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Future Cardiology

Review

Kidney and heart interactions during cardiorenal syndrome: a molecular and clinical pathogenic framework Claudio Napoli†1,2, Amelia Casamassimi1, Valeria Crudele1, Teresa Infante2 & Ciro Abbondanza1 Dipartimento di Patologia Generale, Centro di Eccellenza sulle Malattie Cardiovascolari, Facoltà di Medicina e Chirurgia, Seconda Università di Napoli, Via Costantinopoli 16, 80138 Napoli, Italy 2 Istituto di Ricerca Diagnostica e Nucleare-SDN, IRCCS, Via E. Gianturco 113, 80143 Napoli, Italy † Author for correspondence: Tel.: +39 8156 6756 n Fax: +39 8145 0169 n [email protected] 1

The heart and kidney are physiologically interconnected. Cardiorenal syndrome (CRS) is a pathological disorder where acute or chronic dysfunction in one organ may induce dysfunction in the other one. Although classical studies have proposed a role for hypertension, dyslipidemia and endothelial dysfunction, CRS should be considered as a complex molecular interplay of neurohumoral pathway activation including the sympathetic nervous system, the renin angiotensin aldosterone axis, the endothelin system and the arginine vasopressin system. This activation may induce vascular inflammation, oxidative stress, accelerated atherosclerosis, cardiac hypertrophy and both myocardial and intrarenal fibrosis with progression of CRS treatment. More recently, epigenetics has opened new pathogenic molecular routes for CRS. This will lead to a more rapid development of novel, safe and effective clinical therapies.

The epigenetic mechanisms are essentially DNA methylation, histone modifications and RNA interference. Epigenetics plays a crucial role in several pathological conditions, including immune dysfunction, inflammation, cancer and insulin resistance [1] . Recent studies have demonstrated that epigenetic alterations are associated with inflammation and cardiovascular disease (CVD) in patients with chronic kidney disease (CKD). The reversible nature of the epigenetic changes gives a unique opportunity to halt or even reverse the disease process through targeted therapeutic strategies [1] . Epigenetic change can occur as a real subversion of cell programming produced during normal ontogenetic development of organs and tissues, during differentiation and normal cell turnover. Investigating the role of epigenetic mechanisms in triggering/progression of several common diseases has gained emphasis over the recent years. The study of such complex mechanisms has become very important in order to understand the etiopathology of these diseases, as well as to design appropriate targeted clinical therapies. In this article, we analyze the epigenetic-based mechanisms between heart and kidney in the clinical pathophysiology of cardiorenal syndrome (CRS) (Figure 1) . Cardiorenal axis dysfunction

Coronary artery disease has emerged as the dominant etiologic factor in patients with heart 10.2217/FCA.11.24 © 2011 Future Medicine Ltd

failure (HF) and cardiac ischemia which are among the most common causes of death and hospitalization in most Western countries [2] . Patients with CKD are at higher risk of cardio vascular disease than the general population, and demonstrate a higher rate of cardiovascular mortality [2] . In the Acute Decompensated Heart Failure National Registry (ADHERE), 30% of hospitalized patients with acute HF had a history of chronic renal failure [2] . The early diagnosis and management of HF are important in patients with CKD. Moreover, early recognition and management of CKD is also necessary in patients with HF [2] . Cardiac and renal biomarkers could facilitate and improve the clinical managements of HF and CKD patients [2] . It is also known that many patients with CKD have not achieved optimal treatment levels [3–4] . This phenomenon exists because CKD does not exist in isolation; the multiple risk factors commonly associated with the CKD patient make optimal management difficult, and the intricate relationship between cardiac and renal physiology demand that both organ systems be addressed [3] . Many years ago, the indexes of myocardial ischemia and vasoconstrictive hormonal release were already evaluated in order to investigate the difference between essential hypertension and hypertension during chronic renal failure. Arterial hypertension induces several cardiovascular alterations that reflect Future Cardiol. (2011) 7(4), 485–497

Keywords cardiac ischemia cardiorenal syndrome n cardiovascular disease n chronic kidney disease n epigenetics n heart failure n n

part of

ISSN 1479-6678

485

Review

Napoli, Casamassimi, Crudele, Infante & Abbondanza

Causes

Epigenetic modifications

• ncDNA • Defective DNA repair • Uremic insult? • Exogenous insult

• DNA methylation • Histone modification

Chromosome Consequences • Aberrant gene expression • Loss of imprinting • Chromosomal instability • Microsatellite instability Histone modifications

Heart failure DNA

CH3

Kidney failure

Aberrant methylation ↑ H3 acetyation CH3 Kidney failure

Figure 1. Epigenetic modifications between heart and kidney in cardiorenal syndrome causing both cardiac and renal dysfunction. Epigenetic effects correlate with covalent modifications of the genome resulting from changes in promoter methylation and histone modifications. Thus, epigenetic phenomena are central to the induction of heritable changes in gene expression occurring without alteration of DNA sequence. The H3 acetylation is the only epigenetic direct correlation between kidney and heart during cardiorenal syndrome.

themselves either on the heart and/or on the coronary blood flow enhancing the cardiovascular risk. Since chronic renal failure can influence the neuroendocrine response, various mechanisms involved in hypertension during chronic renal failure are still unclear [4] . Several pathologies such as metabolic syndrome, increased arterial stiffness, anemia, proteinuria, chronic inflammatory state and uremic toxins are described as nontraditional risk factors for HF in CKD patients [4] . Endothelial progenitor cells (EPCs) are very relevant in vascular biology. These progenitors have been studied as potential therapeutic cells 486

Future Cardiol. (2011) 7(4)

for vascular regeneration and as biomarkers to assess the risk of several diseases including CKD and CVD. Particularly, their role as mediators of chronic ischemia and myocardial infarction has been assessed. Indeed, transplantation of EPCs into patients induces blood flow recovery in ischemic limbs and improves myocardial viability after infarction [4,5] . Circulating EPC levels are reduced in CRS patients and, shortterm erythropoietin (EPO) treatment has no effect on EPC levels in these patients, while long term EPO treatment prevents a decline in these cells [6] . Thus, it would be interesting to further investigate the role of EPCs in CRS. future science group

Kidney & heart interactions during cardiorenal syndrome

Hence, dysfunctional cardiac and renal effects can coexist through a complex combination of neurohormonal mechanisms. Drug therapies utilized in the management of renal disease and associated complications may influence cardiac performance. Approximately one-third of the patients with HF have reduced kidney function that is associated with diuretic resistance and increased mortality [7] . Another cardiorenal connection is observed in patients with CKD, who can have an increased risk of cardiovascular complications and death [8,9] . For many years CRS had been generally defined as an acute or chronic renal dysfunction resulting from primary changes in cardiac function. A consensus definition of CRS, stressing the bidirectional nature of heart-kidney interactions, has recently been proposed [10] that describes CRS as a pathological disorder of the heart and the kidney in which acute or chronic dysfunction in one organ may induce acute or chronic dysfunction in the other organ [10] . It includes the five subtypes described below. Cardiorenal syndrome type I, or acute CRS, describes the acute kidney injury as a consequence of a sudden worsening of cardiac function (acute cardiogenic shock or acute decompensation of congestive HF) [11–15] . Cardiorenal syndrome type II, or chronic CRS, describes the progressive and CKD caused by chronic cardiac dysfunction [16–23] . Cardiorenal syndrome type III, or acute renocardiac syndrome, describes a sudden cardiac disorder as a consequence of an impairment of kidney function [10] . Cardiorenal syndrome type IV, or chronic renocardiac syndrome, is attributed to the decreased cardiac function, accelerated atherosclerosis, left ventricular hypertrophy and increased risk of cardiovascular events in patients with CKD [24–25] . Cardiorenal syndrome type V describes a situation in which a systemic condition causes both cardiac and renal dysfunction [26,27] . Epigenetic mechanisms

