Endothelin and endothelin receptors in the renal and cardiovascular systems

Life Sciences 91 (2012) 490–500

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Review

Endothelin and endothelin receptors in the renal and cardiovascular systems Nicolas Vignon-Zellweger a, Susi Heiden a, Takashi Miyauchi b, Noriaki Emoto a, c,⁎ a b c

Kobe Pharmaceutical University, Clinical Pharmacy, Japan Cardiovascular Division, Faculty of Medicine, University of Tsukuba, Japan Kobe University Graduate School of Medicine, Division of Cardiovascular Medicine, Department of Internal Medicine, Japan

a r t i c l e

i n f o

Article history: Received 19 December 2011 Accepted 16 March 2012 Keywords: Endothelin-1 Endothelin receptor Molecular biology Heart Vasculature Kidney

a b s t r a c t Endothelin-1 (ET-1) is a multifunctional hormone which regulates the physiology of the cardiovascular and renal systems. ET-1 modulates cardiac contractility, systemic and renal vascular resistance, salt and water renal reabsorption, and glomerular function. ET-1 is responsible for a variety of cellular events: contraction, proliferation, apoptosis, etc. These effects take place after the activation of the two endothelin receptors ETA and ETB, which are present – among others – on cardiomyocytes, fibroblasts, smooth muscle and endothelial cells, glomerular and tubular cells of the kidney. The complex and numerous intracellular pathways, which can be contradictory in term of functional response depending on the receptor type, cell type and physiological situation, are described in this review. Many diseases share an enhanced ET-1 expression as part of the pathophysiology. However, the use of endothelin blockers is currently restricted to pulmonary arterial hypertension, and more recently to digital ulcer. The complexity of the endothelin system does not facilitate the translation of the molecular knowledge to clinical applications. Endothelin antagonists can prevent disease development but secondary undesirable effects limit their usage. Nevertheless, the increasing understanding of the effects of ET-1 on the cardiac and renal physiology maintains the endothelin system as a promising therapeutic target. © 2012 Elsevier Inc. All rights reserved.

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Generation of endothelin . . . . . . . . . . . . . . . . . . . . . . Endothelin receptors . . . . . . . . . . . . . . . . . . . . . . . . . . ET-1 in the vasculature . . . . . . . . . . . . . . . . . . . . . . . . . Effects of ET-1 on vascular tone . . . . . . . . . . . . . . . . . . . Other effects of ET-1 on the vasculature: growth and inflammation . . . ET-1 in the heart . . . . . . . . . . . . . . . . . . . . . . . . . . . . Inotropic effects of ET-1 . . . . . . . . . . . . . . . . . . . . . . . Hypertrophic and profibrotic effects of ET-1 . . . . . . . . . . . . . . Cardio-protective properties of ET-1 . . . . . . . . . . . . . . . . . Clinical use of endothelin antagonists in heart failure . . . . . . . . . ET-1 in the kidney . . . . . . . . . . . . . . . . . . . . . . . . . . . . ET-1 in the renal vasculature . . . . . . . . . . . . . . . . . . . . . ET-1 in the tubular system . . . . . . . . . . . . . . . . . . . . . . ET-1 controls channels activity and inhibits salt reabsorption . . ET-1 antagonizes vasopressin actions and regulates blood volume ET-1 in proliferative tubular disease . . . . . . . . . . . . . . ET-1 in the glomerulus . . . . . . . . . . . . . . . . . . . . . . . . Clinical use of endothelin antagonists in diabetic nephropathy . . . . .

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⁎ Corresponding author at: Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650–0017, Japan. Tel.: + 81 78 382 5846; fax: + 81 78 382 5859. E-mail address: [email protected] (N. Emoto). 0024-3205/$ – see front matter © 2012 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.lfs.2012.03.026

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Conclusion . . . . . . . . . Conflict of interest statement Appendix A. Supplementary References . . . . . . . . .

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Endothelins comprise a family of three peptides, ET‐1, ET‐2 and ET‐3 derived from three distinct genes. The expression of ET‐2 and ET‐3 differs from ET‐1 relatively to the tissue type (Matsumoto et al., 1989; Saida et al., 2002). ET‐1 is the predominant isoform in vivo. The human and mouse EDN1 genes code for a biologically inactive 212 and 202 amino acids (aa) preproendothelin‐1 (PPET1), respectively. The promoter of the EDN1 gene presents numerous regulatory elements and its transcription is therefore regulated by many hormonal and environmental stimuli (tumor necrosis factor‐alpha, interleukins, insulin, norepinephrine, angiotensin II, thrombin, natriuretic peptides, nitric oxide (NO), prostacyclin) which are extensively reviewed (Stow et al., 2011). PPET1 is cleaved into the 38 aa big endothelin‐1 (big ET‐1) by specific furin‐like proteases (Denault et al., 1995). The active 21 aa peptide ET‐1 is produced from big ET‐1 mainly through the proteolytic action of three endothelin converting enzymes (ECE-1, ECE-2, ECE-3) (Xu et al., 1994; Emoto and Yanagisawa, 1995; Hasegawa et al., 1998), which exist under different splice variants (Emoto et al., 1999; Ikeda et al., 2002), but ET-1 can be produced also by other enzymes (Orleans-Juste et al., 2003). Human and mouse ET‐1 amino acid sequences are identical. Alternatively, chymases can cleave big ET‐1 into a 31 aa active peptide (ET‐11–31) (Nagata et al., 2000). Importantly, ECEs can have proteolytic actions on other peptides (Mzhavia et al., 2003). Big ET‐1 has no biological function apart from the protection from proteolysis cleavage of endothelin and binds to the endothelin receptors but with a much lower affinity (Hemsen et al., 1991). ET‐1, for its part, exhibits low plasma concentration because of the quasi irreversible feature of ET-1 binding to its receptors and the clearing operated by them after binding (Johnstrom et al., 2005). ET-1 acts therefore as a para‐ and autocrine hormone.

