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

Abstract

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-␣ 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-␣ production; proapoptotic caspase-8, -9, and -3 activity; apoptotic cell death; profibrotic transforming growth factor-␤1 production; and ␣-smooth muscle actin expression. In a separate arm, glomerular filtration rate (inulin clearance) was measured in rats pre-and post-UUO. Male and testosterone-treated oophorectomized female rats demonstrated a significant increase in TNF-␣ production, caspase activity, apoptotic cell death, tubulointerstitial fibrosis, and renal dysfunction during UUO compared with castrated males and normal female rats subjected to the same time course of obstruction. These results demonstrate that endogenous testosterone production in normal male rats and testosterone exogenously administered to oophorectomized females significantly increases TNF production and proapoptotic and profibrotic signaling during renal obstruction, resulting in increased apoptotic cell death, tubulointerstitial fibrosis, and renal dysfunction.

Low Serum Testosterone Increases Mortality Risk among Male Dialysis Patients

“…There are a very few studies in the literature indicating a relation between testosterone levels and inflammatory markers. Although the normalization of testosterone in type 2 diabetic patients leads to concomitant reductions of inflammatory cytokines 30 results of experimental studies have been contradictory: Although after renal injury in rats 31 both the endogenous and the exogenous testosterone seem to be pro-inflammatory by stimulating TNF-␣ production, they have been reported to favorably contribute to regulation of atherosclerotic plaque growth and stability by lowering inflammatory molecules in castrated rabbits. 32 Because our cross-sectional study cannot provide the direction of this association, intervention studies addressing this issue are needed to provide evidence for a causal direction.…”

Hypertension-induced renal fibrosis and spironolactone response vary by rat strain and mineralocorticoid receptor gene expression

“…24 There is evidence that testosterone stimulates fibrosis in the kidney. 25,26 The pro-fibrotic effects of aldosterone could potentially be attenuated by androgen receptor blockade with spironolactone.…”

Gender-dependent effects of aging on the kidney

“…Additionally, androgens have been shown to increase proapoptotic signaling (18). Testosterone-induced apoptosis in proximal tubule cells involves the activation of inflammatory cytokines, such as c-Jun amino terminal kinase (JNK), and can be blocked by the AR antagonist flutamide, which reduces JNK phosphorylation (19).…”

“…These differences may be attributed to the protective actions of estrogen on renal morphology, such as anti-growth effects on glomerular (9) 2011 mesangial cells and the inhibition of mesangial extracellular matrix accumulation, which are typical events in the development of glomerular sclerosis (7,8). The deleterious effects of androgens on renal structure, such as apoptosis and increased EMP deposition (16,18) also account for a faster decline in renal function in males compared to females. In addition, castration prevents the increase in RVR found in aged male SHR (46).…”