Epigenetic inheritance is responsible for the huge number of phenotypic differences between cell types in multicellular organisms [28] . This may explain for example why subjects having similar genetic background and both environmental and classical risk factors for CVD and/or CKD could have a very different outcome in clinical manifestation of these diseases. Interestingly, it is still unclear if the altered gene expression patterns can be passed to the progeny upon cell future science group

Review

division or even transgenerationally [29] . The main mechanisms of epigenetic modifications in mammals include DNA methylation, histone modifications, which result in changes of chromatin structure and RNA-based silencing (miRNAs). miRNAs are important for kidney development and homeostasis, and are known to play a pathogenic role in renal diseases. Thus, a better understanding of their mechanisms in this context could revolutionize both the diagnosis and treatment of major renal diseases [30–32] . Indeed epigenetics is a dynamic process, which regulates gene expression patterns in normal and diseased state. These mechanisms alter the physical accessibility to the genome through gene expression and molecular complexes can then alter the function of genes [28] . The mechanism of gene silencing by DNA methylation may be related to stearic obstacle of the transcriptional machinery, recruitment of repressors, or alteration in chromatin configuration [28] . The induction and maintenance of DNA methylation are catalyzed by DNA methylt ransferase-1 and DNA methyltransferase-3b and are responsible for maintaining abnormal promoter methylation in diseased cells [28] . Furthermore, DNA methyltransferases interact directly with histone deacetylases (HDACs) to recruit them to gene promoters. Histone acetyltransferases and HDACs act in an opposing manner to control the acetylation state of proteins. The most well characterized role for protein acetylation is in the control of gene transcription. Acetylation of lysine residues in nucleosome histone tails by histone acetyltransferases makes chromatin structure relaxed by weakening the interaction of histone tails with DNA and accessible to transcriptional activators. On the other side, deacetylation of histones by HDACs alters the electrostatic properties of chromatin thereby facilitating gene repression. A recent study has revealed HDAC activity linked to induction of certain genes, suggesting that HDACs do not only turn genes off, but rather dynamically regulate gene expression levels [31] . Moreover, acetylation additionally provides a mechanism to control the activity of nonhistone proteins [31] . The first mammalian HDAC was isolated in 1996 [33] . Distinct genes encoding 18 mammalian HDACs have now been identified and they are grouped into four classes on the basis of their similarity with yeast. Emerging evidence suggests that aberrant epigenetic modifications have a potential role in several conditions including atherosclerosis, autoimmune diseases and kidney disease among others [33,34] . Thus, we assume www.futuremedicine.com

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that epigenetic mechanisms can also be essential in kidney and heart diseases, especially in their correlation (Figure 1) . Pathophysiology & epigenetics of the cardiorenal axis

Clinical studies have not yet found a direct relationship between kidney dysfunction and cardiac efficiency, with the exception of general hemodynamic parameters, such as intrarenal hemodynamics, transrenal perfusion pressure, central venous pressure [34,35] . Several studies have also proposed a role for hypertension, dyslipidemia and endothelial dysfunction in this context [2] . However, CRS is not limited to hemodynamic changes and should be considered as a complex interplay of neurohumoral pathways activation [2,36] . The involved neurohumoral systems include the sympathetic nervous system, the renin–angiotensin–aldosterone system (RAAS), the endothelin system, and the arginine vasopressin system. Their activation induces inflammation and oxidative stress that lead to vasoconstriction, salt and water retention, accelerated atherosclerosis, cardiac remodeling and hypertrophy, myocardial and intrarenal fibrosis, and progression of renal disease (Figure 2) [36,37] . Pathogenic contribution of increased oxidative stress suggested a role for antioxidant strategies in preserving the atherosclerotic and ischemic kidney in these pathological conditions [38] . It is important to underline the role of BNP that provides some beneficial effects by counteracting many of the negative adaptations. Particularly, BNP inhibits the RAAS and vasoconstriction. Moreover, it promotes diuresis, enhances sodium excretion and may even increase glomerular filtration rate.

CRS

Pathways SNP RAAS Endothelin system AVP

Consequences Inflammation Oxidative stress Vasoconstriction Salt and water retention Atherosclerosis Cardiac remodeling Cardiac hypertrophy Myocardial fibrosis Intrarenal fibrosis

Renal disease

Figure 2. Molecular pathways linking renal failure and progression of cardiac disease. AVP: Arginine vasopressin system; CRS: Cardiorenal syndrome; RAAS: Renin–angiotensin–aldosterone system.

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Molecular mechanisms

In order to understand the pathophysiology of the kidney and heart inter-relationship, it would be interesting to analyze the molecular mechanisms of these complex pathways and highlight their epigenetic correlations. For example, it is still unclear how CRS risk factors such as arterial hypertension, hyperglycemia, hyperinsulinemia, obesity, proteinuria and uremic toxins individually affect histone modifying enzymes. Furthermore, it would be noteworthy to understand whether drugs modulating epigenetic modifications could prevent CRSs such as diabetic nephropathy-associated cardiomyopathy [39] . A recent study by Gaikwad et al has demonstrated that renal failure increased cardiac mRNA expression of most of these genes together with cardiomyocyte size in diabetic mice. This increase might be a direct result of a specific epigenetic histone modification pattern [40] . This currently is the only study which has investigated the mechanism directly linking renal failure with the induction of cardiomyopathy-related genes. However, this link in the cardiorenal axis can be indirectly suggested by studies that have examined epigenetic modifications in the single organ (heart or kidney) diseases. Moreover, it would be interesting to explore in more depth those pathways that are involved in the cardiorenal axis. These studies are discussed below. For instance, it is known that aberrant DNA methylation may contribute to accelerated atherosclerosis by upregulation of atherosclerosissusceptible genes and downregulation of atherosclerosis-protective genes [41] . Since several features of uremia may contribute to aberrant DNA methylation, epigenetic changes can also be involved in CRS. The homocysteine precursor S-adenosylmethionine is a competitive inhibitor of S-adenosylmethionine methyltransferases [42] . Thus, because protein car\1–\2yl methylation and repair is inhibited, this may lead to a state of unbalanced methylation in clinical states with hyperhomocysteinemia. In vascular disease patients increased homocysteine and S-adenosylmethionine concentrations were associated with DNA hypomethylation [41] . Moreover, the presence of inflammation may account for the association between low homocysteine levels and cardiovascular outcome in CKD. Indeed, It is interesting the consideration that inflammation may also cause aberrant DNA methylation [43] . In accordance, another study demonstrated that global DNA future science group