ETA receptor shows an atypical long-lasting agonist-induced effect because ET-1 dissociates particularly slowly from its receptors. Based on a two-state two-site model, it has been proposed that ET1 and ETA receptor antagonists bind to distinct sites and antagonists therefore prevent the binding of ET-1 but may reduce only partly the actions of already bound ET-1 (De Mey et al., 2011). After activation, the ETB receptor is internalized and targeted to the lysosome (Bremnes et al., 2000). ETB receptor selective (Strachan et al., 1999), non-selective (Iglarz et al., 2008) and in a much lesser extent selective ETA receptor antagonists (Opgenorth et al., 2000) elevate the serum level of ET-1. Together these data reveal the predominant role of the ETB receptors for the clearance of circulating ET-1, which occurs mainly in the lungs and the kidneys (Johnstrom et al., 2005). The presence of homo- and heterodimers of the endothelin receptors has been recently observed in vitro and possibly counts for the complexity of ET-1 responses. The types of dimers (ETA/ETA, ETA/ETB, or ETB/ETB) are characterized by different binding density (Evans and Walker, 2008). Moreover, the functional response is different whether homo- or heterodimers are formed: the binding of ET-1 to homodimers induces a transient elevation in Ca2+ concentration, while the response mediated by heterodimers lasts for several minutes (Evans and Walker, 2008). In pulmonary arteries of rats, Sauvageau et al. (2009) could demonstrate by co-immunoprecipitation a heterodimerization of the two endothelin receptors. Furthermore, endothelin receptors could possibly form dimers with other receptors: Zeng et al. proposed that the loss of the dopamine receptor function in renal tubule of hypertensive rats is due to impaired binding to the ETB receptor (Zeng et al., 2008a). The functional relevance of these observations and particularly how pharmacological observations could be explained by the formation of dimers was recently discussed elsewhere (Watts, 2010). Finally, a molecule could represent an alternative target of ET-1: a dual ET-1/angiotensin II receptor called DEAR (Ruiz-Opazo et al., 1998).

Endothelin receptors

ET-1 in the vasculature

Shortly after the discovery of ET‐1, two types of seven transmembrane G protein‐coupled receptors were cloned called endothelin receptor A (ETA) (Arai et al., 1990) and ETB (Sakurai et al., 1990). The affinity of the ETA receptor for ET-3 is less than its affinity for ET-1 and ET-2, while the ETB receptor binds the three endothelins with the same affinity. No specific agonist for the ETA receptor and only two ETB receptor agonists, sarafotoxin 6c and IRL1620, are actually available (Watts, 2010). However, the study of each receptor's role has been facilitated with the development of several selective antagonists for both ETA receptors (e.g. atrasentan) (Jae et al., 2001) and ETB receptors (e.g. BQ‐788) (Ishikawa et al., 1994) and dual antagonists, like bosentan (Clozel et al., 1994) or more recently developed macitentan (Iglarz et al., 2008). ET‐1 has a similar affinity for both receptors (Arai et al., 1990; Sakurai et al., 1990). The intracellular pathways installed after ET‐1-induced ETA and ETB receptors activation involve the Gq, Gs and Gi small G proteins leading to stimulation of phospholipase C (PLC). The consecutive production of inositol triphosphate (IP3) and diacylglycerol (DAG) increases the concentration of intracellular calcium (Ca2+). Ca2+ is recruited from the reticulum by activation of the inositol triphosphate (IP3) receptor and external Ca 2+ influx is increased by opening of the Ca2+ channels on the cellular membrane (Simonson and Dunn, 1990). ETA and ETB receptors can have synergetic or opposing effects depending on cell type, tissue type or physiological situation. The

Effects of ET-1 on vascular tone

Introduction Generation of endothelin

Historically, ET-1 is a hormone responsible for the maintenance of the vascular tone. ETA receptors are expressed on vascular smooth muscle cells and ETB receptors on both endothelial and vascular smooth muscle cells (Fig. 1). 80% of ET-1 produced by endothelial cells (EC) diffuse through the basal side in the vascular wall and bind to both ETA and ETB receptors on smooth muscle cells, which leads to a vasoconstriction of the vessels (Wagner et al., 1992) (Fig. 1). Importantly, each vascular bed presents a different distribution of the receptors, which modulates the response to ET-1 (Calo et al., 1996). The binding of ET-1 to the ETA receptor activates the PLC. The increased production of IP3 promotes the mobilization of the reticular and extracellular Ca 2+ (Bkaily et al., 1995; Curtis and Scholfield, 2001). The Ca 2+ entry provokes a cascade of ion channel opening which tends to depolarize the smooth muscle cells. The opening of chloride channels and the inhibition of potassium channels consequently to the increase of intracellular Ca 2+ participate also to the ET-1 response. The activity of the Na +/H + exchangers plays a role in the ET-1-induced elevation of intracellular Ca 2+ too (Motte et al., 2006). In contrast, ET-1 which diffuses in the plasma activates ETB receptors on endothelial cells, which promotes endothelial nitric oxide synthase (eNOS) derived NO release through a

