Androgen receptor pathway in rats with autosomal dominant polycystic kidney disease

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

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Abstract

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 phosphoextracellular 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 HaruSPRD. 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.

Original languageEnglish
Pages (from-to)2052-2062
Number of pages11
JournalJournal of the American Society of Nephrology
Volume16
Issue number7
DOIs
Publication statusPublished - 09-12-2005

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Autosomal Dominant Polycystic Kidney
Androgen Receptors
Androgens
Flutamide
Kidney
Cysts
Dihydrotestosterone
Phosphotransferases
Orchiectomy
Epithelial Cells
Proliferating Cell Nuclear Antigen
Cell Nucleus
Urea
Nitrogen
Cell Proliferation
Cystic Kidney Diseases
Weights and Measures
Castration
Mitogen-Activated Protein Kinases
Serum

All Science Journal Classification (ASJC) codes

  • Nephrology

Cite this

Nagao, Shizuko ; Kusaka, Masatomo ; Nishii, Kazuhiro ; Marunouchi, Tohru ; Kurahashi, Hiroki ; Takahashi, Hisahide ; Grantham, Jared. / Androgen receptor pathway in rats with autosomal dominant polycystic kidney disease. In: Journal of the American Society of Nephrology. 2005 ; Vol. 16, No. 7. pp. 2052-2062.
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abstract = "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 phosphoextracellular 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 HaruSPRD. 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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Androgen receptor pathway in rats with autosomal dominant polycystic kidney disease. / Nagao, Shizuko; Kusaka, Masatomo; Nishii, Kazuhiro; Marunouchi, Tohru; Kurahashi, Hiroki; Takahashi, Hisahide; Grantham, Jared.

In: Journal of the American Society of Nephrology, Vol. 16, No. 7, 09.12.2005, p. 2052-2062.

Research output: Contribution to journalArticle

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AU - Nagao, Shizuko

AU - Kusaka, Masatomo

AU - Nishii, Kazuhiro

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AU - Kurahashi, Hiroki

AU - Takahashi, Hisahide

AU - Grantham, Jared

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N2 - 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 phosphoextracellular 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 HaruSPRD. 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.

AB - 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 phosphoextracellular 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 HaruSPRD. 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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