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Antiprotenuric and renoprotective effects of combined blockade of angiotensin II – endothelin I, from experimental models to clinical practice

Alfons Segarra

Servicio de Nefrología Hospital Vall d'Hebrón
Barcelona

Es Spain

Abstract

Chronic proteinuric nephropathies that result in substantial damage of glomerular, structures, usually develop an inexorable progression to end-stage renal disease which is independent of the initial insult . Several experimental and clinical studies support that, in this circumstances , angiotensin II plays a major role in the development of progressive renal failure. Moreover, there is convincing evidence that both angiotensin II converting enzyme inhibitors and angiotensin II receptor antagonists exert beneficial effects on proteinuria and delay the progression of chronic renal failure. More recently , several experimental data have provided evidence that endothelin 1 can play a relevant role in progression of renal failure . Direct evidence for a causal role of ET-1 in renal fibrosis has been provided in transgenic mice overexpressing human ET-1 in the kidney. These animals develop glomerulosclerosis, tubulointerstitial fibrosis renal cysts, and reduction in GFR which indicates that increased intrarenal ET-1 production is enough to cause morphological and functional alterations characteristic of chronic renal failure. Furthermore, pre-clinical studies with endothelin receptor antagonists have demonstrated that these drugs can prevent renal fibrosis in several experimental models of renal disease. The beneficial effect of ET1 antagonists could be mainly due to their ability of reducing blood pressure, and decrease renal vascular resistance. Nevertheless, recent reports have demonstrated that ET1 blockade may reduce the synthesis of growth factors and extracellular matrix proteins which participate in renal sclerosis thus preserving renal function even in models without high blood pressure. It has been showed that ET receptor antagonists, that consistently reduce renal damage, do not invariably normalize proteinuria, strenghtening the hypothesis that excessive ET-1 is not a cause but rather a consequence of increased glomerular protein traffic. Ang II induces ET-1 transcription and secretion in vitro in endothelial and vascular smooth muscle cells and ET receptor antagonists attenuate the acute hemodynamic effects of Ang II in rats in vivo Moreover, ACE inhibition, by promoting the effects of bradykinin and ET-1 acting on endothelial ETB receptors both enhance endothelium-dependent vasodilation. The mechanisms by which the association of ET and Ang II antagonism results in a marked systemic and renal vasodilatory response are not well known. Vascular studies in healthy people suggest that these vasodilator effects of ETA receptor antagonism are dependent on the unblocked ETB receptor and NO generation However, in patients with chronic renal failure, a significant decrease of both systemic and renal vascular resistance has also been observed by dual ET blockade. Early studies showed that ETA receptor antagonism, but not non-selective ETA/B receptor blockade, increases renal blood flow and reduces renal vascular resistance , effective filtration fraction (EFF) and proteinuria in CKD patients, supporting a role for the ETA receptor in the increased renal vascular tone seen in CKD. More recent studies have shown that systemic nonselective ETA/B receptor blockade leads to systemic vasodilation , reduces EFF and lowers BP in patients with CKD. This hemodynamic changes could be useful clinically in treating the hypertension associated with CKD. Furthermore, the potentially anti-atherogenic properties of ET receptor antagonists could be useful in reducing the high cardiovascular morbidity and mortality observed in CKD patients.

Data of animal studies indicate that concomitant ET blockade and angiotensin-converting enzyme (ACE) inhibition produce changes greater than those seen with blockade of either system . Additionally, there is experimental evidence that combined administration of ACE inhibitors and ET1 receptor antagonists could prevent renal damage even better than each drug in monotherapy. Overall, these evidences raise the question as the combined blockade of ET 1 and Ang II would preserve better renal function than angiotensin II blockade alone in the clinical practice.

Our hypothesis is that in patients with proteinuric chronic nephropathies, the association of the dual ET inhibitor bosentan to ACEI would potentiate the renal vasodilatory and antiproteinuric effects of ACEI .

We report the results of experimental and clinical studies showing and additive or synergistic renal and systemic vasodilatory and antiproteinuric effect between dual ET receptor antagonism and ACE inhibition in patients with proteinuric chronic nephropathies and we analyze the mechanisms by which such an interaction might occur.

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