Testosterone exacerbates obstructive renal injury by stimulating TNF-α production and increasing proapoptotic and profibrotic signaling

Upper urinary tract obstruction is a common cause of renal dysfunction in children and adults. While there is clinical evidence of an increased male incidence and mortality rate with acute renal failure, the effect of gender and testosterone on obstructive renal injury has not previously been evaluated. We hypothesized that testosterone exacerbates proinflammatory TNF-α production and proapoptotic and profibrotic signaling during renal obstruction, resulting in increased apoptotic cell death and tubulointerstitial fibrosis. To study this, male, female, castrated male, and testosterone-treated oophorectomized female rats were subjected to sham operation or 3 days of unilateral ureteral obstruction (UUO). Renal cortical tissue was then analyzed for TNF-α production; proapoptotic caspase-8, -9, and -3 activity; apoptotic cell death; profibrotic transforming growth factor-β1 production; and α-smooth muscle actin expression. In a separate arm, glomerular filtration rate (inulin clearance) was measured in rats ...