. Natl. Acad. Sci. U. S. A. 100 (14) (2003) 8258–8263. G. Gorelik, L.A. Carbini, A.G. Scicli, Angiotensin 1-7 induces bradykinin-mediated relaxation in porcine coronary artery, J. Pharmacol. Exp. Ther. 286 (1) (1998) 403–410. R.A.S. Santos, W.O. Sampaio, A.C. Alzamora, D. Motta-Santos, N. Alenina, M. Bader, M.J. Campagnole-Santos, The ACE2/angiotensin-(1-7)/MAS axis of the renin-angiotensin system: focus on angiotensin-(1-7), Physiol. Rev. 98 (1) (2018) 505–553. J. Mori, V.B. Patel, T. Ramprasath, O.A. Alrob, J. DesAulniers, J.W. Scholey, G.D. Lopaschuk, G.Y. Oudit, Angiotensin 1-7 mediates renoprotection against diabetic nephropathy by reducing oxidative stress, inflammation, and lipotoxicity, Am. J. Physiol. Ren. Physiol. 306 (8) (2014) F812–F821. R.A. Santos, A.J. Ferreira, E.S.A.C. Simoes, Recent advances in the angiotensinconverting enzyme 2-angiotensin(1-7)-Mas axis, Exp. Physiol. 93 (5) (2008) 519–527. J. Varagic, S. Ahmad, S. Nagata, C.M. Ferrario, ACE2: angiotensin II/angiotensin(1-7) balance in cardiac and renal injury, Curr. Hypertens. Rep. 16 (3) (2014) 420. S.Q. Savergnini, M. Beiman, R.Q. Lautner, V. de Paula-Carvalho, K. Allahdadi, D.C. Pessoa, F.P. Costa-Fraga, R.A. Fraga-Silva, G. Cojocaru, Y. Cohen, M. Bader, A.P. de Almeida, G. Rotman, R.A. Santos, Vascular relaxation, antihypertensive effect, and cardioprotection of a novel peptide agonist of the MAS receptor, Hypertension 56 (1) (2010) 112–120. A. Machado-Silva, D. Passos-Silva, R.A. Santos, R.D. Sinisterra, Therapeutic uses for angiotensin-(1-7), Expert Opin. Ther. Patents 26 (6) (2016) 669–678.


N. Sharma et al.

[172] P.A. Karpe, J. Gupta, R.F. Marthong, P. Ramarao, K. Tikoo, Insulin resistance induces a segmental difference in thoracic and abdominal aorta: differential expression of AT1 and AT2 receptors, J. Hypertens. 30 (1) (2012) 132–146. [173] M.C. Munoz, V. Burghi, J.G. Miquet, I.A. Cervino, D.T. Quiroga, L. Mazziotta, F.P. Dominici, Chronic blockade of the AT2 receptor with PD123319 impairs insulin signaling in C57BL/6 mice, Peptides 88 (2017) 37–45. [174] A. Ortiz, C. Lorz, M.P. Catalan, T.M. Danoff, Y. Yamasaki, J. Egido, E.G. Neilson, Expression of apoptosis regulatory proteins in tubular epithelium stressed in culture or following acute renal failure, Kidney Int. 57 (3) (2000) 969–981. [175] Y. Wan, C. Wallinder, B. Plouffe, H. Beaudry, A. Mahalingam, X. Wu, B. Johansson, M. Holm, M. Botoros, A. Karlen, Design, synthesis, and biological evaluation of the first selective nonpeptide AT2 receptor agonist, J. Med. Chem. 47 (24) (2004) 5995–6008. [176] A. Pandey, A.B. Gaikwad, AT 2 receptor agonist compound 21: a silver lining for diabetic nephropathy, Eur. J. Pharmacol. 815 (2017) 251–257. [177] C.A. McCarthy, A. Vinh, A.A. Miller, A. Hallberg, M. Alterman, J.K. Callaway, R.E. Widdop, Direct angiotensin AT2 receptor stimulation using a novel AT2 receptor agonist, compound 21, evokes neuroprotection in conscious hypertensive rats, PloS One 9 (4) (2014) e95762. [178] J.P. Joseph, A.P. Mecca, R.W. Regenhardt, D.M. Bennion, V. Rodríguez, F. Desland, N.A. Patel, D.J. Pioquinto, T. Unger, M.J. Katovich, The angiotensin type 2 receptor agonist compound 21 elicits cerebroprotection in endothelin-1 induced ischemic stroke, Neuropharmacology 81 (2014) 134–141. [179] S.-Y. Dai, Y.-P. Zhang, W. Peng, Y. Shen, J.-J. He, Central infusion of angiotensin II type 2 receptor agonist compound 21 attenuates DOCA/NaCl-induced hypertension in female rats, Oxid. Med. Cell. Longev. 