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Fig. 1. ET-1 expression, regulation and actions inside the vessel wall. NO = nitric oxide, eNOS = endothelial nitric oxide synthase, PLC = phospholipase C, sGC = soluble guanylyl cyclase, IP3 = inositoltriphosphate, cGMP = cyclic guanoside monophosphate, TNFα = tumor necrotic factor alpha, ANP = atrial natriuretic peptide, BNP = brain natriuretic peptide.

tyrosine kinase-dependent and a Ca 2+/calmodulin-dependent pathway. NO, in turn, reduces the concentration of intracellular Ca 2+ with concomitant vasodilation (Tsukahara et al., 1994) (Fig. 1). The ETB-induced vasodilation involves also cyclooxygenases, prostacyclins and voltage-dependent potassium channels (Tirapelli et al., 2005). In rats, infusion of exogenous ET-1 leads to a short vasodilation and decrease in blood pressure followed by a strong and lasting elevation of blood pressure (Yanagisawa et al., 1988). The initial vasodilation was later attributed specifically to the ETB receptor (McMurdo et al., 1994), while the contractile effect is the result of the activation of both receptors (Pernow and Modin, 1993). Selective blockade of ETA receptors enhances NO-mediated vasodilation (Verhaar et al., 1998; Prié et al., 1998; Barton et al., 1998) that can be acutely blocked by ETB receptor antagonists (Verhaar et al., 1998) whereas blockade of ETB receptors induces vasoconstriction (Pernow and Modin, 1993; Matsuura et al., 1997). Genetic deficiency of ET-1 slightly elevates blood pressure in mice (Kurihara et al., 1994), this hypertension is probably due to the renal effect of ET-1 discussed later. Systemic genetic overexpression of ET-1 or limited to the vasculature induces vascular dysfunction but does not impact blood pressure (Hocher et al., 1997; Amiri et al., 2004). A compensation of the functional antagonist of ET-1 nitric oxide may be responsible for the lack of hypertension in these mice (Hocher et al., 2004). However, mice in which ET-1 is deleted specifically in vascular EC are moderately hypotensive confirming the importance of ET-1 in vascular tone (Kisanuki et al., 2010). Other effects of ET-1 on the vasculature: growth and inflammation Beside its major role on vascular tone, ET‐1 possesses mitogenic effects on vascular smooth muscle cells. Proto-ocongenes are activated subsequently to the mitogen activated protein kinases (MAPK) cascades, under the control of ET-1 (Clerk et al., 2002). ET-1 is also responsible for fibroblasts proliferation (MacNulty et al., 1990) and induces cytokine production through the ETA receptor on macrophages (Ruetten and Thiemermann, 1997). In mice, genetic overexpression of

ET-1 in EC enhances oxidative stress due to increase NADPH oxidase activity, promotes vascular hypertrophy and induces a local inflammation characterized by macrophage infiltration (Amiri et al., 2008). After carotid ischemia, ET-1 from EC origin is responsible for inflammation through the elevation of adhesion molecule expression and for vascular smooth muscle proliferation leading to neointima formation (Anggrahini et al., 2009). These effects are associated particularly with pulmonary hypertension and atherosclerosis. ET-1 in the heart Inotropic effects of ET-1 Both ETA and ETB receptors are expressed throughout the cardiac muscle, including the coronary vasculature. Cardiomyocytes express predominantly ETA receptors while both receptors are equally represented on cardiofibroblasts (Fareh et al., 1996). Activation of the ETA receptor results in increased contractility (MacCarthy et al., 2000). In consequence, overexpression of ET-1 in mice reduces time of diastolic relaxation (Vignon-Zellweger et al., 2011). The molecular mechanisms mediating this positive inotropic effect include an increase in intracellular Ca 2+ concentration (Talukder et al., 2001). The activation of ETA receptors elevates the production of IP3 by the PLC, which results in reticular Ca 2+ recruitment. The L-type Ca 2+ channels, which are responsible for the main depolarizing current, provide the response to ET-1 after activation of ETA receptors, protein kinase C (PKC) and the Ca 2+/calmodulin kinase (Komukai et al., 2010). ET-1 induces an alkalization of the myocytes through an activation of the Na +/H + exchanger by a mechanism involving the DAG-stimulated PKC and tyrosine kinases. This alkalization increases the sensitivity of the myofilament to Ca 2+ (Endoh, 2006). The activity of the Na +/H + exchanger induces the activation of the Na +/Ca 2+ exchangers, which further increases intracellular Ca 2+. Superoxide produced by the NADPH oxydase activated by ET-1 may also participate to the activation of Ca 2+ channels (Zeng et al., 2008b). Endogenous

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Fig. 2. Actions of ET-1 on water and salt handling in the renal tubules. AQP2 = aquaporin 2, AC = adenylate cyclase, PKC = protein kinase C, MAPK = mitogen-activated protein kinases, eNOS: endothelial nitric oxide synthase, ENaC = sodium channel, PGE = prostaglandin.

