- Loss of endothelin B receptor function impairs sodium excretion in a time- and sex-dependent manner
- Endothelin in Renal Physiology and Disease : C. Ronco :
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Loss of endothelin B receptor function impairs sodium excretion in a time- and sex-dependent manner
Barton , D. Molecular Biology and Physiology of Endothelin in the Kidney. Author Index. Endothelin in Renal Physiology and Disease M. Endothelin-1 ET-1 , largely through activation of endothelin A receptors, has been strongly implicated in renal cell injury, proteinuria, inflammation and fibrosis leading to CKD.
This review summarizes the role of ET in CKD pathogenesis and discusses the potential therapeutic benefit of targeting the ET system in CKD, with attention to the risks and benefits of such an approach.
Endothelin in Renal Physiology and Disease : C. Ronco :
The global community is witnessing steadily increasing numbers of patients with chronic kidney disease CKD , with diabetes and hypertension accounting for the majority of cases 1 , 2. While multiple potential drug targets are in the development pipeline, the endothelin ET system has received particularly high attention. In addition, blocking specific ET system pathways holds the promise to be of significant therapeutic benefit in slowing CKD progression. However, due to the potential for side effects, use of endothelin system blockers must be undertaken carefully and judiciously.
Herein, we briefly describe the physiology and pathophysiology of the renal ET system, followed by review of clinical experience with ET blockers, their potential side effects, and finally discuss the future therapeutic potential of, and approach to, targeting the ET system in CKD. While ET-1 was originally described as an endothelium-derived vasoconstrictor 5 , it is now evident that the peptide is produced by and acts upon virtually every cell type in the body 6. In general, under healthy conditions, binding to ET A promotes vasoconstriction, cell proliferation and matrix accumulation; ET B activation is vasodilatory, antiproliferative and antifibrotic, however under some pathological conditions, ET B can promote tissue injury and scarring please see following sections.
These effects of ET-1, whether in health or disease, are primarily exerted through local binding, i. Endogenous renal ET is an important regulator of renal sodium and water excretion 7. Volume loading increases nephron ET-1 production which, largely through autocrine activation of thick ascending limb and collecting duct ET B leading to production of nitric oxide as well as other signaling molecules , inhibits sodium and water reabsorption 7.
Nephron, and particularly collecting duct, ET A also appears to exert a natriuretic effect 8 , 9 , however the mechanisms by which this occurs remain unclear.
Blockade of ET receptors is associated with fluid retention and, as will be described, this side effect has had significant clinical impact. Based on predicted ET-1 actions in the kidney, such fluid retention is perhaps not surprising.
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In support of a renal cause of fluid retention, recent studies in mice using two different relatively ET A -selective antagonists atrasentan and ambrisentan showed that the fluid retention was prevented by either nephron or collecting duct-specific deletion of ET A receptors 8.
Endothelin involvement in renal acid secretion may take on particular relevance in CKD. Acid loading increases renal ET-1 production which, in turn, stimulates proximal and distal nephron proton secretion; blockade of the ET system impairs normal renal acid excretion As will be discussed, acidemia that occurs in the setting of CKD promotes renal ET-1 production that, through promotion of pro-fibrotic pathways, may contribute to progressive deterioration of renal function.
Endothelin plays an important role in the development of proteinuria, fibrosis, and CKD progression 6.
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ET-1 promotes cell proliferation, hypertrophy, inflammation and extracellular matrix accumulation, all of which are important factors in progression of CKD 11 , Renal ET-1 production increases in conditions associated with renal disease progression, such as diabetes, insulin resistance, obesity, immune system activation, dyslipidemia, reactive oxygen species formation, nitric oxide deficiency and others reviewed in 11 , Figure 1. Infusion of non-pressor doses of ET-1 increases renal cortical inflammation ICAM-1, MCP-1 and macrophages 13 as well as podocyte effacement and urinary albumin excretion 14 , effects that are largely prevented by concomitant treatment with an ET A antagonist 13 , Endothelin-1 also increases formation of other vasoconstrictors and growth factors such as angiotensin II In turn, angiotensin II activates renal ET-1 formation 16 , thereby creating a positive feedback loop.