hypermethylation was associated with inflammation and increased mortality in CVD [44] . However, there are also discordant recent data that do not support the role of DNA hypomethylation in CKD-associated vascular disease in patients with advanced CKD [45] . Most evidence regarding histone modifications have been primarily obtained through the use of HDAC inhibitors (HDACis) especially in the control of cardiac hypertrophy. Indeed, the heart responds to stress signals by hypertrophic growth and an important role for HDACs in the regulation of cardiac growth was initially revealed by the discovery that some HDACs act as signal-responsive repressors of pathological cardiac hypertrophy through the regulation of a specific transcription factor and reprogramming of cardiac gene expression [46] . Several studies also suggested that pharmacological inhibitors of HDACs have antihypertrophic action through neutralization of HDACs [47–52] . With regards to the molecular basis for the cardioprotective effects of HDACis in the heart, studies indicate that they de-repress the expression of protective cardiac genes mainly coding for endogenous antioxidant enzymes. Moreover, another example involves the so called ‘myosin isoform switch’ that is predicted to have adverse functional consequences for the heart failure [53] with the a-myosin heavy chain found to be cardioprotective [54] . HDACis have been found to reverse the myosin isoform switch [55] . A further cardiac protective gene that is derepressed by HDACis is the Kruppel-like factor-4 (Klf4) transcription factor. Its expression is downregulated by hypertrophic agonists and induced in cardiomyocytes exposed to HDACis [56] . It has been demonstrated that many genes are important during development of the fetal heart are re-expressed in the adult tissue, resulting in pathophysiological changes leading to arrhythmias, cardiac failure and sudden death. One transcription factor thought to be important in repressing the expression of fetal genes in the adult heart is the transcriptional repressor repressor element 1-silencing transcription factor (REST) [57] . Indeed, it has been demonstrated that continued REST expression prevents increases in the levels of the BNP (Nppb) and ANP (Nppa) genes, encoding brain and atrial natriuretic peptides respectively, in adult rat ventricular myocytes in response to endothelin-1 (ET-1), the most powerful endothelium-derived vasoconstrictor. Likewise, REST inhibition results in increased expression of these genes, which future science group

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correlates with increased histone H4 acetylation and histone H3 lysine 4 methylation of their gene promoters [57] . The peptide hormone ET-1 plays multiple, complex roles in both cardiovascular and renal physiology [56,57] . Arterial hypertension is a significant risk factor for the high rate of cardiovascular disease in chronic uremic patients [58,59] . Indeed, the elevation in ET-1 levels was correlated with diastolic dysfunction in man, thus suggesting the possibility of an early therapeutic approach in these patients [60] . High ET-1 levels have been found both in arterial hypertension and during chronic renal failure [61,62] . Studies targeting the ET-1 pathway for patients suffering from a range of disorders, including the progression of CKD and CVDs, are under investigation. Transcriptional activity of the ET-1 encoding gene (edn1) is also modulated by DNA methylation and histone modification patterns [63] . Endothelial dysfunction has been shown to participate in postischemic vasoconstriction following reperfusion, with the nitric oxide (NO) pathway as a main player. NO is well known for its role in vascular tone regulation and is generated through a reaction catalyzed by nitric oxide synthase (NOS), which exists in three different isoforms, all of which functioning in heart and kidney. NOS inhibitors have highlighted the role of NO in maintaining also regional renal blood flow. Importantly, the inability of hypoxic endothelial cells to produce NO has been suggested to have detrimental effects and participate in renal damage [64] . Epigenetic mechanisms involved in the expression of endothelial, and inducible NOS isoforms have been recognized [65–67] . In addition to promoting expression of protective genes, HDACis also appear to directly block the expression of pathological genes, which could be considered a paradox since HDAC action is usually associated with gene repression. Two recent studies have clarified the mechanism by which HDACis repress genes in the heart. Expression of the gene encoding BNP is dramatically enhanced in ventricular myocytes during pathological cardiac hypertrophy. In a study on cultured rat cardiac myocytes, it has been demonstrated that upregulation of BNP in response to endothelin signaling is dependent on association of HDAC2 with the yin-yang 1 (YY1) transcription factor on the BNP gene promoter [68] . YY1 was found in the acetylated form in cardiac myocytes and, when deacetylated by HDAC2, its capability to stimulate BNP gene transcription increased. www.futuremedicine.com

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TSA treatment disrupted YY1/HDAC2 complexes and suppressed endothelin-induced BNP expression. Similarly, in a model of cultured adult feline cardiac myocytes, other authors demonstrated that HDAC1 activity stimulates sodium/calcium exchanger (NCX1) gene expression during cardiac hypertrophy (Table 1) [69] . Kidney & heart associations

In the development of a targeted therapy for CKD an important issue is the multifactorial nature of the renal fibrosis pathogenesis [70] . Tissue fibrosis is a common pathway involved in the response to chronic stress and injury and is the result of epithelial to mesenchymal transition (EMT), the activation of fibroblasts to produce extracellular matrix, recruitment of inflammatory cells, and cellular regeneration at sites of damage. In the kidney chronic hypertension damages glomerular cells, resulting in cytokine release and inflammation. For example, TGF-b has been demonstrated to induce tubular EMT and it is thought to be one of the major causes of renal fibrosis [71,72] . An in vitro study demonstrated that an HDACi (TSA) blocked TGF-bdriven EMT [64] . TSA also increased expression of a renal-protective factor, the bone morphogenetic protein-7, which is an endogenous inhibitor of TGF-b signaling known to suppress EMT and reverse renal fibrosis [73,74] . More recently, TSA was also demonstrated to reduce fibrosis, suppress EMT and improve renal function in a rat model of diabetic nephropathy [75] . In the kidney, tubulointerstitial fibrosis is also associated with hypoxia and the activation of hypoxia-inducible Table 1. Relevant epigenetic mechanisms for the heart and kidney. Epigenetic mechanism

Heart

Kidney

DNA methylation HDAC inhibitors Histone H4 acetylation Histone H3 lysine methylation NO pathway on NOS isoforms HIF pathways RAAS and AVP pathways Fetal programming

Yes Yes Yes Yes Yes Yes No Yes

Yes Yes No No Yes Yes Yes Yes

Implications of miRNA in CRS: cardiomyocyte hypertrophy: miR-1, miR-21, miR-23, miR-133, miR-208a; Cardiomyocyte apoptosis and regeneration: miR-195, miR-199a, miR-320; fibrosis and heart failure: miR-133, miR-21, miR-29; restenosis: miR-21, miR-145, miR-221; angiogenesis: miR-221, miR-222, miR-210, miR-126, miR-17~92 cluster; diabetic nephropathy: miR-192, miR-216a, miR-217, miR-382, miR-129, miR-377, miR-93; acute kidney injury: miR-132, miR-362, miR-379, miR-668, miR-687, miR-34a; polycystic kidney disease: miR-17, miR-15a; renal allograft rejection: miR-142-5p, miR-155; kidney cancer: miR-210, miR-21, miR-155, miR-562, miR-185, miR-483-3p; other renal diseases: miR-371-5P, miR-423-5P, miR-638, miR-1224-3P, miR-663, miR-200c, miR-141, miR-205, miR-192, miR-200a, miR-200b, miR-429, miR-205, miR-29b. AVP: Arginine vasopressin system; HDAC: Histone deacetylase; HIF: Hypoxia-inducible factor; NO: Nitric oxide; NOS: Nitric oxide synthase; RAAS: Renin–angiotensin–aldosterone system.