ET-1 is also responsible for the positive inotropic effect of angiotensin II via the production of reactive oxygen species (Cingolani et al., 2006). In the mouse heart, endogenous ET-1 may increase and decrease contractility via ETA and ETB receptors, respectively (Piuhola et al., 2003a). Moreover, the actual knowledge suggests that the effects of endogenous ET-1 may differ depending on the pathological situations. ET1 has been showed to induce a negative inotropic effect reportedly after activation of ETB receptors and consecutive activation of Na +/Ca2+ exchangers (Nishimaru et al., 2007). This may be the case in the failing heart, where Na+/Ca 2+ exchanger are overexpressed (Namekata et al., 2008). In order to investigate the local effect of ET-1 on the cardiac muscle independently from systemic effects on the vasculature, intracoronary injection of the ETA receptor antagonist BQ-123 has been used. This experimental setting revealed that, in healthy humans, the positive inotropic effect of ET-1 is rather modest and that in patients with heart failure, blocking endogenous ET-1 actions on ETA receptors tends to increase contractility (MacCarthy et al., 2000). In the normal isolated rat heart, bosentan has no effect on contractility but decreases systolic function in hypertrophic hearts (Piuhola et al., 2003b). Hypertrophic and profibrotic effects of ET-1 ET-1 promotes cardiac hypertrophy via several pathways. The binding of ET-1 to ETA receptors induces the dissociation of small G

proteins, the activation of PLC and production of IP3 and DAG in myocytes (Shubeita et al., 1990). In response to ET-1, mainly PKCδ and PKCε are activated by DAG. PKC provokes the exchange of GDP to GTP from the small G protein Ras, which can thus activate the protein kinase cascade Raf-MKK1/2-ERK1/2 (Bogoyevitch et al., 1994). Finally, ERK1/2 promotes the transcription of the genes coding for early response transcription factor, which causes hypertrophy (Marshall et al., 2010). Ion exchangers mediate also the hypertrophic response of the heart to ET-1 (Dulce et al., 2006). The vascular endothelial growth factor and tumor growth factor-beta pathways participate in the hypertrophic response of myocytes to endothelin-1 treatment (Shimojo et al., 2006, 2007). ET-1 induces thus myocardial hypertrophy and is overexpressed in case of heart failure. The long-term blockade of ET-1 actions improves the survival rate in a rat model for chronic heart failure (Sakai et al., 1996). We reported that these beneficial effects include the prevention of the alteration in the expression of the genes coding for the angiotensin-converting enzyme, angiotensin II type 1 receptor among others (Sakai et al., 2000). Using cultured cardiomyocytes and rats with aortic bandinginduced cardiac hypertrophy, we have shown that the transcription of the ET-1 gene is regulated by PPARα, the phorbol-ester-sensitive c-fos and c-jun complexes, the nuclear factor-1, AP-1, and GATA proteins (Irukayama-Tomobe et al., 2004). Additionally, fibroblasts express ET-1, which induces their growth via the ETA receptor. This

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mechanism can be induced and suppressed by angiotensin II and natriuretic peptides, respectively (Fujisaki et al., 1995). We have showed that ET-1 from EC may be responsible for the induction of fibroblasts formation in the failing diabetic heart (Widyantoro et al., 2010). Finally, genetic ECE-1 inhibition in mice reduces doxorubicin-induced cardiomyopathy by a prevention of mitochondrial dysfunction (Miyagawa et al., 2010).

Cardio-protective properties of ET-1 On the other hand, some animal models revealed a rather neutral role for cardiac ET-1. For instance, mice lacking the ETA receptor in cardiomyocytes develop normally and do not present a modified cardiac hypertrophic response to stress (Kedzierski et al., 2003). This in line with observations from our group, which indicate that ET-1 from EC is not required for afterload-induced cardiac hypertrophy in mice (Heiden et al., unpublished). Importantly, myocardial ET-1 depicts beneficial effects depending on the physiological situation. In the myocardium, ET-1 may prevent excessive apoptosis after cardiac overload induced by aortic banding (Zhao et al., 2006). Signaling of the antiapoptotic effects of ET-1 involves calcineurin, the mitochondrial function and the classical MEK1/2-ERK1/2 and PI3 kinase pathways (Iwai-Kanai and Hasegawa, 2004). We reported that ET-1 prevents the early phase of doxorubicin-induced cytotoxicity via the upregulation of the antioxidant manganese superoxide dismutase through the ETA receptor in cultured cardiomyocytes (Suzuki and Miyauchi, 2001). Preconditioning infusion of ET-1 can reduce infarct size in rats subjected to ischaemia/reperfusion (Gourine et al., 2005). The transgenic expression of ET-1 in mice lacking a functional gene for eNOS restores diastolic function presumably through modulation of oxidative stress and a change of metabolic substrate (Vignon-Zellweger et al., 2011). In line with this, the enhanced glycolysis in the failing heart, which is a beneficial compensatory mechanism, is accompanied by a hypoxia-inducible factor-1α dependant elevation of ET-1 expression (Kakinuma et al., 2001).

Clinical use of endothelin antagonists in heart failure Taken together, cardiac ET-1 induces numerous cellular responses which may be contradictory depending on the situations. On the light of this, one may guess the reasons why treatment with either bosentan, tezosentan, enrasentan or darusentan did not improve outcome in chronic heart failure patients (Mylona and Cleland, 1999; O'Connor et al., 2003; Anand et al., 2004; Battistini et al., 2006). In these clinical studies, the patients were receiving already recommended doses of classical drugs (angiotensin-converting-enzyme inhibitors, angiotensin receptor antagonists, β-blockers, aldosterone antagonist, or spironolactone). These treatments may have masked the effects of endothelin antagonists. Whether treatment with endothelin receptor antagonists alone may present a favorable effect is currently questionable. Nevertheless, heart failure patients receiving these various endothelin antagonists suffered from an even higher number of adverse events. These side effects could have possibly been prevented by the use of lower doses but this question has already been addressed for bosentan unsuccessfully (Kalra et al., 2002). In most of these studies, the patients were severely affected (NYHA classes III–IV) and endothelin antagonists may be effective in the early phases of the pathology only. Moreover, this category of patients is very sensitive to drugs having strong hemodynamic effects like endothelin antagonists. Finally, the cardio-protective properties of ET-1 discussed earlier might account for the results of these studies. In spite of these disappointing clinical results, the question whether chronic blockade of the endothelin system might be beneficial in particular cardiac conditions remains open.

