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Molecular basis of the counteraction by calcium channel blockers of Cyclosporine nephrotoxicity

Abstract

Nephrotoxicity is a serious side effect for the immunosuppressant drug cyclosporine (CSA). In this study, we tested the hypothesis that administration of calcium channel blockers such as verapamil or nifedipine ameliorate renal CSA-induced renal dysfunction. Furthermore, our study investigates the roles of inflammatory, oxidative, and fibrotic pathways in CSA-induced renal dysfunction. Six groups of male rats (n=6/group) were used and received one of the following treatments for 7 consecutive days: vehicle (cremophor EL, i.p.), CSA (25 mg.kg-1.day-1, i.p.), verapamil (2 mg.kg-1.day-1, i.p.), nifedipine (3 mg.kg-1.day-1, i.p.), CSA in the presence or absence of either verapamil, or nifedipine. Biochemical and histomorphometric analyses showed that rats treated with CSA exhibited clear signs of nephrotoxicity that included: (i) proteinuria and elevations in serum creatinine and blood urea nitrogen, (ii) Mesangial expansion (iii) increases in glomerular and tubular type IV collagen expression, and (iv) increases in the glomerulosclerosis and tubulointerstitial fibrosis indices. While the single administration of nifedipine or verapamil had no significant effect on renal pathology, or its biochemical and physiological function, the concurrent use of either calcium channel blockers significantly and equipotently ameliorated the biochemical, morphological and functional derangements caused by CSA. More importantly, we report that the oxidative (ROS production, NADPH-oxidase activity and DUOX1/2 levels), fibrotic (TGF-β1 expression) and inflammatory (NF-κB expression), manifestations of renal toxicity induced by CSA were significantly reversed upon administration of nifedipine or verapamil. Together, these results highlight the efficacy of calcium channel blocking agents in attenuating CSA-induced nephrotoxicity and predisposing biochemical and molecular machineries.

Author(s)

Safaa Hisham Hammoud

Coauthor(s)

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

Journal/Conference Information

American Journal of Physiology- Renal Physiology ,DOI: doi: 10.1152/ajprenal.00275.2017, Volume: Epub ahead of print, Issue: 0, Pages Range: 0-0