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Author El-Gowelli, Hanan M. ♦ Helmy, Maged W. ♦ Ali, Rabab M. ♦ El-Mas, Mahmoud M.
Source United States Department of Energy Office of Scientific and Technical Information
Content type Text
Language English
Subject Keyword APPLIED LIFE SCIENCES ♦ ATROPHY ♦ CREATININE ♦ CYCLOSPORINE ♦ FIBROSIS ♦ GROWTH FACTORS ♦ INFLAMMATION ♦ KIDNEYS ♦ RATS ♦ RECEPTORS ♦ UREA
Abstract Endothelin (ET) signaling provokes nephrotoxicity induced by the immunosuppressant drug cyclosporine A (CSA). We tested the hypotheses that (i): celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, counterbalances renal derangements caused by CSA in rats and (ii) the COX-2/endothelin ET{sub B} receptor signaling mediates the CSA-celecoxib interaction. Ten-day treatment with CSA (20 mg/kg/day) significantly increased biochemical indices of renal function (serum urea, creatinine), inflammation (interleukin-2, IL-2) and fibrosis (transforming growth factor-β{sub 1}, TGF-β{sub 1}). Histologically, CSA caused renal tubular atrophy along with interstitial fibrosis. These detrimental renal effects of CSA were largely reduced in rats treated concurrently with celecoxib (10 mg/kg/day). We also report that cortical glomerular and medullary tubular protein expressions of COX-2 and ET{sub B} receptors were reduced by CSA and restored to near-control values in rats treated simultaneously with celecoxib. The importance of ET{sub B} receptors in renal control and in the CSA-celecoxib interaction was further verified by the findings (i) most of the adverse biochemical, inflammatory, and histopathological profiles of CSA were replicated in rats treated with the endothelin ET{sub B} receptor antagonist BQ788 (0.1 mg/kg/day, 10 days), and (ii) the BQ788 effects, like those of CSA, were alleviated in rats treated concurrently with celecoxib. Together, the data suggest that the facilitation of the interplay between the TGF-β1/IL-2/COX-2 pathway and the endothelin ET{sub B} receptors constitutes the cellular mechanism by which celecoxib ameliorates the nephrotoxic manifestations of CSA in rats. - Highlights: • Celecoxib abolishes nephrotoxic manifestations of CSA in rats. • Blockade of ETB receptors by BQ788 mimicked the nephrotoxic effects of CSA. • CSA or BQ788 reduces renal protein expression of COX-2 and endothelin ETB receptors. • Enhanced TGFβ1/IL-2/COX2/ETB signaling mediates celecoxib renoprotection.
ISSN 0041008X
Educational Use Research
Learning Resource Type Article
Publisher Date 2014-03-01
Publisher Place United States
Journal Toxicology and Applied Pharmacology
Volume Number 275
Issue Number 2


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