Effects of Endothelin Receptor Antagonists on the Progression of Diabetic Nephropathy

Abstract

Background: Diabetic nephropathy is the leading cause of end-stage renal disease in European countries and is associated with an enhanced renal synthesis of endothelin (ET)-1. ETs are – beside its potent vasoconstrictor properties – very potent profibrotic acting paracrine hormones especially in the kidney. Methods: We analyzed in rats with streptozotocin-induced diabetes the effects of an ETA-type (ETA) receptor antagonist (LU 135252) in comparison to a combined ETA/ETB receptor antagonist (LU 224332) on the expression of interstitial and glomerular collagen type I, III and IV as well as on fibronectin and laminin by quantitative immunohistochemistry using a computer-aided image analysis system. Global glomerular matrix deposition was analyzed after PAS staining. In addition to the morphometric examination of the kidneys, we also investigated GFR, urinary albumin and total protein excretion. The diabetic rats were treated for 36 weeks. Results: Treatment with either LU 135252 or LU 224332 normalized the amount of PAS-positive material within the glomeruli. The expression of glomerular fibronectin and type IV collagen was increased 36 weeks after induction of diabetes. The overexpression of these two matrix proteins within the glomeruli of diabetic rats was completely abolished by both ET receptor antagonists, whereas protein excretion was only reduced by about 50% as compared to diabetic rats without treatment. Conclusion: The present study indicates that ETA receptor antagonists as well as combined ETA/ETB receptor antagonists reduce proteinuria and completely normalize the renal matrix protein expression in hyperglycemic rats with streptozotocin-induced diabetes. The antifibrotic effect seems to be mediated via the ETA receptor. ET receptor antagonists might be a new approach in the treatment of diabetic nephropathy.

Endothelin Antagonists in Diabetic Nephropathy

“…9 Finally, several studies have shown that ET receptor antagonists ameliorate experimental diabetic nephropathy. 8,12,13 It is within this context that two In the experimental study, Lenoir et al 14 used a novel mutant mouse wherein podocyte-specific, double deletion of the ET A and ET B receptors was induced. They not only demonstrated that these mice were protected against diabetes-induced podocyte loss and the attendant glomerulosclerosis but also provide evidence that the ET B receptor may play as important a role as does the ET A receptor; this finding challenges the widely held notion that the deleterious effects of ET in diabetes are due to activation of the ET A receptor.…”

Avosentan Reduces Albumin Excretion in Diabetics with Macroalbuminuria

“…21 Antifibrotic effects of ERAs in experimental disease that reduce proteinuria, renal fibrosis, and survival are mainly ET A receptor mediated. 22,23 Macrophage infiltration in renal tissue and urinary TGF-␤ and prostaglandin E2 metabolites can be reduced using an ET A -selective antagonist, an effect that is associated with a reduction in albuminuria in rats with streptozotocin-induced diabetes. This indicates that the activation of renal ET A receptors mediates renal inflammation and TGF-␤ production in diabetes.…”

Endothelin-1 Gene Polymorphisms rs5370, rs1476046, and rs3087459 are not Associated with Diabetic Nephropathy in Caucasians with Type 2 Diabetes Mellitus

“…47 In contrast, blockade of ET-1 signaling revealed renoprotective effects in experimental models of DN, independent of blood pressure reduction 12 , with a decrease in proteinuria, and evidence of reduced glomerulosclerosis. 11 In addition, anti-infl ammatory effects of ET receptor antagonists resulted in reduced expression of intercellular adhesion molecule 1 and MCP-1 48 , as well as reduced renal monocyte infi ltration and expression of proinfl ammatory cytokines in different models of DN 49,50 . Atrasentan, a selective ETA receptor antagonist, was effi cacious in lowering residual albuminuria in subjects with T2DM on stable doses of RAS inhibitors.…”

“…8 Patients with T2DM have elevated systemic circulatory levels of ET-1, which correlate with markers of DN, such as hyperfi ltration, mesangial expansion, and albuminuria. 9,10 Importantly, several studies showed that ET receptor antagonists ameliorate DN in experimental models 11,12 and the results were confi rmed by subsequent clinical trials. [13][14][15] ET-1 has also been shown to play an important role in the pathogenesis of diabetic retinopathy, another major microvascular complication of diabetes.…”