ET-1 in the kidney ET-1 in the renal vasculature Similarly to the rest of the vasculature, ETA receptors are present on both smooth muscle cells and EC while ETB receptor expression is restricted to EC in the kidney (Wendel et al., 2006) (Fig. 3). Physiological doses of ET-1 contribute to renal hemodynamics and regulate thereby glomerular pressure (Qiu et al., 1995). Whether ET-1 contracts predominantly afferent or efferent arterioles and thereby controls glomerular filtration rate (GFR) remains disputed. Seminal studies showed that ET-1 sensitivity is relatively greater in afferent than in efferent arterioles and ET-1 thus may reduce GFR (Edwards et al., 1990). In isolated cortical arterioles from ETB receptor deficient mice, the ETA receptor participates to afferent and efferent arterioles contraction whereas ETB receptor activation in wild type (WT) mice has no effect in cortical afferent arterioles but induces NO-mediated vasodilatation in efferent arterioles (Schildroth et al., 2011). ET-1 constricts therefore preferentially afferent arterioles and diminishes GFR. Consistently, infusion of ET-1 slightly reduces GFR in humans too (Vuurmans et al., 2004). Denton et al. showed that infusion of ET-1 constricts both afferent and efferent arterioles without modifying GFR but increasing filtration fraction, which may suggest an increased glomerular pressure (Denton et al., 2004). ET-1 effect on the resistance of efferent vessels might be stronger because of their smaller diameter. Moreover, specific ETA receptor blockade elevates renal plasma flow, reduces filtration fraction, possibly reduces glomerular pressure but does not affect GFR in patients with chronic kidney disease (Goddard et al., 2004; Dhaun et al., 2007). Again, this points to a preferential constrictor effect of ET-1 on efferent arterioles. The inconsistent observations regarding the constrictor actions of ET-1 in afferent and efferent arterioles may be explained by different experimental set-up (isolated arterioles vs. in vivo infusion studies) and species related differences (mouse, rabbit or humans). An actual consensus would be that ETA and ETB receptors on cortical afferent arterioles have constrictor effects whereas ETB receptors on efferent arterioles are rather dilator. In a rat model of renovascular hypertension in which the renal artery of one kidney is clipped in order to decrease blood supply to the kidney, chronic ETA receptor blockade increases ischemia-induced fibrosis in the clipped kidney. In this particular case, ETA receptor blockade – like angiotensin-converting-enzyme inhibition – may further reduce perfusion pressure, which leads to more severe ischemia (Hocher et al., 2000). However, ET-1 generally tends to reduce renal blood flow mainly through the ETA receptor (Evans et al., 2001; Denton et al., 2004). ETB receptors on EC counter the effect of ETA receptors and participate in tonic vasodilation via activation of eNOS and release of prostaglandins (Matsuura et al., 1997). However, ETB receptor antagonists have little effect on renal blood flow and GFR in rodents and humans (Evans et al., 2001; Dhaun et al., 2007). Unlike in the cortical nephrons, ETB receptors on both afferent and efferent arterioles of perfused juxtamedullary nephrons mediate constriction under normal conditions (Inscho et al., 2005). In the same in vitro system, a high salt diet increases ETB receptor expression and ETB receptors mediate then vasodilation in afferent arterioles (Schneider et al., 2007). Renal infusion of ET-1 which reduces cortical blood flow has no effect on medullary blood flow, even though juxtamedullary arterioles diameter is reduced. A reason for this is the smaller impact of ET-1 on the resistance of juxtamedullary vessels compared to cortical arterioles, in regard to their bigger resting diameter. Moreover, juxtamedullary arterioles may affect medullary blood flow only marginally (Denton et al., 2004). The vasa recta are branches of efferent arterioles which perfuse the renal medulla. Regulation of vasa recta contraction plays therefore a major role in medullary blood flow, water and sodium retention. In the vasa recta, ETB receptors are expressed on EC and ETA receptors on the

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Fig. 3. The endothelin system in the glomerulus and possible intercellular actions of ET-1.

