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Diabetic Endothelin B Receptor–Deficient Rats Develop Severe Hypertension and Progressive Renal Failure

Thiemo Pfab^*,, Christa Thöne-Reineke^*, Franziska Theilig, Ines Lange^*, Henning Witt^*,, Christiane Maser-Gluth^¶, Michael Bader^||, Johannes-Peter Stasch^**, Patricia Ruiz^*,, Sebastian Bachmann, Masashi Yanagisawa and Berthold Hocher^*

^* Center for Cardiovascular Research/Institute of Pharmacology and Institute of Anatomy, Charité Mitte, Department of Nephrology, Charité Campus Benjamin Franklin, Max Planck Institute for Molecular Genetics, and ^|| Max-Delbrück 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, Charité Mitte, Hessische Strasse 3-4, 10115 Berlin, Germany. Phone: +49-30-450-514098; Fax: +49-30-450-514938; E-mail: berthold.hocher{at}charite.de

Received for publication August 9, 2005. Accepted for publication January 18, 2006.

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.

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Copyright © 2009 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673