Celecoxib Offsets The Negative Renal Influences of Cyclosporine Via COX‐2/Endothelin ETB Receptor crosstalk

Abstract

We tested the hypotheses that (i) celecoxib, a selective COX‐2 inhibitor, counterbalances renal derangements caused by cyclosporine A (CSA) in male rats, and (ii) the endothelin ETB receptor mediates the CSA‐celecoxib interactions. Ten‐day treatment with CSA (20 mg/kg/day) significantly increased biochemical indices of renal function (serum urea and creatinine) and inflammatory cytokines (renal transforming growth factor‐β and interleukin‐2). CSA also caused renal tubular atrophy and congestion in renal arterioles along with perivascular and interstitial fibrosis. These detrimental renal effects of CSA were dramatically reduced in rats treated concurrently with celecoxib (10 mg/kg/day). Moreover, immunohistochemical analyses showed that glomerular and tubular protein expressions of COX‐2 and ETB were reduced by CSA and restored to near‐control values in rats treated simultaneously with celecoxib. The adverse biochemical, inflammatory, and histopathological profiles of CSA were replicated in rats treated with the endothelin ETB receptor antagonist BQ788 (0.1 mg/kg/day, 10 days). The BQ788 effects, like those of CSA, were alleviated in rats treated concurrently with celecoxib. Together, facilitation of the interplay between COX‐2 and endothelin ETB receptors is the cellular mechanism by which celecoxib ameliorates the nephrotoxic manifestations of CSA in male rats.