Androgen‐Dependent Provocation by Tacrolimus of Nephrotoxic and Inflammatory Consequences of Endotoxemia in Rats

Abstract

Reported data on the interaction of immunosuppressants and endotoxic insult on end organ damage have been conflicting. In this report, we assessed the (i) renal profile in rats treated individually or concurrently with tacrolimus and lipopolysaccharide (LPS), and (ii) role of androgens and their receptors in the interaction. The data showed that a single exposure of male rats to LPS (3 mg/kg i.p.) for 6 hr caused significant elevations in serum urea and creatinine together with evidence of cellular vacuolation and degeneration in proximal and distal tubules. Moreover, quantitative morphometric analysis revealed significant increases in the width of renal tubules in endotoxic rats. Except for tubular dilation, tacrolimus (2 mg/kg i.p.) exhibited no signs of renal damage on its own, but it aggravated the rises in serum biomarkers of renal function and histopathological derangements when administered to endotoxic rats. Similarly, ELISA determinations demonstrated that tacrolimus potentiated the LPS‐evoked increases in serum levels of the inflammatory cytokines tumor necrosis factor alpha and myeloperoxidase. We also report that the detrimental biochemical and histopathological renal outcomes caused by tacrolimus in endotoxic rats were virtually eliminated after surgical (castration) or pharmacologic (androgen receptor blockade by flutamide) interruption of androgenic activity. Overall, the data highlight a pivotal role for male gonadal hormones in worsened renal profile evoked by tacrolimus in endotoxic rats. If necessary, immunosuppressants other than tacrolimus are advised in humans with endotoxemia.