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factor (HIF) signaling. HIF activation has been shown to promote EMT and renal fibrogenesis [76] . Moreover, it is important to consider that a variety of human disorders, including ischemic heart disease, stroke and kidney disease, all share the deleterious consequences of a common, hypoxic and oxidative stress pathway with HIF as the key player. Epigenetics has been demonstrated to play a crucial role in the cellular response to hypoxia with the involvement of HIF family and its transcriptional targets [77] . Moreover, hypoxia is closely related to oxidative stress and these two phenomena are also strictly linked in both organs. Thus, it would be interesting to analyze their related epigenetic mechanisms to potentially gain a greater understanding of CRS. Chronic inflammation triggers pathological fibrosis in the heart and kidney. Potent antiinflammatory effects of HDACis on multiple immune cell types have been observed [78] , thus explaining the broad efficacy observed with HDACis in preclinical models of cardiorenal disease. The main suggested mechanisms of action seem to be diverse, since also several nonhistone proteins have been demonstrated as targets of HDACs, including the transcription factors STAT1 [79,80] and nuclear factor kB [81] . For inflammatory diseases with no currently effective treatments HDACis may represent a new therapeutic approach and it would be interesting to determine whether induction of regulatory T cells also contributes to the efficacy of HDACs in the settings of heart and renal failure [82] . Recent findings strongly support an important role of angiotensin II in the pathophysiology of renal water and sodium retention associated with HF [83] . Renal water retention in HF is in part mediated through the release of arginine vasopressin system, which acts, through binding to vasopressin-2 receptor, on the water channel aquaporin-2 (AQP2) in the collecting duct. Moreover, in HF the increase of angiotensin II and aldosterone levels upregulated type 2 11b-hydroxysteroid dehydrogenase and epithelial sodium channel subunits [83] . However, no studies have investigated the involvement of possible epigenetic mechanisms in this important molecular pathway (Table 1) . Fetal programming

Several genetic factors as well as lifelong environmental factors, such as salt and fat intake, obesity, diabetes, smoke and alcohol consumption, amongst others, clearly contribute to the development of hypertension and/or other risk future science group


Hypertension Metabolic disease

Inflammation

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Inflammation

Organ damage/dysfunction

HDACi

HDACi Hormonal factors

BNP

Systemic disease Diabetes Amyloidosis Vasculitis and sepsis

HDACi AC

YY1

BNP gene

Low expression of BNP

HDAC2

YY1

BNP gene

High expression of BNP

Figure 3. Pathophysiological interactions between heart and kidney during cardiorenal syndrome leading to kidney injury. HDACis target multiple pathological mechanisms of chronic cardiac and renal disease. The chronic stresses of hypertension and diabetes produce cardiomyocyte hypertrophy and inflammation leading to cardiorenal fibrosis, reduced organ function, cell death and, ultimately, organ failure. In the pathological state, the YY1 transcription factor is bound to HDAC. HDAC deacetylates YY1, enhancing its ability to stimulate BNP gene expression. HDAC inhibition may reduce development of CRS and acetylation of YY1 occurring during heart failure. CRS: Cardiorenal syndrome; HDAC: Histone deacetylase; HDACi: Histone deacetylase inhibitor.

factors for these disorders, but it has also been established that stress in utero may program the later development of these diseases [84,85] . This phenomenon, known as fetal programming can be modeled in a range of experimental animal models and is related to epigenetic mechanisms. Interestingly, recent studies have underlined the importance of epigenetic alterations in the renin–angiotensin system following maternal high salt intake or low-protein diet during pregnancy in the fetal programming of adult hypertension [85–88] . These data suggest a link between epigenetic modification of genes during fetal life and the consequent alteration of gene expression in adult life leading ultimately to the development of hypertension. Although these results have been obtained in future science group

animal models, similar mechanisms may also be involved in the development of hypertension and other pathologic conditions in humans. Indeed, animal models have established causeeffect relationships consistent with epidemiological findings in humans and have demonstrated, in principle, that interventions before or during pregnancy can reduce or prevent pathogenic in utero programming of CVD (Table 1) [89,90] . In the context of the fetal programming of renal disease, metabolic responses play an important role by metabolic responses. The best-investigated conditions are nutrient deficiency leading to low birth weight, as well as maternal obesity or maternal diabetes mellitus during pregnancy, resulting in www.futuremedicine.com

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Table 2. Controlled ongoing clinical trials on cardiorenal syndrome. Status

NCT

Study

Active, not recruiting Recruiting Completed

NCT00348556

Intra-Renal Infusion of BNP in Enhancing Renal Function in Human CHF with CRS

[101]

NCT00356733 NCT01265615

[102]

Recruiting

NCT00608491

Not yet recruiting Not yet recruiting Recruiting

NCT01211886

Mechanisms of Erythropoietin Action in the Cardiorenal Syndrome Paricalcitol versus Calcitriol for the Management of Renocardiac Syndrome in Renal Transplant Patient Effectiveness of Ultrafiltration in Treating People With Acute Decompensated Heart Failure and Cardiorenal Syndrome (The CARRESS Study) Utility of Brain Natriuretic Peptide (BNP) in Patients with Type IV CRS Admitted to the Intensive Care Unit (ICU) Reverse Worsening Renal Function in Decompensated Heart Failure (REWORD-HF)

Completed

NCT00842023

Recruiting

NCT00881439

Not yet recruiting Terminated

NCT00527059

Recruiting Recruiting

NCT00140790 NCT01028170

Terminated

NCT00818701

Recruiting Recruiting

NCT01204645 NCT00577135

Completed Recruiting

NCT00186329 NCT01260259

NCT01140399 NCT00853541

NCT00575484

Ref.

[103] [104] [105] [106]

Calcium, Phosphate, Renal Impairment and Coronary Artery Disease in the Cardio-Renal Syndrome (The CAPRICORN-CRS) Study Assessment of Biomarkers and Cardiorenal Syndrome in Acute Decompensated Heart Failure With Vasodilator Therapy Safety and Efficacy Study of Add On Aliskiren in Patients With Heart Failure and Renal Impairment Renal Effects of Levosimendan in Patients Admitted With Acute Decompensated Heart Failure Concentrated Saline Infusions and Increased Dietary Sodium With Diuretics for Heart Failure With Kidney Dysfunction Valsartan in Cardiovascular Disease With Renal Dysfunction (The V-CARD) Study Safety and Efficacy of Low Dose Hypertonic Saline Solution and High Dose Furosemide for Congestive Heart Failure (REaCH) Study of Low Dose Nesiritide With or Without Sildenafil in Congestive Heart Failure Patients With Renal Dysfunction Karolinska Cardiorenal Theme-Centre Determining Optimal Dose and Duration of Diuretic Treatment in People With Acute Heart Failure (The DOSE-AHF Study) BNP for Cardio-Renal Decompensation Syndrome (BNP-CARDS) Seattle Cardiorenal Remote Ischemic Preconditioning Trial

[107] [108] [109] [110] [111] [112] [113] [114] [115] [116] [117] [118]

CHF: Chronic heart failure; CRS: Cardiorenal syndrome.

high-birthweight infants. These birth conditions can cause adverse renal outcomes which can become evident during early childhood. Exposure to corticosteroids, particularly glucocorticoids, during pregnancy has also been suggested to have an effect on the fetal programming of these diseases. However, to date only animal studies clearly demonstrate an adverse effect of glucocorticoids on renal development. Potential underlying mechanisms of fetal programming can include a marked reduction of nephron number through reduced nephrogenesis, inhibition of the intrarenal RAAS, diminished circulating insulin-like growth factor 1, and increased apoptosis. Moreover, early-life nutrition can alter the metabolic responses and influence renal outcome postnatally [91,92] . Conclusion