2016 (2016) 1–9. [180] A. Pandey, A.B. Gaikwad, Compound 21 and Telmisartan combination mitigates type 2 diabetic nephropathy through amelioration of caspase mediated apoptosis, Biochem. Biophys. Res. Commun. 487 (4) (2017) 827–833. [181] N. Basso, N.A. Terragno, History about the discovery of the renin-angiotensin system, Hypertension 38 (6) (2001) 1246–1249. [182] H.L. Jackman, M.G. Massad, M. Sekosan, F. Tan, V. Brovkovych, B.M. Marcic, E.G. Erdos, Angiotensin 1-9 and 1-7 release in human heart: role of cathepsin A, Hypertension 39 (5) (2002) 976–981. [183] J.O. Kokkonen, J. Saarinen, P.T. Kovanen, Regulation of local angiotensin II formation in the human heart in the presence of interstitial fluid. Inhibition of chymase by protease inhibitors of interstitial fluid and of angiotensin-converting enzyme by Ang-(1-9) formed by heart carboxypeptidase A-like activity, Circulation 95 (6) (1997) 1455–1463. [184] K. Kramkowski, A. Mogielnicki, A. Leszczynska, W. Buczko, Angiotensin-(1-9), the product of angiotensin I conversion in platelets, enhances arterial thrombosis in rats, J. Physiol. Pharmacol. 61 (3) (2010) 317–324. [185] C.A. McKinney, C. Fattah, C.M. Loughrey, G. Milligan, S.A. Nicklin, Angiotensin(1-7) and angiotensin-(1-9): function in cardiac and vascular remodelling, Clin. Sci. (Lond., Engl. : 1979) 126 (12) (2014) 815–827. [186] L. Gonzalez, U. Novoa, J. Moya, L. Gabrielli, J.E. Jalil, L. Garcia, M. Chiong, S. Lavandero, M.P. Ocaranza, Angiotensin-(1-9) reduces cardiovascular and renal inflammation in experimental renin-independent hypertension, Biochem. Pharmacol. 156 (2018) 357–370. [187] C.A. McKinney, S. Kennedy, G. Baillie, G. Milligan, S.A. Nicklin, 178 angiotensin(1-9) inhibits vascular smooth muscle cell proliferation and migration in vitro and neointimal formation in vivo, Br. Cardiovasc. Soc. (BMJ Publishing Group Ltd.) (2015) A1–A136. [188] M.P. Ocaranza, I. Godoy, J.E. Jalil, M. Varas, P. Collantes, M. Pinto, M. Roman, C. Ramirez, M. Copaja, G. Diaz-Araya, Enalapril attenuates downregulation of angiotensin-converting enzyme 2 in the late phase of ventricular dysfunction in myocardial infarcted rat, Hypertension 48 (4) (2006) 572–578. [189] J. Hrenak, L. Paulis, F. Simko, Angiotensin a/alamandine/mrgd axis: another clue to understanding cardiovascular pathophysiology, Int. J. Mol. Sci. 17 (7) (2016) 1–9. [190] N. Leao, G. Etelvino, R. Santos, Abstract P281: alamandine-induced vasorelaxation is selectively increased in Sp-shr, Am. Heart Assoc. (2016). [191] G.M. Etelvino, A.A.B. Peluso, R.A.S. Santos, New components of the renin-angiotensin system: alamandine and the mas-related G protein-coupled receptor D, Curr. Hypertens. Rep. 16 (6) (2014) 433–439. [192] D.C. Villela, D.G. Passos-Silva, R.A.S. Santos, Alamandine: a new member of the angiotensin family, Curr. Opin. Nephrol. Hypertens. 23 (2) (2014) 130–134. [193] A. Tetzner, K. Gebolys, C. Meinert, S. Klein, A. Uhlich, J. Trebicka, Ó. Villacañas, T. Walther, G-protein-coupled receptor MrgD is a receptor for angiotensin-(1-7) involving adenylyl cyclase, cAMP, and phosphokinase A novelty and significance, Hypertension 68 (1) (2016) 185–194. [194] A.J. Allred, M.C. Chappell, C.M. Ferrario, D.I. Diz, Differential actions of renal ischemic injury on the intrarenal angiotensin system, Am. J. Physiol. Ren. Physiol. 279 (4) (2000) F636–F645. [195] F. Moslemi, P. Taheri, M. Azimipoor, S. Ramtin, M. Hashemianfar, A. MomeniAshjerdi, F. Eshraghi-Jazi, A. Talebi, H. Nasri, M. Nematbakhsh, Effect of angiotensin II type 1 receptor blockade on kidney ischemia/reperfusion; a gender-related difference, J. Ren. Inj. Prev. 5 (3) (2016) 140–143.

