Gender-specific effects of endogenous testosterone: Female α-estrogen receptor-deficient C57Bl/6J mice develop glomerulosclerosis

Young female mice on a C57Bl/6J (B6) background are considered glomerulosclerosis (GS)-resistant but aging B6 mice develop mild GS. Estrogen deficiency accelerates while estrogen replacement retards GS in young sclerosis-prone oligosyndactyly mutant mice on an ROP background. To explore the effects of sex hormones on glomerular structure and function in the context of gender and genetic background, we studied mice in which the estrogen-receptor (ER) genes α- or -β were deleted (α- or βER knockout (KO) and crossed into the B6 background. We also studied ovariectomized (Ovx) B6 mice given testosterone. Male and female βERKO and male αERKO mice had no glomerular dysfunction at 9 months of age; however, αERKO female mice displayed albuminuria and GS. Ovx prevented glomerular dysfunction in αERKO female mice by eliminating endogenous testosterone production while exogenous testosterone induced GS in Ovx B6 mice. Androgen receptor (AR) expression and function was found in microdissected glomeruli and cultured mesangial cells. Testosterone compared to placebo increased both AR expression and TGF-β1 mRNA levels in glomeruli isolated from female B6 mice. Estrogen deficiency had no deleterious effects on the glomeruli in B6 mice. Our study shows that genetic traits strongly influence the GS-promoting effects of estrogen deficiency while testosterone induces GS in a gender-specific manner.