Effects of endothelin receptor antagonists on the progression of diabetic nephropathy

Background: Diabetic nephropathy is the leading cause of end-stage renal di sease in European countries and is associated with an enhanced renal synthe sis of endothelin (ET)-1. ETs are - beside its potent vasoconstrictor prope rties - 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 compari son 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 f ibronectin and laminin by quantitative immunohistochemistry using a compute r-aided image analysis system. Global glomerular matrix deposition was anal yzed after PAS staining. In addition to the morphometric examination of the kidneys, we also investigated GFR, urinary albumin and total protein excre tion. The diabetic rats were treated for 36 weeks. Results: Treatment with either LU 135252 or LU 224332 normalized the amount of PAS-positive materia l within the glomeruli. The expression of glomerular fibronectin and type I V collagen was increased 36 weeks after induction of diabetes. The overexpr ession of these two matrix proteins within the glomeruli of diabetic rats w as completely abolished by both ET receptor antagonists, whereas protein ex cretion was only reduced by about 50% as compared to diabetic rats without treatment. Conclusion: The present study indicates that ETA receptor antago nists as well as combined ETA/ETB receptor antagonists reduce proteinuria a nd completely normalize the renal matrix protein expression in hyperglycemi c 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. Copyright (C) 2001 S. K arger AG, Basel.