[147] M. Bertagnolli, K.R. Casali, F.B. De Sousa, K. Rigatto, L. Becker, S.H. Santos, L.D. Dias, G. Pinto, D.R. Dartora, B.D. Schaan, R.D. Milan, M.C. Irigoyen, R.A. Santos, An orally active angiotensin-(1-7) inclusion compound and exercise training produce similar cardiovascular effects in spontaneously hypertensive rats, Peptides 51 (2014) 65–73. [148] S.H. Santos, J.F. Giani, V. Burghi, J.G. Miquet, F. Qadri, J.F. Braga, M. Todiras, K. Kotnik, N. Alenina, F.P. Dominici, R.A. Santos, M. Bader, Oral administration of angiotensin-(1-7) ameliorates type 2 diabetes in rats, J. Mol. Med. (Berlin, Germany) 92 (3) (2014) 255–265. [149] S. Heringer-Walther, K. Eckert, S.M. Schumacher, L. Uharek, A. Wulf-Goldenberg, F. Gembardt, I. Fichtner, H.P. Schultheiss, K. Rodgers, T. Walther, Angiotensin-(17) stimulates hematopoietic progenitor cells in vitro and in vivo, Haematology 94 (2009) 857–860. [150] D.D. Ellefson, T. Espinoza, N. Roda, S. Maldonado, K.E. Rodgers, Synergistic effects of co-administration of angiotensin 1-7 and Neupogen on hematopoietic recovery in mice, Cancer Chemother. Pharmacol. 53 (1) (2004) 15–24. [151] S. Reule, S. Gupta, Kidney regeneration and resident stem cells, Organogenesis 7 (2) (2011) 135–139. [152] A.J. Villar, R.A. Pedersen, Parental imprinting of the mas protooncogene in mouse, Nat. Genet. 8 (4) (1994) 373–379. [153] R. Metzger, M. Bader, T. Ludwig, C. Berberich, B. Bunnemann, D. Ganten, Expression of the mouse and rat mas proto-oncogene in the brain and peripheral tissues, FEBS Lett. 357 (1) (1995) 27–32. [154] M. Bader, R.A. Santos, T. Unger, U.M. Steckelings, New therapeutic pathways in the RAS, J. Renin Angiotensin Aldosterone Syst. 13 (4) (2012) 505–508. [155] C. Berry, R. Touyz, A.F. Dominiczak, R.C. Webb, D.G. Johns, Angiotensin receptors: signaling, vascular pathophysiology, and interactions with ceramide, Am. J. Physiol. Heart Circ. Physiol. 281 (6) (2001) 2337–2365. [156] M. de Gasparo, K.J. Catt, T. Inagami, J.W. Wright, T. Unger, International union of pharmacology. XXIII. The angiotensin II receptors, Pharmacol. Rev. 52 (3) (2000) 415–472. [157] S.S. Karnik, H. Unal, J.R. Kemp, K.C. Tirupula, S. Eguchi, P.M. Vanderheyden, W.G. Thomas, International Union of basic and clinical pharmacology. XCIX. Angiotensin receptors: interpreters of pathophysiological angiotensinergic stimuli [corrected], Pharmacol. Rev. 67 (4) (2015) 754–819. [158] P.M. Abadir, J.D. Walston, R.M. Carey, Subcellular characteristics of functional intracellular renin-angiotensin systems, Peptides 38 (2) (2012) 437–445. [159] R.M. Carey, AT2 receptors: potential therapeutic targets for hypertension, Am. J. Hypertens. 