Original Paper Nephron 2001;87:161–169 Effects of Endothelin Receptor Antagonists on the Progression of Diabetic Nephropathy Berthold Hocher a,c Anja Schwarz a,c Daniel Reinbacher c Jaqueline Jacobi a Andreas Lun b Friedrich Priem b Christian Bauer c Hans-H. Neumayer a Manfred Raschack d Departments of a Nephrology and b Clinical Biochemistry, Charité, Humboldt University of Berlin, c Institute of Molecular Biology and Biochemistry, Free University of Berlin, and d Department of Cardiovascular Pharmacology, Knoll AG, Ludwigshafen, Germany Accepted: May 8, 2000 PD Dr. Berthold Hocher Universitätsklinikum Charité der Humboldt Universität zu Berlin Department of Nephrology, Schumannstrasse 20–21 D–10098 Berlin (Germany) Tel. +49 30 2802 5979, Fax +49 30 2802 8471, E-Mail berthold.hocher@rz.hu-berlin.de ABC Fax + 41 61 306 12 34 E-Mail karger@karger.ch www.karger.com © 2001 S. Karger AG, Basel 0028–2766/01/0872–0161$17.50/0 Accessible online at: www.karger.com/journals/nef Key Words Diabetic nephropathy W Endothelin receptor antagonists W Streptozotocin 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 endothe- lin (ET)-1. ETs are – beside its potent vasoconstrictor properties – very potent profibrotic acting paracrine hor- mones 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 glomer- ular collagen type I, III and IV as well as on fibronectin and laminin by quantitative immunohistochemistry us- ing a computer-aided image analysis system. Global glo- merular matrix deposition was analyzed after PAS stain- ing. 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 mate- rial 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 antago- nists, whereas protein excretion was only reduced by about 50% as compared to diabetic rats without treat- ment. Conclusion: The present study indicates that ETA receptor antagonists as well as combined ETA/ETB re- ceptor antagonists reduce proteinuria and completely normalize the renal matrix protein expression in hyper- glycemic rats with streptozotocin-induced diabetes. The antifibrotic effect seems to be mediated via the ETA receptor. ET receptor antagonists might be a new ap- proach in the treatment of diabetic nephropathy. Copyright © 2001 S. Karger AG, Basel Introduction Diabetic nephropathy is the leading cause of end-stage renal disease (ESRD) in western societies and accounts for 30–35% of patients on renal replacement therapy in Europe. Insulin-dependent diabetes mellitus (IDDM) and non-insulin-dependent diabetes mellitus (NIDDM) affect