Gender and the effect of gonadal hormones on the progression of inherited polycystic kidney disease in rats

Abstract

Human autosomal dominant polycystic kidney disease (ADPKD) is a common inherited disease and displays a gender dimorphism in renal disease progression. Han:SPRD-Cy rats manifest a form of ADPKD that is similar in many respects to that seen in humans. In Han:SPRD rats, male Cy/+ rats have more prominent renal changes and develop renal failure at an early age, whereas female Cy/+ rats exhibit less severe renal cystic change and have normal renal function until advanced age. To determine whether the male gonadal hormone, testosterone, contributes to this gender dimorphism, males were sham operated or castrated; some castrated rats were repleted with 5a-dihydrotestosterone. Female rats were sham operated or ovariectomized before sham operation or testosterone treatment. All treatments started at 4 weeks of age and ended at 10 weeks of age. Renal enlargement, cystic change, and renal function were assessed. In the males, castration reduced renal enlargement and cystic change; testosterone treatment abrogated these effects. Neither of these manipulations affected azotemia in male Cy/+ rats. In the females, testosterone was renotropic for both normal and cystic kidneys. In the Cy/+ females, testosterone treatment caused azotemia and an increase in the severity of the PKD. Ovariectomy blunted the effect of testosterone on cystic kidney enlargement. Testosterone treatment did not completely erase the gender-associated differences in azotemia in the Cy/+ rat. These data confirm the renotropic effects of testosterone and indicate that testosterone influences the progression of renal cystic change in male and female rats with ADPKD.