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Aggravated Nephrotoxicity Evoked By Concurrent Exposure To Cyclosporine And Indomethacin In Rats: Role Of The Endothelin ETA Receptor/TGF‐beta/COX‐2 Pathway
Author(s) -
Helmy Maged W,
ElGowelli Hanan M,
AbdelHalim Rabab M,
ElMas Mahmoud M
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.654.10
Subject(s) - nephrotoxicity , medicine , endothelin receptor , creatinine , pharmacology , endothelin 1 , endocrinology , kidney , fibrosis , receptor
The management of several arthritic and autoimmune diseases necessitates the use of cyclosporine (CSA) along with NSAIDs. In this study we tested if the use of this combination elicits exaggerated nephrotoxicity in rats and the role of the endothelin/inflammatory cytokine pathway in this interaction. Treatment with CSA (20 mg/kg/day) or indomethacin (5 mg/kg/day) for 10 days (i) elevated serum urea and creatinine, (ii) caused histopathological damage manifested as renal tubular atrophy, renal arteriolar congestion, and perivascular and interstitial fibrosis, (iii) increased renal TGF‐β1 and malondialdehyde, and (iv) reduced renal endothelin ETA receptor and COX‐2 protein expressions. Renal endothelin‐1 and interleukin‐2 were increased by CSA only. Treatment with CSA plus indomethacin caused more dramatic increases in serum urea and creatinine and histopathological and oxidative damage. The blockade of ETA receptors by atrasentan (5 mg/kg/day) ameliorated the biochemical, tubular, fibrotic, inflammatory, and oxidative damage caused by individual or combined CSA/indomethacin regimens. In conclusion, COX‐2 downregulation due probably to the overproduction of TGF‐β1 is pivotal for triggering nephrotoxicity caused by CSA or indomethacin. The pharmacologic elimination of ETA receptors might constitute a therapeutic strategy against renal damage caused by single or combined use of the two drugs.