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Molecular Mechanisms of the Protective Effects of Calcium Channel Blockers against Cyclosporine Nephrotoxicity in Rats

Abstract

Nephrotoxicity is a serious side effect for the immunosuppressant drug cyclosporine (CSA). In this study, we tested the hypothesis that the concurrent administration of calcium channel blockers such as verapamil or nifedipine guard against renal dysfunction induced by CSA in rats. Studies were then extended to investigate the roles of inflammatory, oxidative, and fibrotic pathways in the interaction. Six groups of male rats (n=6 each) were employed and allocated to receive one of the following treatments for 7 consecutive days: vehicle (cremophor), CSA (25 mg.kg−1.day−1), verapamil (2 mg.kg−1.day−1), nifedipine (3 mg.kg−1.day−1), CSA plus verapamil, or CSA plus nifedipine. Biochemical and histomorphometric analyses showed that compared with respective vehicle values, rats treated with CSA exhibited clear signs of nephrotoxicity that included: (i) proteinuria and elevations in serum creatinine and blood urea nitrogen, (ii) deposition of collagen IV in glomerular and tubular areas, and (iii) increases in the glomerulosclerosis index. While the single administration of nifedipine or verapamil caused no specific renal effects, the concurrent use of either calcium channel blocker significantly and equipotently ameliorated the biochemical and morphological derangements caused by CSA. We also report that the inflammatory (NF-κB expression), oxidative (NADPH-oxidase activity, reactive oxygen species production), and fibrotic (TGF-β1 expression) manifestations of renal toxicity induced by CSA were eliminated upon concurrent administration of nifedipine or verapamil. Together, these results highlight the usefulness of calcium channel blocking agents in negating the CSA-induced nephrotoxicity and predisposing biochemical and molecular machinaries.

Author(s)

Safaa Hisham Hammoud

Coauthor(s)

Amal G Omar , Assaad A Eid , Mahmoud M El-Mas

Journal/Conference Information

The FASEB Journal,ISSN: 08926638, 15306860, Volume: 31, Issue: 1, Pages Range: 998-998