pericytes (Wendel et al., 2006) (Fig. 2). ET-1 is a potent constrictor of the isolated vasa recta mostly through an ETA receptor pathway (Pallone and Silldorff, 2001). This occurs through the depolarization of pericytes consecutive to inhibition of potassium channels. ET-1 could in this way reduce renal medullary blood flow (Cao et al., 2005). Nevertheless, after intravenous injection in rats, ET-1-induced production of NO and prostaglandin dilates the vasa recta and thereby elevates medullary blood flow (Rubinstein et al., 1995). This observation is confirmed by the fact that ETB receptor blockade prevent ET-1-induced elevation of medullary blood flow (Evans et al., 2001). In conclusion, ET-1/ETA contributes to constriction of glomerular arterioles and reduces renal and cortical blood flow. ET-1 tends to enhance medullary blood flow mainly through the ETB receptor, which participates in tonic renal vascular dilatation. ET-1 in the tubular system ET-1 controls channels activity and inhibits salt reabsorption Proximal tubule. In the rat proximal tubule, ETB receptors, but not ETA, are expressed and it modulates sodium excretion. ET-1 facilitates natriuresis, by inhibiting the Na +/K +-ATPase after activation of ETB receptors and consequent enhancement of Ca 2+ recruitment (Liu et al., 2009). On the other hand, ETB receptors in the proximal tubule increase the activity of the Na +/H + exchanger 3 (Laghmani et al., 2001) and Na +-citrate cotransporter (Liu et al., 2010) which may counteracts the effect toward the Na +/K +-ATPase. This phenomenon seems particularly relevant in the context of acidosis, during which ET-1 expression by the proximal tubule is enhanced. Henle's loop. ET-1 expression is relatively low in the thin limb segments of Henle's loop (Moridaira et al., 2003). In ascending and descending thin limbs, the expression of ETA and ETB receptors is disputed depending on the species. The presence of a functional ETA-induced Ca 2+ signaling, which may be involved in blood pressure regulation, has been revealed in the rat thin descending limb (Bailey et al., 2003). In rats, recent immunohistochemical studies showed however no receptor expression at all in this part of the nephron (Wendel et al., 2006; Yamamoto et al., 2008).

In the medullary thick ascending limb (TAL), ET-1 expression increases with osmolality. The ETB receptor is the only receptor in the TAL. It inhibits sodium reabsorption through the activation of phosphatidylinositol 3-kinase (PI3K), Akt/Protein kinase B (AKT) and eNOS, and consecutive elevation in NO production which inhibits the Na +/K +/Cl - cotransporter (Herrera et al., 2009). In the cortical TAL of rats, the ETB receptor activation elevates Ca 2+ concentration and NO production which participates to the inhibition of chloride reabsorption (Plato et al., 2000) (Fig. 2). Collecting duct. The collecting duct (CD) shows the highest density of ETB receptors and the strongest ET-1 expression compared to other cell types but expresses low amount of ETA receptors (Moridaira et al., 2003). Activation of ETB receptors on the epithelial cells of the CD inhibits sodium reabsorption (Fig. 2). ET-1 prevents the activation of the Na+/K +-ATPase in the CD presumably because of an enhanced ETB-induced cyclooxygenase activity and prostaglandin production (Zeidel et al., 1989). Secondly, ET-1 regulates the activity of the epithelial sodium channel (ENaC). In the long term, ET-1 inhibits the opening probability of ENaC by promoting the guanine exchange factor βpix to bind the 14-3-3 protein. This prevents the binding of the latter with nedd4-2 protein, which is required for ENaC activation (Pavlov et al., 2010). In a rapid fashion, ET-1 induces via the ETB receptor a src kinase dependent MAPK1/2 activation, which may modify directly the phosphorylation status of ENaC. This mechanism does not required PLC or protein kinase C and may rely specifically on the ETB receptor (Bugaj et al., 2011). Finally, eNOS and inducible NOS (iNOS) are both involved in the inhibition of sodium reabsorption mediated by ET-1 (Fig. 2). In cells from the inner medullary CD, ET-1 enhances the neuronal NOS (nNOS) activity via the ETB receptor (Stricklett et al., 2006). eNOS and nNOS activity is reduced in the CD isolated from ETB-KO mice, but ETA receptors may be able in these mice to promote nNOS expression (Sullivan et al., 2007). Finally, the activity of both eNOS and nNOS is lower in CD specific ET-1 deficient mice and this is accompanied by sodium retention (Schneider et al., 2008). Taken together, both ETA and ETB receptors from the CD prevent sodium reabsorption. Effects of tubular ET-1 on blood pressure; experiments in animal models. ETB-KO mice develop salt-sensitive hypertension without endothelial