It is clear that inflammation and metabolic stress encountered in CKD could promote epigenetic 492


changes, leading to altered gene expression and abnormal cellular function (Figure 1) . As regard to the epigenetic effects in CKD an important example are the HDACis, as described in this article, with some studies that indicate they are able to de-repress the expression of important protective cardiac genes. Thus, we can also assume that many genes with important functions during development of the fetal heart can be re-expressed in the adult tissue. This expression modification can result in pathophysiological changes leading to cardiac ischemia and HF. Chronic kidney disease has been associated with increased cardiovascular morbidity and mortality and this risk has been demonstrated in several clinical studies. Indeed, as described in this article, all risk factors in patients with kidney disease, such as modifiable, nonmodifiable and uremia related risk factors, contribute to generate coronary artery disease, peripheral artery disease and left ventricular hypertrophy future science group


finally leading to myocardial infarction and congestive heart failure. Patients with moderate to severe CKD have an increase in mortality from cardiovascular disease, even long before they develop kidney failure. Emerging evidence suggests that endothelial dysfunction, oxidative stress, vascular calcification, systemic diseases, infections and inflammation are strongly interrelated and together play a major role in the initiation and progression of vascular disease in CKD (Figure 3) . Future perspective

Currently, controlled clinical studies involving CRS are based on molecules such as homocysteine, EPO and Natrecor drug (nasiritide), which is a recombinant form of BNP (Table 2) . Other clinical trials in cardiovascular disease with renal dysfunction are based on valsartan, a specific drug with an indication of an active substance against hypertension. From the clinical

Review

perspective it is clear that it is necessary a better understanding of the underlying mechanisms of kidney and heart diseases, to achieve better diagnostic, preventive and therapeutic measures. Overall, there is an emerging interest in the possible pathogenic role of endoplasmic reticulum stress in the framework of cardiac hypertrophy, HF, and CKD [93] . Similarly, epoxyeicosatrienoic acids [94] or statins [90] could have a therapeutic value in the treatment of chronic CRS. Epigenetic studies may be helpful in the identification of new vascular markers or biofactors and facilitate a more rapid development of novel, safe and effective therapies [95,96] . Future perspectives could be based on the study of those genes playing an essential role during development of the fetal heart and vasculature [90] that are re-expressed in the adult tissue with later pathophysiological consequences. These findings could be useful

Executive summary Kidney & heart interaction Heart and kidney function are closely interconnected. Cardiorenal syndrome (CRS) is a pathological disorder where acute or chronic dysfunction in one organ may induce dysfunction in the other organ.

n n

Cardiorenal axis dysfunction The early diagnosis and management of heart failure are important in patients with chronic kidney disease (CKD). Cardiac and renal biomarkers facilitate and improve the clinical managements of heart failure and CKD patients. n CRS type I describes the acute kidney injury as a consequence of a sudden worsening of cardiac function. n CRS type II describes the progressive and permanent kidney disease caused by chronic cardiac dysfunction. n CRS type III describes a sudden cardiac disorder as a consequence of an impairment of kidney function. n CRS type IV is attributed to the decreased cardiac function and increased risk of cardiovascular events in patients with CKD. n CRS type V describes a situation in which a systemic condition causes both cardiac and renal dysfunction. n n

Epigenetic mechanisms The main epigenetic mechanisms include DNA methylation, histone modification and RNA interference, which result in changes of chromatin structure and miRNA alterations. n Recent studies have demonstrated that epigenetic alterations are also associated with inflammation and cardiovascular disease in patients with CKD and CRS. n Hypertension, dyslipidemia and endothelial dysfunction are important in this context. n CRS is not limited to hemodynamic changes and should be considered as a complex interplay of neurohumoral pathways activation. n

Pathophysiology & epigenetics in the cardiorenal axis CRS involves neurohumoral systems that include the sympathetic nervous system, the renin–angiotensin–aldosterone system, the endothelin system, and the arginine vasopressin system. n The activation of the sympathetic nervous system, renin–angiotensin–aldosterone system, endothelin system and arginine vasopressin system induces inflammation and oxidative stress that lead to vasoconstriction, salt and water retention, accelerated atherosclerosis, cardiac remodeling and hypertrophy, myocardial and intrarenal fibrosis and progression of CKD. n

Conclusion Histone deacetylase inhibitor studies indicate they are able to de-repress the expression of important protective cardiac genes. Genes with important functions during heart development can be re-expressed in the adult, thereby leading to pathophysiological modifications ultimately responsible of cardiac ischemia, heart failure and CRS.

n n

Future perspective Epigenetic studies may be helpful in the identification of new vascular markers or factors that ultimately may facilitate a more rapid development of novel, safe and effective therapies in CRS patients.

n

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to utilize compounds that act on epigenetic mechanisms as novel therapeutic strategies. To date, the available molecules targeting epigenetic modifications have been studied mainly in tumors [91–98] , while studies involving the cardiovascular and kidney diseases, as well as CRS, are still at a preliminary stage. For example, with regard to atherosclerosis and HF, the administration of curcumin (an inhibitor KAT) has been tested [99] . Bibliography

9.

Papers of special note have been highlighted as: n of interest nn of considerable interest 1.

2.

3.

n

4.

5.

6.

n

7.

8.

Dwivedi RS, Herman JG, McCaffrey et al. Beyond genetics: epigenetic code in CKD. Kidney Int. 79(1), 23–32 (2011). Iwanaga Y, Miyazaki S. Heart failure, chronic kidney disease, and biomarkers--an integrated viewpoint. Circ. J. 74(7), 1274–1282 (2010).

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.

Kendrick J, Chonchol MB. Nontraditional risk factors for cardiovascular disease in patients with CKD. Nat. Clin. Pract. Nephrol. 4(12), 672–681 (2008).

10. Ronco C, Haapio M, House AA et al.

Cardiorenal syndrome. J. Am. Coll. Cardiol. 52(19), 1527–1539 (2008). nn

In this paper a consensus definition of cardiorenal syndrome, that emphasizes the bidirectional nature of heart–kidney interactions, has been proposed for the first time.

Balestrieri ML, Giovane A, Milone L et al. Modification of the detrimental effect of TNF-a on human endothelial progenitor cells by fasudil and Y27632. J. Biochem. Mol. Toxicol. 24(6), 351–360 (2010).

11. Han WK, Bonventre JV. Biologic markers for

First evidence that some drugs modify detrimental effect of TNF-a on endothelial progenitor cells.

12. Devarajan P, Mishra J, Supavekin S et al.

Smith GL, Masoudi FA, Shlipak MG et al. Renal impairment predicts long-term mortality risk after acute myocardial infarction. J. Am. Soc. Nephrol. 19(1), 141–150 (2008). Napoli C, Balestrieri A, Ignarro LJ. Therapeutic approaches in vascular repair induced by adult bone marrow cells and circulating progenitor endothelial cells. Curr. Pharm. Des. 13(31), 3245–3251 (2007). Jie KE, van der Putten K, Bergevoet MW et al. Short- and long-term effects of erythropoietin treatment on endothelial progenitor cell levels in patients with cardiorenal syndrome. Heart 97(1), 60–65 (2011). Data presented in this paper show that circulating endothelial progenitor cell levels are reduced in cardiorenal syndrome patients also after erythropoietin treatment. Smith GL, Lichtman JH, Bracken MB et al.: Renal impairment and outcomes in heart failure: systematic review and meta-analysis. J. Am. Coll. Cardiol. 47(10), 1987–1996 (2006). Levin A. Clinical epidemiology of cardiovascular disease in CKD prior to dialysis. Semin. Dial. 16(2), 101–105 (2003).

