Pathophysiology of Renal Disease and ProgressionDiabetic Endothelin B Receptor–Deficient Rats Develop Severe Hypertension and Progressive Renal FailurePfab, Thiemo*, †; Tho[Combining Diaeresis]ne-Reineke, Christa*; Theilig, Franziska‡; Lange, Ines*; Witt, Henning*, §; Maser-Gluth, Christiane¶; Bader, Michael‖; Stasch, Johannes-Peter**; Ruiz, Patricia*, §; Bachmann, Sebastian‡; Yanagisawa, Masashi††; Hocher, Berthold* Author Information *Center for Cardiovascular Research/Institute of Pharmacology and ‡Institute of Anatomy, Charite[Combining Acute Accent] Mitte, †Department of Nephrology, Charite[Combining Acute Accent] Campus Benjamin Franklin, §Max Planck Institute for Molecular Genetics, and ‖Max-Delbru[Combining Diaeresis]ck Center for Molecular Medicine, Berlin, Germany; ¶Institute of Pharmacology, University of Heidelberg, Heidelberg, Germany; **Bayer AG, Wuppertal, Germany; and ††Howard Hughes Medical Institute, University of Texas, Dallas, Texas Address correspondence to: Prof. Berthold Hocher, Center for Cardiovascular Research/Institute of Pharmacology, Charite[Combining Acute Accent] Mitte, Hessische Strasse 3-4, 10115 Berlin, Germany. Phone: +49-30-450-514098; Fax: +49-30-450-514938; E-mail: [email protected] Accepted January 18, 2006 Received August 9, 2005 Journal of the American Society of Nephrology 17(4):p 1082-1089, April 2006. | DOI: 10.1681/ASN.2005080833 Buy Metrics Abstract The endothelin (ET) system has been implicated in the pathogenesis of diabetic nephropathy. The role of the ET-B receptor (ETBR) is still unclear. The effect of ETBR deficiency on the progression of diabetic nephropathy in a streptozotocin model was analyzed in four groups: (1) Homozygous ETBR-deficient (ETBRd) diabetic rats, (2) ETBRd rats, (3) diabetic controls, and (4) wild-type controls. BP and kidney function were measured for 10 wk, followed by biochemical and histologic analysis of the kidneys. The study demonstrates that ETBRd diabetic rats on a normal-sodium diet develop severe hypertension, albuminuria, and a mild reduction of creatinine clearance. The strong BP rise seems not to be caused by activation of the renin-angiotensin-aldosterone system or by suppression of the nitric oxide system. Elevated plasma ET-1, possibly reflecting a reduced ETBR-dependent clearance, seems to cause the severe hypertension via the ETA receptor. The results do not support the hypothesis that a reduction of ETBR activity inhibits the progression of diabetic nephropathy. The study demonstrates for the first time that the combination of diabetes and ETBR deficiency causes severe low-renin hypertension with progressive renal failure. Copyright © 2006 The Authors. Published by Wolters Kluwer Health, Inc. All rights reserved.