Of note, ET-1 also appears to be involved in the priming effect of acute ischemic renal injury on future CKD development, and this effect that can be largely prevented by blocking ET A Pathophysiological role of endothelin in CKD development. Intrinsic aging , physico-chemical acidemia, hypoxia , biochemical cytokines, oxidative stress, growth factors, procoagulants , metabolic insulin, hyperglycemia, dyslipidemia , vasoactive angiotensin II, aldosterone, vasoconstrictors , and pathological factors proteinuria enhance renal endothelin-1 ET-1 production.
CKD development is associated with increased formation of renal ET-1 which - primarily via ET A receptors — promotes renal injury and fibrosis through modulation of multiple renal cell types.
One aspect of ET activity in renal pathophysiology deserving of particular mention is podocyte involvement. Podocyte injury is a hallmark of proteinuric renal diseases and precedes the development of glomerulosclerosis 18 , In podocytes from humans and experimental animals, ET A has been primarily implicated in mediating cellular injury 18 , although preliminary data from the Tharaux laboratory suggest that, at least in mice, activation of podocyte ET B might also cause podocyte dysfunction The mechanisms by which ET-1 contributes to podocyte injury are not fully understood and are likely to be multifactorial.
Exposure to ET-1 in vitro disrupts the podocyte actin cytoskeleton 21 , 22 , while treatment with ERAs prevents disruption of the podocyte actin cytoskeleton in experimental focal segmental glomerulosclerosis FSGS Interestingly, exposure of podocytes to protein in vitro mimicking proteinuria in vivo induces synthesis of ET-1 and reduces glomerular permselectivity, an effect sensitive to ET A blockade 22 , Further, exogenous ET-1 chronically increases glomerular permeability via ET A -mediated mechanisms 14 , Benigni et al.
Since then, numerous preclinical ERA treatment studies have lent much support to the notion that endothelin, primarily via activation of ET A , contributes to renal disease progression under hypertensive as well as normotensive conditions Diabetes remains the predominant cause of CKD; the prevalence of diabetic nephropathy is likely to increase due to the obesity pandemic.
Numerous factors contribute to increased renal ET-1 production in diabetic nephropathy, however hyperglycemia is a particularly strong inducer of ET-1 production In podocytes, both hyperglycemia and endothelin cause disassembly of the podocyte actin cytoskeleton, apoptosis, and podocyte depletion 22 , These effects may be due, at least in part, to altered nephrin production since ET-1 triggers nephrin loss from human podocytes, an effect that is prevented by ET A antagonism Several studies report a beneficial effect of ERAs on diabetic nephropathy in experimental animal models 31 — Notably, the renoprotective effect of ERAs was not consistently associated with a fall in blood pressure 35 , suggesting that ET-1 contributes to diabetic renal injury via non-hemodynamic effects.
Hypertensive nephropathy is associated with increased renal ET-1 production Numerous preclinical studies have demonstrated nephroprotective effects of ERAs in various forms of hypertensive nephropathy, including angiotensin-II-dependent, renin-dependent, salt-loaded renin-dependent, aldosterone-induced, genetically salt-sensitive and deoxycorticosterone—salt-induced hypertension ERAs caused regression of hypertension-associated vascular hypertrophy and glomerulosclerosis in a model of NO-deficient hypertension 37 , Vaneckova et al.
These investigators demonstrated that ET A blockade not only delays renovascular CKD progression in swine with renal artery stenosis, but that ET A but not ET B antagonism induces regression of glomerulosclerosis and albuminuria independent of hypertension; CKD regression was associated with improved renal blood flow and improved cortical microvessel structure in the stenotic kidney 43 , Focal segmental glomerulosclerosis is a widely varying clinicopathological entity characterized by injury to the glomerular filtration barrier Podocyte-specific mechanisms have been proposed as underlying FSGS development 46 , In humans and rodents, aging is associated with spontaneous development of FSGS 46 , the susceptibility for which has recently been linked to autophagy-related mechanisms controlling podocyte vacuolization.