494

the early detection of acute kidney injury. Curr. Opin. Crit. Care 10(6), 476–482 (2004). Gene expression in early ischemic renal injury: clues towards pathogenesis, biomarker discovery, and novel therapeutics. Mol. Genet. Metab. 80(4), 365–376 (2003). 13. Nguyen MT, Ross GF, Dent CL et al. Early

prediction of acute renal injury using urinary proteomics. Am. J. Nephrol. 25(4), 318–326 (2005). 14. Ronco C. NGAL: an emerging biomarker of

acute kidney injury. Int. J. Artif. Organs 31(3), 199–200 (2008). 15. Nickolas TL, Barasch J, Devarajan P.

Biomarkers in acute and CKD. Curr. Opin. Nephrol. Hypertens. 17(2), 127–132 (2008). 16. Dharnidharka VR, Kwon C, Stevens G.

Serum cystatin C is superior to serum creatinine as a marker of kidney function: a meta-analysis. Am. J. Kidney Dis. 40(2), 221–226 (2002). 17. Han WK, Bailly V, Abichandani R et al.

Kidney injury molecule-1 (KIM-1): A novel biomarker for human renal proximal tubule injury. Kidney Int. 62(1), 237–244 (2002). 18. Vaidya VS, Ramirez V, Ichimura T et al.

Urinary kidney injury molecule-1: a sensitive quantitative biomarker for early detection of kidney tubular injury. Am. J. Physiol. Renal. Physiol. 290(2), F517–F529 (2005). 19. Parikh CR, Abraham E, Ancukiewicz M,

Edelstein CL. Urine IL-18 is an early diagnostic marker for acute kidney injury and Future Cardiol. (2011) 7(4)

predicts mortality in the intensive care unit. J. Am. Soc. Nephrol. 16(10), 3046–3052 (2005). 20. Liang KV, Williams AW, Greene EL et al.

Acute decompensated heart failure and the cardiorenal syndrome. Crit. Care Med. 36(Suppl. 1), S75–S88 (2008). 21. Jie KE, Verhaar MC, Cramer MJ

et al. Erythropoietin and the CRS: Cellular mechanisms on the cardiorenal connectors. Am. J. Physiol. Renal Physiol. 291(5), F932–F944 (2006). 22. Riksen NP, Hausenloy DJ, Yellon DM.

Erythropoietin: ready for prime-time cardioprotection. Trends Pharmacol. Sci. 29(5), 258–267 (2008). 23. Palazzuoli A, Silverberg DS, Iovine F et al.

Effects of b-erythropoietin treatment on left ventricular remodeling, systolic function, and B-type natriuretic peptide levels in patients with the cardiorenal anemia syndrome. Am. Heart J. 154(4), 645e9–645e15 (2007). 24. Rattazzi M, Puato M, Faggin E et al. New

markers of accelerated atherosclerosis in end-stage renal disease. J. Nephrol. 16(1), 11–20 (2003). 25. Tonelli M, Wiebe N, Culleton B et al.

Chronic kidney disease and mortality risk: a systematic review. J. Am. Soc. Nephrol. 17(7), 2034–2047 (2006). 26. Cunningham PN, Dyanov HM, Park P et al.

Acute renal failure in endotoxemia is caused by TNF acting directly on TNF receptor-1 in kidney. J. Immunol. 168(11), 5817–5823 (2002). 27. Kumar A, Paladugu B, Mensing J et al. Nitric

oxide-dependent and -independent mechanisms are involved in TNF-a-induced depression of cardiac myocyte contractility. Am. J. Physiol. Regul. Integr. Comp. Physiol. 292(5), R1900–R1906 (2007). 28. Portela A, Esteller M. Epigenetic

modifications and human disease. Nat. Biotechnol. 28(10), 1057–1068 (2010). 29. Kaufman PD, Rando OJ. Chromatin as a

potential carrier of heritable information. Curr. Opin. Cell Biol. 22(3), 284–290 (2010).



nn

Illustrates the evidence found in the literature that some chromatin states are indeed heritable.

30. Bhatt K, Mi QS, Dong Z. Invited review-

microRNAs in kidneys: biogenesis, regulation and pathophysiological roles. Am. J. Physiol. Renal Physiol. (2011) (Epub ahead of print). 31. Wang Z, Zang C, Cui K et al. Genome-wide

mapping of HATs and HDACs reveals distinct functions in active and inactive genes. Cell 138(5), 1019 –1031 (2009). 32. Small EM, Frost RJ, Olson EN. MicroRNAs

add a new dimension to cardiovascular disease. Circulation 121(8), 1022–1032 (2010). 33. Taunton J, Hassig CA, Schreiber SL. A

mammalian histone deacetylase related to the yeast transcriptional regulator Rpd3p. Science 272(5260), 408–411 (1996). 34. Wierda RJ, Geutskens SB, Jukema JW et al.

Epigenetics in atherosclerosis and inflammation. J. Cell. Mol. Med. 14(6A), 1225–1240 (2010). 35. Mullens W, Abrahams Z, Francis GS et al.

Importance of venous congestion for worsening of renal function in advanced decompensated heart failure. J. Am. Coll. Cardiol. 53(7), 589–596 (2009). 36. Schetz M. Cardiorenal syndrome. F1000

Medicine Reports 1, 78 (2009). 37. Kociol R, Rogers J, Shaw A. Organ cross

talk in the critically ill: the heart and the kidney. Blood Purif. 27(4), 311–320 (2009). 38. Chade AR, Rodriguez-Porcel M,

Herrmann J et al. Antioxidant intervention blunts renal injury in experimental renovascular disease. J. Am. Soc. Nephrol. 15(4), 958–966 (2004). n

First evidence that antioxidant intervention blunts renal failure.

39. Berry JM, Cao DJ, Rothermel BA et al.

Histone deacetylase inhibition in the treatment of heart disease. Expert Opin. Drug Saf. 7(1), 53–67 (2008). 40. Gaikwad AB, Sayyed SG, Lichtnekert J

et al. Renal failure increases cardiac histone h3 acetylation, dimethylation, and phosphorylation and the induction of cardiomyopathy-related genes in type 2 diabetes. Am. J. Pathol. 176(3), 1079–1083 (2010). nn

Investigates for the first time the epigenetic mechanism directly linking renal failure with the induction of cardiomyopathy-related genes.

41. Turunen MP, Aavik E, Ylä-Herttuala S.

Epigenetics and atherosclerosis. Biochim. Biophys. Acta 1790(9), 886–891 (2009).


42. Castro R, Rivera I, Struys EA et al.

55. Davis FJ, Pillai JB, Gupta M et al.

Increased homocysteine and S-adenosylhomocysteine concentrations and DNA hypomethylation in vascular disease. Clin. Chem. 49(8), 1292–1296 (2003).

Concurrent opposite effects of trichostatin A, an inhibitor of histone deacetylases, on expression of a-MHC and cardiac tubulins: implication for gain in cardiac muscle contractility. Am. J. Physiol. Heart Circ. Physiol. 288(3), H1477–H1490 (2005).

43. Teitell M, Richardson B. DNA methylation

in the immune system. Clin. Immunol. 109(1), 2–5 (2003).

56. Kee HJ, Kook H. Kruppel-like factor 4

mediates histone deacetylase inhibitorinduced prevention of cardiac hypertrophy. J. Mol. Cell. Cardiol. 47(6), 770 –780 (2009).

44. Stenvinkel P, Karimi M, Johansson S et al.

Impact of inflammation on epigenetic DNA methylation: A novel risk factor for cardiovascular disease? J. Intern. Med. 261(5), 488–499 (2007).