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dysfunction (Quaschning et al., 2005). Accordingly, ETB receptor deficiency in EC does not modify blood pressure, on neither normal nor high salt diet (Bagnall et al., 2006). Interestingly, female ETB-KO rats are normotensive but the high salt diet-induced elevation of blood pressure is stronger than in males (Taylor et al., 2003). The protective ETB/ eNOS pathway has a stronger effect in females than in males and may be responsible for this phenotype (Chappell et al., 2003). To note, renal ETA receptor expression is diminished in ETB-KO mice. This could result from an enhanced tissue level of ET-1 consecutive to a reduced ET-1 clearance by ETB receptors (Schildroth et al., 2011). The generation of CD specific deficient mice for ET-1, ETB, ETA and combined ETA/ETB receptors revealed that CD-ET-1 is necessary for maintaining normal blood pressure in vivo. Except CD-ETA KO, all strains are hypertensive suggesting that the ETB receptor alone is responsible for BP regulation. These results confirmed the predominant role of the ETB receptor in inhibition of sodium reabsorption. Nevertheless, deletion of the ETB receptor alone leads to a smaller elevation of arterial BP (10 mmHg) compared to CD-ET-1-KO and combined ETA/ETB-KO (20 mmHg) (Ge et al., 2008). Under high salt diet, blood pressure further increases in CD-ET-1 KO mice and, if rather modestly, in CD-ETB-KO mice too (15 and 5 mmHg higher than under normal diet, respectively), while BP remains unchanged in WT and CD-ETA-KO mice. In combined CD-ETA/ETB KO mice, blood pressure reaches the level of CD-ET-1 KO mice after four days high salt diet (Ge et al., 2008). Using ETB receptor deficient rats, Nakano et al. revealed that ETA receptors can induce natriuresis independently of its hemodynamic effects through the activation of nNOS in CD (Nakano and Pollock, 2009). See that ETB receptors show a much higher density compared to ETA receptors in the CD, absence of the latter alone may not change CD physiology. ETA receptors may regulate sodium reabsorption at least in the absence of ETB receptors. The question whether this effect is due to chronic gene deletion remains open. Because response to high salt diet in CD-ET-1 KO mice is different than in combined CD-ETA/ETB KO mice, CD-ET-1 may act on adjacent structure. This is in line with the lower BP observed in single KO compared to CD-ET-1 KO mice under high-salt diet (Ge et al., 2006, 2008). Hypotensive effect of furosemide in CD-ET-1 KO mice and amiloride in CD-ET-1 KO mice and ETB-KO rats confirm the role of ET-1/ETB on the activity of Na +/K +/Cl − cotransporter and ENaC channel, respectively (Gariepy et al., 2000; Ahn et al., 2004). In conclusion, ETB and probably ETA receptors as well are responsible for braking salt reabsorption. ET-1 antagonizes vasopressin actions and regulates blood volume ET-1 controls water handling in the CD, but not in the TAL. In perfused CD, it was first demonstrated that the vasopressin (AVP)-induced elevation of water permeability was inhibited by ET-1. ET-1 reduces cAMP concentration, independently of prostaglandin but dependent on PKC; this effect is specific to ETB activation (Kohan et al., 1993). Using the ACcAMP-PKA pathway, activation of vasopressin receptor 2 (V2R) phosphorylates ETB receptors and provokes its internalization. In a long term, the same pathway can reduce ETB expression (Wong et al., 2000) while ET1/ETB interaction increases V2R expression (Wang et al., 2007). Furthermore, both aquaporin (AQP2) and V2R receptor expression is reduced by bosentan treatment (Wong et al., 2003). CD-ET-1 KO mice have an impaired ability to manage an acute water load. In these mice, the authors observed an elevated AVPinduced cAMP accumulation, which further proposes that ET-1 decreases AVP-induced adenylate cyclase (AC) activity (Ge et al., 2005a). Abundance of AC itself is enhanced in the CD of CD-ET-1 KO mice showing that CD-ET-1 exerts a diuretic effect by tonic repression of AC expression (Strait et al., 2007). Contrarily, CD-ETA KO reduces sensitiveness to AVP associated and AVP-induced cAMP accumulation, and increases diuresis after an acute water load. ETA receptors seem to oppose the effects of ETB receptors (Ge et al., 2005b). These data suggest that ETA receptors could moderate ET-1 predominant diuretic action, at least after hyperhydration. Given that ET-1 is

overexpressed in such situation, ETA receptors may compensate ET1/ETB-induced water loss. On the other hand, recent unpublished observations using a selective ETA receptor antagonist and tissue specific ETA receptor deficient mice suggest a diuretic role for CD-ETA. In conclusion, activation of ETB receptors inhibits AVP-induced AQP2 activity. ET-1 thereby facilitates diuresis. ETA receptors may attenuate this effect in stress situation. ET-1 in proliferative tubular disease In addition to its role in regulating water and salt reabsorption, ET-1 may participate in the development of tubular diseases through its mitogen and pro-fibrotic properties. The endothelin system is activated in polycystic kidney disease in animal models and humans (Song et al., 2009). Moreover, genetic overexpression of ET-1 in mice leads to spontaneous development of renal cysts (Hocher et al., 1997). In spite of this, the specific blockade of ETA or ETB receptors worsens the symptoms, while combined blockade had no effect in polycystic mice. In this model, ETB-activated pathway under ETA receptor blockade increases tubular cell proliferation, and ETA receptor pathway promotes interstitial inflammation and fibrosis after ETB receptor inhibition (Chang et al., 2007). In rats with inherited renal cystic disease, an ETA receptor antagonist treatment deteriorates renal condition as well (Hocher et al., 2003). ET-1-induced ischaemia could account for the deleterious effect mediated by ETB receptors under ETA receptor blockade (Kakinuma et al., 2001). This particular effect of ET blockade seems to be specific to cystic disease: in a proteinuric model, bosentan prevents tubulo-interstitial lesion and inflammation (Suzuki et al., 2001). ET-1 in the glomerulus The endothelin system is present throughout the glomerulus (Fig. 3) (Moridaira et al., 2003; Wendel et al., 2006) and is involved in both the normal function and pathophysiology of the glomerular filtration. Under diabetic conditions, the expression of the receptors remains stable (Watson et al., 2010) but ET-1 expression is enhanced in the glomerulus (Benigni et al., 1998). In mesangium (MG), ET-1 induces contraction, proliferation and extracellular matrix accumulation (collagen I, IV and fibronectin). This leads to glomerulosclerosis and kidney failure. Mice carrying an ET-1 transgene develop spontaneously glomerulosclerosis and renal fibrosis (Hocher et al., 1997). Importantly, the effects of AVP and ANGII on MG proliferation and extracellular matrix production are in part modulated by ET-1/ETA (Kuo et al., 2006; Tahara et al., 2008). The signaling pathways involved have been well documented. Activation of ETA receptors activates PLC which produces IP3 and DAG. DAG activates PKC which phosphorylates non-receptor tyrosine kinase Src and stimulates ras and thus proliferation (Mishra et al., 2005). IP3 promotes release of Ca 2+ from the reticular sarcomere. The tyrosine kinase Pyk2 is thus activated, mediates ET-1 signaling via p130Cas/BCAR3/rap1 and disturbs MG structure and function (Rufanova et al., 2009). ET-1 inhibits iNOS expression through ETA receptors. ETB receptor activation in turn enhances NO production (Owada et al., 1994). This effect is Ca 2+ dependent which excludes the involvement of iNOS. eNOS is present in MG under high glucose situation only indicating that nNOS may be the source of ETB-induced NO (Zhang et al., 2007). ET-1 induces epidermal growth factor receptor (EGFR) transactivation, which stimulates proliferative and profibrotic pathways involving Gαi, β1Pix, and ERK1/2 (Chahdi and Sorokin, 2010). Additionally, ERk5 may transactivate EGFR under the control of ET-1 (Dorado et al., 2008). ET-1 promotes also MG hypertrophy through a pathway implicating PI3K, AKT, NFAT4 and p8 proteins (Goruppi and Kyriakis, 2004). Podocytes represent the last layer of the glomerular filtration barrier and their cytoskeleton structure resembling foot process is essential for correct function. ET-1 destabilizes f-actin filaments in these cells and promotes nephrin shedding, which causes foot process effacement, podocytes detachment and ultimately proteinuria and glomerular

