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In this study, we tested whether calcineurin\u2010dependent (cyclosporine\/tacrolimus) and \u2010independent (sirolimus) immunosuppressants variably influence nephrotoxicity induced by endotoxaemia and whether this interaction is modulated by testosterone. We investigated the effects of immunosuppressants on renal histopathological, biochemical and inflammatory profiles in endotoxic male rats and the role of androgenic state in the interaction. Six\u2010hour treatment of rats with lipopolysaccharide (LPS, 3\u00a0mg\/kg) increased (i) serum urea\/creatinine, (ii) width of proximal\/distal tubules, (iii) tubular degeneration and vacuolation, (iv) Western protein expressions of renal toll\u2010like receptor 4, monocyte chemoattractant protein\u20101, and NADPH oxidase\u20102, and (v) serum tumour necrosis factor\u2010\u03b1 and myeloperoxidase. These endotoxic manifestations were intensified and eliminated upon concurrent exposure to cyclosporine and sirolimus, respectively. The cyclosporine actions appear to be a class rather than a drug effect because similar exacerbation of LPS nephrotoxicity was observed in rats treated with tacrolimus, another calcineurin inhibitor (CNI). Moreover, the deteriorated renal outcomes in LPS\/tacrolimus\u2010treated rats were reduced after castration or androgen receptor blockade by flutamide. The data suggest opposite effects for calcineurin\u2010dependent (exaggeration) and \u2010independent immunosuppressants (amelioration) on renal defects of endotoxaemia and implicate androgenic pathways in the worsened endotoxic renal profile induced by CNIs.<\/jats:p>","DOI":"10.1111\/1440-1681.13526","type":"journal-article","created":{"date-parts":[[2021,5,27]],"date-time":"2021-05-27T10:51:23Z","timestamp":1622112683000},"page":"1261-1270","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Distinct effects of calcineurin dependent and independent immunosuppressants on endotoxaemia\u2010induced nephrotoxicity in rats: Role of androgens"],"prefix":"10.1111","volume":"48","author":[{"given":"Shrouk S.","family":"Elzokm","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Toxicology Faculty of Pharmacy Pharos University in Alexandria Alexandria 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