Renoprotective Effects of ETA Receptor Antagonists Therapy in Experimental Non-Diabetic Chronic Kidney Disease: Is There Still Hope for the Future?

Abstract

Chronic kidney disease (CKD) is a life-threatening disease arising as a frequent complication of diabetes, obesity and hypertension. Since it is typically undetected for long periods, it often progresses to end-stage renal disease. CKD is characterized by the development of progressive glomerulosclerosis, interstitial fibrosis and tubular atrophy along with a decreased glomerular filtration rate. This is associated with podocyte injury and a progressive rise in proteinuria. As endothelin-1 (ET-1) through the activation of endothelin receptor type A (ETA) promotes renal cell injury, inflammation, and fibrosis which finally lead to proteinuria, it is not surprising that ETA receptors antagonists have been proven to have beneficial renoprotective effects in both experimental and clinical studies in diabetic and non-diabetic CKD. Unfortunately, fluid retention encountered in large clinical trials in diabetic CKD led to the termination of these studies. Therefore, several advances, including the synthesis of new antagonists with enhanced pharmacological activity, the use of lower doses of ET antagonists, the addition of diuretics, plus simply searching for distinct pathological states to be treated, are promising targets for future experimental studies. In support of these approaches, our group demonstrated in adult subtotally nephrectomized Ren-2 transgenic rats that the addition of a diuretic on top of renin-angiotensin and ETA blockade led to a further decrease of proteinuria. This effect was independent of blood pressure which was normalized in all treated groups. Recent data in non-diabetic CKD, therefore, indicate a new potential for ETA antagonists, at least under certain pathological conditions.

Distinct Effects of Bosentan on NO-Dependent Vasodilation and Calcium Influx in Heterozygous Ren-2 Transgenic Rats on High-Salt Diet

“…When atrasentan (ET A receptor antagonist) was added to these RAS blockers, it did not influence the BP and hence the major vasoactive systems. However, it substantially decreased nifedipine-sensitive calcium influx through voltagedependent calcium channels (Vaněčková et al 2016). A similar reduction of calcium influx was also demonstrated in a study evaluating the effects of ET A receptor blockade alone showing a four-fold decrease of this parameter in heterozygous TGR on a high-salt diet.…”

“…There is some controversy on the superiority of the selective ET A over the nonselective (dual) ET A /ET B receptor blockade. Some authors favor the selective ET A blockers due to their antihypertensive, anti-inflammatory and antiproliferative effects, while others prefer the use of dual ET A /ET B endothelin receptor blockers (Vaněčková et al 2018). Our studies in Ren-2 transgenic rats have shown that atrasentan decreased blood pressure and reduced cardiac hypertrophy in both young and adult heterozygous as well as homozygous TGR.…”

“…While the reduction of NO-dependent vasodilation is understandable in the present study with bosentan, having in mind that ET B receptors mediate the endothelin effects on nitric oxide and cyclooxygenase production, the same finding with a selective ET A blockade was rather surprising. We cannot offer a satisfactory explanation for this finding but one should consider a possible interaction of both receptors, which has been recently described by Vercauteren et al (2017). These authors demonstrated that for fluid retention encountered during an endothelin ET A receptor blockade, the increased vascular permeability resulting from the concurrent activation of ET B receptors is responsible.…”

Unfavorable Reduction in the Ratio of Endothelin B to A Receptors in Experimental 5/6 Nephrectomy and Adenine Models of Chronic Renal Insufficiency

“…We previously found that the correction of the calcium-phosphate balance ameliorated renal and vascular pathophysiology in experimental CRI, possibly via suppressed renal and vascular RAS components [33][34][35]. There is a well-established link between the RAS and the ET-systems [5]. The present hyperuricemia had a minor increasing effect on ETB protein expression, but this was not reflected as changes in the ETB:ETA ratio in the kidney.…”

“…Promising experimental and clinical results suggest that, even on top of renin-angiotensin system (RAS) inhibition, selective endothelin receptor A (ETA) antagonists may improve the prognosis of CKD [2][3][4]. A recent review provided a comprehensive overview of the potential renoprotective effects of ETA antagonists [5].…”