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disease (Fligny et al., 2011). A protein overload promotes cytoskeleton disassembly in podocytes and elevates ET-1 production, which, in turn, further destabilizes cytoskeleton arrangement of podocytes. The podocyte monolayer loses thereby its permeability and proteinuria develops (Morigi et al., 2005). In isolated glomeruli and in rats, an ETA receptor blockade can reduce albuminuria caused by an ET-1 infusion or hyperglycemia, independently of vasoconstriction (Saleh et al., 2010, 2011). The decrease of podocyte number induced by diabetes can be prevented by an ETA receptor blockade in rats (Gagliardini et al., 2009). Notably, these mechanisms may be induced by angiotensin but angiotensin-converting enzyme inhibition and ETA receptor blockade show additive protective effects, indicating ET-1 specific effects (Gagliardini et al., 2009). Changes in the structure of the podocytes caused by puromycin aminonucleoside, an in vitro model for podocyte damage, are prevented by blocking ETA receptor (but not ETB) in cultured podocytes. In agreement with this, a regression of glomerulosclerosis accompanied by better podocyte function can be observed after a chronic treatment with darusentan, an ETA antagonist, in aging rats (Ortmann et al., 2004). The reduction in proteinuria by ETA receptor antagonism is accompanied by changes of the glomerular basement membrane composition in experimental diabetes (Hocher et al., 2001). The presence of ETB receptors on the foot processes suggests a role in filtration (Yamamoto et al., 2002). In diabetic mice, the genetic deletion of ETB receptors worsens glomerulosclerosis and albuminuria. In this model, ETB receptor deficiency elevates ET-1 serum levels, which induce a strong hypertension under diabetic condition (Pfab et al., 2006). Within the glomerulus, the paracrine characteristic of ET-1 is certainly relevant because of the strong intercellular communication present in this structure (Coppo et al., 2010) (Fig. 3). For instance, ET-1 produced by glomerular EC may affect the structure of adjacent podocytes (Collino et al., 2008). Clinical use of endothelin antagonists in diabetic nephropathy In light of the aforementioned preclinical results, the use of endothelin antagonists has been considered for the treatment of kidney diseases, and particularly diabetic nephropathy. The largest phase III clinical trial to date testing an endothelin receptor, avosentan 25 and 50 mg/day, confirmed the anti-proteinuric potential of endothelin antagonists in diabetic nephropathy. However, this study has been stopped because treated patients developed fluid retention leading to heart failure (Mann et al., 2010). The selectivity of avosentan has been put into question earlier (Battistini et al., 2006). A recent study indicates that blocking specifically ETA receptors reduces proteinuria in chronic kidney disease patients receiving already an optimal treatment. On a short term (six weeks), these improvements were not accompanied by adverse side effects (Dhaun et al., 2011). Moreover, lower dose of avosentan (5–10 mg/day) may be sufficient to prevent albuminuria with a limited occurrence of fluid retention compared to higher dose (Wenzel et al., 2009). Finally, the use of diuretics should be permitted in the protocol of future clinical studies (Kohan et al., 2011). Another option to overcome the adverse side effects of endothelin antagonists due to their tubular effects might be endothelinconverting-enzyme/neutral endopeptidase inhibitors. These drugs are effective in reducing diabetes-induced kidney damage in rats (ThöneReineke et al., 2004). The increased ANP serum level and the consecutive elevated sodium excretion may counteract the tubular effects of pure endothelin receptor blockade. The prevention of organ damage is similar to the one provoked by angiotensin blockade, but presents the advantage to be blood pressure independent (Kalk et al., 2011). Conclusion ET-1 is a multifunctional hormone with complex effects on the renal, cardiac and vascular physiology. ET-1 is a strong vasoconstrictor while the activation of the endothelial ETB receptor induces the production of

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vasodilator NO. ET-1 has positive inotropic feature but has been shown to reduce contractility in disease state. ET-1 is overexpressed in the failing heart but may prevent apoptosis and restore cardiac function in stress situation. In the kidney, ET-1 is a diuretic and natriuretic hormone in which it antagonizes its vascular effect on blood pressure. The accumulating research in the endothelin field reveals further the complexity of this system but provides knowledge, which will most probably end up in the development of novel therapies. Conflict of interest statement No conflict of interest.

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