57. Bingham AJ, Ooi L, Kozera L et al. The

repressor element 1-silencing transcription factor regulates heart-specific gene expression using multiple chromatin-modifying complexes. Mol. Cell. Biol. 27(11), 4082– 4092 (2007).

45. Nanayakkara PW, Kiefte-de Jong JC,

Stehouwer CD et al. Association between global leukocyte DNA methylation, renal function, carotid intima-media thickness and plasma homocysteine in patients with stage 2–4 chronic kidney disease. Nephrol. Dial. Transplant. 23(8), 2586–2592 (2008).

58. Wada A, Tsutamoto T, Ohnishi M et al.

Effects of a specific endothelin-converting enzyme inhibitor on cardiac, renal, and neurohumoral functions in congestive HF: comparison of effects with those of endothelin A receptor antagonism. Circulation 99(4), 570–577 (1999).

46. Zhang CL, McKinsey TA, Chang S et al.

Class II histone deacetylases act as signalresponsive repressors of cardiac hypertrophy. Cell 110(4), 479–488 (2002). 47. Antos CL, McKinsey TA, Dreitz M et al.

Dose-dependent blockade to cardiomyocyte hypertrophy by histone deacetylase inhibitors. J. Biol. Chem. 278(31), 28930–28937 (2003).

59. Chade AR, Best PJ, Rodriguez-Porcel M

et al. Endothelin-1 receptor blockade prevents renal injury in experimental hypercholesterolemia. Kidney Int. 64(3), 962–969 (2003).

48. Kook H, Lepore JJ, Gitler AD et al. Cardiac

hypertrophy and histone deacetylasedependent transcriptional repression mediated by the atypical homeodomain protein Hop. J. Clin. Invest. 112(6), 863–871 (2003). 49. Kee HJ, Sohn IS, Nam KI et al. Inhibition of

histone deacetylation blocks cardiac hypertrophy induced by angiotensin II infusion and aortic banding. Circulation 113(1), 51–59 (2006).

60. Napoli C, Liguori A, Sorice P et al. Relations

between vasoactive hormones and diastolic function in hypertensive uraemic patients. J. Intern. Med. 240(6), 389–394 (1996). 61. Napoli C, Di Gregorio F, Sorice P et al. High

prevalence of myocardial ischemia and vasoconstrictive hormonal release in hypertension during chronic renal failure. Nephron 76(4), 434–444 (1997).

50. Kee HJ, Eom GH, Joung H et al. Activation

of histone deacetylase 2 by inducible heat shock protein 70 in cardiac hypertrophy. Circ. Res. 103(11), 1259–1269 (2008). 51. Cardinale JP, Sriramula S, Pariaut R et al.

HDAC inhibition attenuates inflammatory, hypertrophic, and hypertensive responses in spontaneously hypertensive rats. Hypertension 56(3), 437–444 (2010). 52. Trivedi CM, Luo Y, Yin Z et al. Hdac2

regulates the cardiac hypertrophic response by modulating Gsk3 b activity. Nat. Med. 13(3), 324 –331 (2007). 53. Gupta MP. Factors controlling cardiac

myosin-isoform shift during hypertrophy and heart failure. J. Mol. Cell. Cardiol. 43(4), 388–403 (2007). 54. James J, Martin L, Krenz M et al. Forced

expression of a-myosin heavy chain in the rabbit ventricle results in cardioprotection under cardiomyopathic conditions. Circulation 111(18), 2339–2346 (2005).


Review

n

Seminal study establishing that cardiac ischemia is more severe in hypertension during chronic kidney disease.

62. Napoli C, Di Gregorio F, Leccese M et al.

Evidence of exercise-induced myocardial ischemia in patients with primary aldosteronism: the cross-sectional primary aldosteronism and heart Italian multicenter study. J. Investig. Med. 47(5), 212–221 (1999). 63. Stow LR, Jacobs ME, Wingo CS et al.

Endothelin-1 gene regulation. FASEB J. 25(1), 16–28 (2010). 64. Legrand M, Mik EG, Johannes T et al. Renal

hypoxia and dysoxia after reperfusion of the ischemic kidney. Mol. Med. 14(7–8), 502–516 (2008). 65. Ignarro LJ, Cirino G, Casini A et al. Nitric

oxide as a signaling molecule in the vascular system: an overview. J. Cardiovasc. Pharmacol. 34(6), 879–886 (1999).

495

Review


66. Chan Y, Fish JE, D’Abreo C et al. The

cell-specific expression of endothelial nitric-oxide synthase: a role for DNA methylation. J. Biol. Chem. 279(33), 35087–35100 (2004).

78. Halili MA, Andrews MR, Sweet MJ et al.

79. Klampfer L, Huang J, Swaby LA et al.

67. Chan GC, Fish JE, Mawji IA et al.

Epigenetic basis for the transcriptional hyporesponsiveness of the human inducible nitric oxide synthase gene in vascular endothelial cells. J. Immunol. 175(6), 3846–3861 (2005).

Requirement of histone deacetylase activity for signaling by STAT1. J. Biol. Chem. 279(29), 30358–30368 (2004). 80. Kramer OH, Knauer SK, Greiner G et al. A

phosphorylation-acetylation switch regulates STAT1 signaling. Genes Dev. 23(2), 223–235 (2009).

68. Glenn DJ, Wang F, Chen S et al. Endothelin

nn

stimulated human B-type natriuretic peptide gene expression is mediated by Yin Yang 1 in association with histone deacetylase 2. Hypertension 53(3), 549–555 (2009).

81. Calao M, Burny A, Quivy V et al. A pervasive

Demonstrates that upregulation of BNP in response to endothelin signaling is dependent on the association of histone deacetylase 2 with Y Y1 transcription factor on its promoter.

82. Bush EW, McKinsey TA. Protein acetylation in

role of histone acetyltransferases and deacetylases in an NF-kB signaling code. Trends Biochem. Sci. 33(7), 339–349 (2008). the cardiorenal axis: the promise of histone deacetylase inhibitors. Circ. Res. 106(2), 272–284 (2010). 83. Lütken SC, Kim SW, Jonassen T et al. Changes

69. Chandrasekaran S, Peterson RE, Mani SK

of renal AQP2, ENaC, and NHE3 in experimentally induced HF: response to angiotensin II AT1 receptor blockade. Am. J. Physiol. Renal Physiol. 297(6), F1678-F1688 (2009).

et al. Histone deacetylases facilitate sodium/calcium exchanger up-regulation in adult cardiomyocytes. FASEB J. 23(11), 3851–3864 (2009). 70. Liu Y. Renal fibrosis: new insights into the

84. Napoli C, Lerman LO, de Nigris F et al.

pathogenesis and therapeutics. Kidney Int. 69(2), 213–217 (2006).

Rethinking primary prevention of atherosclerosis-related diseases. Circulation 114(23), 2517–2527 (2006).

71. Kalluri R, Weinberg RA. The basics of

epithelial-mesenchymal transition. J. Clin. Invest. 119(6), 1420 –1428 (2009).

85. Napoli C, Cacciatore F: Novel pathogenic

insights in the primary prevention of cardiovascular disease. Prog. Cardiovasc. Dis. 51(6), 503–523 (2009).

72. Yoshikawa M, Hishikawa K, Marumo T

et al. Inhibition of histone deacetylase activity suppresses epithelial-tomesenchymal transition induced by TGF-b1 in human renal epithelial cells. J. Am. Soc. Nephrol. 18(1), 58–65 (2007). 73. Zeisberg M, Hanai J, Sugimoto H et al.

