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Androgen Receptor Pathway in Rats with Autosomal Dominant Polycystic Kidney Disease

Shizuko Nagao^*,, Masatomo Kusaka^*, Kazuhiro Nishii^*, Tohru Marunouchi, Hiroki Kurahashi, Hisahide Takahashi^* and Jared Grantham

^* Education and Research Center of Animal Models for Human Diseases, Divisions of Cell Biology and Molecular Genetics, Fujita Health University, Toyoake, Aichi, Japan; and The Kidney Institute, The University of Kansas Medical Center, Kansas City, Kansas

Address correspondence to: Dr. Jared J. Grantham, The Kidney Institute, Mail Stop 3018, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS 66160. Phone: 913-588-7607; Fax: 913-588-9251; E-mail: jgrantha{at}kumc.edu

Received for publication July 23, 2004. Accepted for publication April 5, 2005.

Androgens have been implicated in mediating disease escalation in autosomal dominant polycystic kidney disease (ADPKD). Dihydrotestosterone (DHT), an agonist, and flutamide (FLT), an antagonist, were administered to Han:SPRD rats with ADPKD, and the role of androgen receptor (AR) abundance and activation on the enlargement and function of cystic kidneys was evaluated. Renal AR abundance determined by immunoblots in 8- to 10-wk-old Cy/+ male rats was naturally increased four-fold above that of littermate +/+ controls. In male Cy/+, castration decreased AR abundance below control +/+ by –89.4%, and AR expression within cyst mural epithelial cells was strikingly decreased. Castration of Cy/+ male rats also reduced the usual increases in kidney weight by –49.7%, kidney cyst area by –34.0%, and serum urea nitrogen by –72.8%; these indices were restored to precastration levels by DHT. In Cy/+ male rats, FLT administration reduced the increase in kidney weight by –27.6% and serum urea nitrogen by –53.7% and decreased the increment in AR expression by –84.2% in comparison with untreated +/+ controls. There was no effect of FLT in female rats. Immunoblot expression of phospho–extracellular signal-regulated kinase 1/2 (P-ERK) and B-Raf, key intermediates in the mitogen-activated protein kinase pathway that are abnormally elevated in Cy/+, was unaffected by castration and/or administration of DHT or FLT. AR was not expressed in renal epithelial cell nuclei of androgen-deficient rats but was displayed in most tubule and mural cyst cell nuclei of androgen-replete rats. In androgen-deficient Cy/+, 80.6% of renal epithelial cells that had entered the cell cycle (proliferating cell nuclear antigen positive) also expressed P-ERK. In androgen-replete rats, proliferating cell nuclear antigen–positive cells co-expressed AR (12.7%), P-ERK (36.4%), and P-ERK + AR (45.0%); 5.9% were probably stimulated by other mitogenic mechanisms. It is concluded that androgens potentiate renal cell proliferation and cyst enlargement through ERK_1/2-dependent and ERK_1/2-independent signaling mechanisms in Han:SPRD. It is suggested that the basal rate of cell proliferation is determined by ERK_1/2 signaling to a major extent and that androgens have additive effects.

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