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ETA Receptor Blockade Induces Tubular Cell Proliferation and Cyst Growth in Rats with Polycystic Kidney Disease

Berthold Hocher^*, Philipp Kalk^*, Torsten Slowinski^*, Michael Godes^*, Alexander Mach^*, Sophia Herzfeld^*, Doreen Wiesner, Petra Clara Arck, Hans-H. Neumayer^* and Benno Nafz

Departments of *Nephrology and Physiology, and Biomedical Research Center, University Hospital Charité, Humboldt University of Berlin, D-10098 Berlin, Germany.

Correspondence to Priv. Doz. Dr. Berthold Hocher; Universitätsklinikum Charité der Humboldt Universität zu Berlin, Klinik für Nephrologie, Schumannstr. 20-21, 10098 Berlin, Germany. Phone: 49-30-450514098; Fax: 49-30-450514938;

ABSTRACT. Tissue concentrations of ET-1 are markedly elevated in the kidneys of Han:Sprague-Dawley (Han:SPRD) rats, a model of human autosomal dominant polycystic kidney disease (ADPKD). This study analyzed whether disease progression might be attenuated by endothelin receptor antagonists. Heterozygous Han:SPRD rats received an ETA receptor antagonist (LU 135252), a combined ETA/ETB receptor antagonist (LU 224332), or placebo for 4 mo. Glomerulosclerosis, protein excretion, and GFR remained unchanged, whereas interstitial fibrosis was enhanced by both compounds. BP was not reduced by both compounds in Han:SPRD rats. Renal blood flow (RBF) decreased in ADPKD rats treated with the ETA receptor antagonist. Long-term ETA receptor blockade furthermore increased markedly the number of renal cysts (ADPKD rats, 390 ± 119 [cysts/kidney section ± SD]; LU 135252-treated APKD rats, 1084 ± 314; P < 0.001), cyst surface area (ADPKD rats, 7.97 ± 2.04 [% of total section surface ± SD]; LU 135252-treated ADPKD rats, 33.83 ± 10.03; P < 0.001), and cell proliferation of tubular cells (ADPKD rats, 42.2 ± 17.3 [BrdU-positive cells/1000 cells]; LU 135252-treated ADPKD rats, 339.4 ± 286.9; P < 0.001). The additional blockade of the ETB receptor attenuated these effects in Han:SPRD rats. Both endothelin receptor antagonists had no effect on BP, protein excretion, GFR, and kidney morphology in Sprague-Dawley rats without renal cysts. It is concluded that ETA receptor blockade enhances tubular cell proliferation, cyst number, and size and reduces RBF in Han:SPRD rats. This is of major clinical impact because endothelin receptor antagonists are upcoming clinically used drugs. E-mail: berthold.hocher@charite.de

This article has been cited by other articles:

				T. Slowinski, P. Kalk, M. Christian, F. Schmager, K. Relle, M. Godes, H. Funke-Kaiser, H.-H. Neumayer, C. Bauer, F. Theuring, et al. Cell-type specific interaction of endothelin and the nitric oxide system: pattern of prepro-ET-1 expression in kidneys of L-NAME treated prepro-ET-1 promoter-lacZ-transgenic mice J. Physiol., June 15, 2007; 581(3): 1173 - 1181. [Abstract] [Full Text] [PDF]

				M.-Y. Chang, E. Parker, M. El Nahas, J. L. Haylor, and A. C.M. Ong Endothelin B Receptor Blockade Accelerates Disease Progression in a Murine Model of Autosomal Dominant Polycystic Kidney Disease J. Am. Soc. Nephrol., February 1, 2007; 18(2): 560 - 569. [Abstract] [Full Text] [PDF]

Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673