BMP-7 counteracts TGF-b1-induced epithelial-to-mesenchymal transition and reverses chronic renal injury. Nat. Med. 9(7), 964–968 (2003). 74. Zeisberg M, Kalluri R. Reversal of

experimental renal fibrosis by BMP7 provides insights into novel therapeutic strategies for chronic kidney disease. Pediatr. Nephrol. 23(9), 1395–1398 (2008). 75. Noh H, Oh EY, Seo JY et al. Histone

deacetylase-2 is a key regulator of diabetesand transforming growth factor-b1-induced renal injury. Am. J. Physiol. Renal Physiol. 297(3), F729–F739 (2009). 76. Higgins DF, Kimura K, Iwano M et al.

Hypoxia-inducible factor signaling in the development of tissue fibrosis. Cell Cycle 7(9), 1128–1132 (2008). 77. Watson JA, Watson CJ, McCann A et al.

Epigenetics, the epicenter of the hypoxic response. Epigenetics 5(4), 293–296 (2010).

496

90. Napoli C. Developmental mechanisms

Histone deacetylase inhibitors in inflammatory disease. Curr. Top. Med. Chem. 9(3), 309–319 (2009).

n

An updated review regarding novel pathogenic insights in primary prevention of cardiovascular disease.

86. Bogdarina I, Welham S, King PJ et al.

Epigenetic modification of the reninangiotensin system in the fetal programming of hypertension. Circ. Res. 100(4), 520–526 (2007). nn

Suggests a link between epigenetic modification during fetal life of genes belonging to the renin–angiotensin system and the development of hypertension.

87. Ding Y, Lv J, Mao C et al. High-salt diet during

pregnancy and angiotensin-related cardiac changes. J. Hypertens. 28(6), 1290–1297 (2010). 88. Gilbert JS and Nijland MJ. Sex differences in

the developmental origins of hypertension and cardiorenal disease. Am. J. Physiol. Regul. Integr. Comp. Physiol. 295(6), R1941–R1952 (2008). 89. Palinski W, Nicolaides E, Liguori A et al.

Influence of maternal dysmetabolic conditions during pregnancy on cardiovascular disease. J. Cardiovasc. Transl. Res. 2(3), 277–285 (2009).


involved in the primary prevention of atherosclerosis and cardiovascular disease. Curr. Atheroscler. Rep. 13(2), 170–175 (2011). nn

An update review on developmental mechanisms in the prevention of cardiovascular disease.

91. Woroniecki R, Gaikwad AB, Susztak K.

Fetal environment, epigenetics, and pediatric renal disease. Pediatr. Nephrol. 26(5), 705–711 (2011). 92. Dötsch J, Plank C, Amann K. Fetal

programming of renal function. Pediatr. Nephrol. (2011) (Epub ahead of print). 93. Dickhout JG, Carlisle RE, Austin RC.

Interrelationship between cardiac hypertrophy, heart failure, and chronic kidney disease: endoplasmic reticulum stress as a mediator of pathogenesis. Circ. Res. 108(5), 629–642 (2011). 94. Huang H, Chen J, Lin T et al.

Epoxyeicosatrienoic acids–novel mechanism and pharmacological therapy of chronic renocardiac syndrome. Med. Hypotheses 76(4), 550–552 (2011). 95. Stenvinkel P, Carrero JJ, Axelsson J et al.

Emerging biomarkers for evaluating cardiovascular risk in the CKD patient: how do new pieces fit into the uremic puzzle? Clin. J. Am. Soc. Nephrol. 3(2), 505–521 (2008). 96. Ingelman-Sundberg M, Gomez A. The

past, present and future of pharmacoepigenomics. Pharmacogenomics 11(5), 625–627 (2010). 97. Mann BS, Johnson JR, He K, Sridhara R

et al. Vorinostat for treatment of cutaneous manifestations of advanced primary cutaneous T-cell lymphoma. Clin. Cancer Res. 13(8), 2318–2322 (2007). 98. Gerstner T, Bell N, König S. Oral valproic

acid for epilepsy--long-term experience in therapy and side effects. Expert Opin. Pharmacother. 9(2), 285–292 (2008). 99. Wongcharoen W, Phrommintikul A.

The protective role of curcumin in cardiovascular diseases. Int. J. Cardiol. 133(2), 145–151 (2009).

Websites 101. Intra-Renal Infusion of BNP in Enhancing

Renal Function in Human CHF with CRS http://clinicaltrials.gov/ct2/show/ NCT00348556 102. Mechanisms of Erythropoietin Action in the

Cardiorenal Syndrome http://clinicaltrials.gov/ct2/show/ NCT00356733



103. Paricalcitol versus Calcitriol for the

management of Renocardiac Syndrome in Renal Transplant Patient http://clinicaltrials.gov/ct2/show/ NCT01265615 104. Effectiveness of Ultrafiltration in Treating

People With Acute Decompensated Heart Failure and Cardiorenal Syndrome (The CARRESS Study) http://clinicaltrials.gov/ct2/show/ NCT00608491 105. Utility of Brain Natriuretic Peptide (BNP) in

Patients with Type IV CRS Admitted to the Intensive Care Unit (ICU) http://clinicaltrials.gov/ct2/show/ NCT01211886 106. Reverse Worsening Renal Function in

Decompensated Heart Failure (REWORDHF) http://clinicaltrials.gov/ct2/show/ NCT01140399 107. Calcium, Phosphate, Renal Impairment and

Coronary Artery Disease in the Cardio-Renal Syndrome (The CAPRICORN-CRS) Study http://clinicaltrials.gov/ct2/show/ NCT00853541


108. Assessment of Biomarkers and Cardiorenal

Syndrome in Acute Decompensated Heart Failure With Vasodilator Therapy http://clinicaltrials.gov/ct2/show/ NCT00842023 109. Safety and Efficacy Study of Add On

Aliskiren in Patients With Heart Failure and Renal Impairment http://clinicaltrials.gov/ct2/show/ NCT00881439 110. Renal Effects of Levosimendan in Patients

Admitted With Acute Decompensated Heart Failure http://clinicaltrials.gov/ct2/show/ NCT00527059 111. Concentrated Saline Infusions and Increased

Dietary Sodium With Diuretics for Heart Failure With Kidney Dysfunction http://clinicaltrials.gov/ct2/show/ NCT00575484 112. Valsartan in Cardiovascular Disease With

Renal Dysfunction (The V-CARD) Study http://clinicaltrials.gov/ct2/show/ NCT00140790


Review

113. Safety and Efficacy of Low Dose Hypertonic

Saline Solution and High Dose Furosemide for Congestive Heart Failure (REaCH) http://clinicaltrials.gov/ct2/show/ NCT01028170 114. Study of Low Dose Nesiritide With or

Without Sildenafil in Congestive Heart Failure Patients With Renal Dysfunction http://clinicaltrials.gov/ct2/show/ NCT00818701 115. Karolinska Cardiorenal Theme-Centre

http://clinicaltrials.gov/ct2/show/ NCT01204645 116. Determining Optimal Dose and Duration of

Diuretic Treatment in People With Acute Heart Failure (The DOSE-AHF Study) http://clinicaltrials.gov/ct2/show/ NCT00577135 117. BNP for Cardio-Renal Decompensation

Syndrome (BNP-CARDS) http://clinicaltrials.gov/ct/show/ NCT00186329?order=1 118. Seattle Cardiorenal Remote Ischemic

Preconditioning Trial http://clinicaltrials.gov/ct2/show/ NCT01260259

497