30 (4) (2017) 339–347. [160] R.M. Carey, Cardiovascular and renal regulation by the angiotensin type 2 receptor: the AT2 receptor comes of age, Hypertension 45 (5) (2005) 840–844. [161] R.M. Carey, Update on angiotensin AT2 receptors, Curr. Opin. Nephrol. Hypertens. 26 (2) (2017) 91–96. [162] L.A. De Luca Jr., J.V. Menani, A.K. Johnson, Neurobiology of Body Fluid Homeostasis: Transduction and Integration, CRC Press, 2013. [163] L.C. Matavelli, J. Huang, H.M. Siragy, Angiotensin AT(2) receptor stimulation inhibits early renal inflammation in renovascular hypertension, Hypertension 57 (2) (2011) 308–313. [164] F. Rompe, M. Artuc, A. Hallberg, M. Alterman, K. Stroder, C. Thone-Reineke, A. Reichenbach, J. Schacherl, B. Dahlof, M. Bader, N. Alenina, M. Schwaninger, T. Zuberbier, H. Funke-Kaiser, C. Schmidt, W.H. Schunck, T. Unger, U.M. Steckelings, Direct angiotensin II type 2 receptor stimulation acts anti-inflammatory through epoxyeicosatrienoic acid and inhibition of nuclear factor kappaB, Hypertension 55 (4) (2010) 924–931. [165] G. Castoldi, C.R. di Gioia, C. Bombardi, S. Maestroni, R. Carletti, U.M. Steckelings, B. Dahlof, T. Unger, G. Zerbini, A. Stella, Prevention of diabetic nephropathy by compound 21, selective agonist of angiotensin type 2 receptors, in Zucker diabetic fatty rats, Am. J. Physiol. Ren. Physiol. 307 (10) (2014) 1123–1131. [166] D. Villela, J. Leonhardt, N. Patel, J. Joseph, S. Kirsch, A. Hallberg, T. Unger, M. Bader, R.A. Santos, C. Sumners, Angiotensin type 2 receptor (AT2R) and receptor mas: a complex liaison, Clin. Sci. 128 (4) (2015) 227–234. [167] S.-i. Miura, Y. Matsuo, Y. Kiya, S.S. Karnik, K. Saku, Molecular mechanisms of the antagonistic action between AT1 and AT2 receptors, Biochem. Biophys. Res. Commun. 391 (1) (2010) 85–90. [168] T. Ichiki, P.A. Labosky, C. Shiota, S. Okuyama, Y. Imagawa, A. Fogo, F. Niimura, I. Ichikawa, B.L. Hogan, Effects on blood pressure and exploratory behaviour of mice lacking angiotensin II type-2 receptor, Nature 377 (6551) (1995) 748–750. [169] E.R. Porrello, A. D’amore, C.L. Curl, A.M. Allen, S.B. Harrap, W.G. Thomas, L.M. Delbridge, Angiotensin II type 2 receptor antagonizes angiotensin II type 1 receptor-mediated cardiomyocyte autophagy, Hypertension 53 (6) (2009) 1032–1040. [170] L. Yvan-Charvet, P. Even, M. Bloch-Faure, M. Guerre-Millo, N. Moustaid-Moussa, P. Ferre, A. Quignard-Boulange, Deletion of the angiotensin type 2 receptor (AT2R) reduces adipose cell size and protects from diet-induced obesity and insulin resistance, Diabetes 54 (4) (2005) 991–999. [171] K. Ohshima, M. Mogi, F. Jing, J. Iwanami, K. Tsukuda, L.J. Min, A. Ogimoto, B. Dahlof, U.M. Steckelings, T. Unger, J. Higaki, M. Horiuchi, Direct angiotensin II type 2 receptor stimulation ameliorates insulin resistance in type 2 diabetes mice with PPARgamma activation, PloS One 7 (11) (2012) e48387.

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