Celecoxib offsets the negative renal influences of cyclosporine via modulation of the TGF-β1/IL-2/COX-2/endothelin ET(B) receptor cascade.
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(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-β₁, TGF-β₁). 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(B) receptors were reduced by CSA and restored to near-control values in rats treated simultaneously with celecoxib. The importance of ET(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 ETB 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(B) receptors constitutes the cellular mechanism by which celecoxib ameliorates the nephrotoxic manifestations of CSA in rats.
Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt.
Hanan M
HM
El-Gowelli
Pharmacology and Toxicology, Faculty of Pharmacy, Pharos University, Alexandria, Egypt.
Maged W
MW
Helmy
Pharmacology and Toxicology, Faculty of Pharmacy, Pharos University, Alexandria, Egypt.
Rabab M
RM
Ali
Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt. Electronic address: mahelm@hotmail.com.
Mahmoud M
MM
El-Mas
D000818:Animals; D000068579:Celecoxib; D003404:Creatinine / Q000097:blood / Q000652:urine; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D016572:Cyclosporine / Q000008:administration & dosage / Q000009:adverse effects*; D005355:Fibrosis / Q000209:etiology / Q000473:pathology; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000009:adverse effects; D007376:Interleukin-2 / Q000235:genetics / Q000378:metabolism; D007668:Kidney / Q000187:drug effects* / Q000473:pathology; D007674:Kidney Diseases / Q000209:etiology / Q000473:pathology; D008297:Male; D011720:Pyrazoles / Q000008:administration & dosage*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017466:Receptors, Endothelin / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013449:Sulfonamides / Q000008:administration & dosage*; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism
D007166:Immunosuppressive Agents; D007376:Interleukin-2; D011720:Pyrazoles; D017466:Receptors, Endothelin; D013449:Sulfonamides; C508962:Tgfb1 protein, rat; D053773:Transforming Growth Factor beta1; D016572:Cyclosporine; D003404:Creatinine; D051546:Cyclooxygenase 2; C489691:Ptgs2 protein, rat; D000068579:Celecoxib
Celecoxib; Cyclooxygenase-2; Cyclosporine; Endothelin ET(B) receptor; Kidney