Ultrastructural and histological images demonstrating short-term effects of ERA treatment darusentan on aging-associated FSGS in the rat. Panels adapted 21 and reproduced with permission of the publisher. Systemic and renal ET-1 production is increased in the setting of CKD, regardless of the underlying cause of the renal disease.
http://daleem2.com/images/90/oerenci-devamszlk-takip-program.php Plasma ET-1 is increased by inflammation, vascular damage, lower renal clearance, acidosis and other factors, and directly correlates with urinary albumin excretion and the severity of CKD 52 , Plasma ET-1 is an independent predictor of vascular dysfunction in CKD patients, being associated with reduced flow-mediated brachial artery dilatation and increased carotid-femoral pulse wave velocity PWV Urinary ET-1 excretion, which reflects renal ET-1 production, is increased in every cause of CKD in which it has been studied, including diabetes, hypertension, glomerulonephritides, polycystic kidney disease and others 55 , In this regard, blockade of ET receptors increases urinary net acid excretion, renal ammoniagenesis, and serum bicarbonate in healthy human volunteers Taken together with the preclinical studies, the above findings suggest that ERAs may be of therapeutic benefit in slowing CKD progression.
In this same study, BQ, an ET B -selective antagonist, constricted the renal circulation and prevented BQinduced renal vasodilation, suggesting that ET B blockade may have deleterious effects on renal blood flow in CKD patients. All diabetic nephropathy was type 2. Avosentan decreased UACR by The most significant side effect was fluid retention that was greatest at the highest avosentan dose Thus, there was a possible small dose-dependent reduction in UACR of questionable significance, but potential adverse events associated with the 50 mg dose. Avosentan decreased ACR after a median follow-up of 4 months Importantly, another study published at the same time as the initial Phase 2 avosentan trial showed a clear dose-dependent reduction in fractional excretion of sodium between 0.
It was hypothesized that at the higher doses, avosentan may act on the ET B receptor to promote additional fluid retention 7. Taken together with the Phase 2 avosentan trial described above, it is apparent that the use of 25 and 50 mg avosentan doses in the ASCEND trial was ill-advised, particularly in patients with more advanced CKD who have a propensity towards fluid retention.
Sitaxsentan, but not the active comparator nifedipine, reduced proteinuria, while no clinically significant adverse events occurred. Atrasentan reduced ACR in the 0. This reduction in BP, and a possible consequent decrease in glomerular capillary pressure, however, is unlikely to fully explain the reduced ACR since the BP drop was not associated with a detectable decrease in eGFR; it raises the possibility that glomerular permeability was affected.
Patients received atrasentan 0. By repeated measures analysis, UACR did not change in the placebo group, but decreased by The edema was generally mild and there was no difference in diuretic usage between groups.
In this, as well as the other trials with atrasentan, patients were excluded if, among other criteria, they had a history of heart failure, were taking large doses of diuretics, or the BNP was elevated. In summary, Phase 2 trials using ET A -selective antagonists in patients with moderate CKD due to type II diabetes have shown significant reductions in albuminuria in the setting of maximal labeled-dose RAS blockade and at ERA doses that are generally well tolerated; an added benefit of improved lipid profile may also exist.
These studies raise the possibility that ET A antagonists, particularly in the setting of a multi-drug approach involving maximal tolerated RAS blockade, may be beneficial in treating CKD progression.
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The effect of daglutril, an inhibitor of endothelin converting enzyme ECE and neutral endopeptidase NEP the latter should increase natriuretic peptides, bradykinin and substance P , has now been assessed in type 2 diabetes patients with albuminuria Daglutril increased plasma big ET-1 levels, however plasma or urine ET-1 levels were not determined — the latter would be useful in determining how effectively ECE which has several isoforms 11 was inhibited.
This is now a very fast-moving field as indicated by recent publications and the tremendous need for therapeutics to treat acute and chronic kidney diseases. The Research Topic should have broad interest since it covers acute kidney injury, chronic kidney disease, diabetes, hypertension, metabolic syndrome, and renal physiology.
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