Oxidative stress-mediated renal dysfunction by cyclosporine A in rats: attenuation by trimetazidine.
Cyclosporine A (CsA) is one of the first line immunosuppressants employed in the management of solid organ transplantation and autoimmune diseases. The clinical utility of CsA is limited by the frequent occurrence of chronic nephrotoxicity, characterized by tubular atrophy, interstitial fibrosis and progressive renal impairment. The pathogenesis of CsA nephrotoxicity is still not well delineated. Recent evidences suggest that reactive oxygen species (ROS) play an important role in CsA nephrotoxicity. The present study was designed to demonstrate the role of oxidative stress, its relation to renal dysfunction and to investigate the effect of trimetazidine (TMZ), an anti-ischemic agent with free radical scavenging property, in CsA-induced nephrotoxicity. TMZ (2.5 mg/kg, p.o., twice a day) was administered 24 h before and 21 days concurrently with CsA (20 mg/kg, s.c.). Tissue lipid peroxidation was measured as thiobarbituric acid reacting substances (TBARS). Renal function was assessed by measuring the plasma and urine creatinine concentrations, blood and urine urea nitrogen levels and the creatinine and urea clearances. Renal morphological alterations were assessed by histopathological examination of Hematoxylin-Eosin, PAS and Masson's trichome stained sections of the kidneys. CsA (20 mg/kg, s.c) administration for 21 days produced elevated levels of TBARS and decreased renal function as assessed by increased plasma creatinine, BUN and decreased creatinine and urea clearances as compared to vehicle treated rats. The kidneys of CsA treated rats showed severe striped interstitial fibrosis, arteriolopathy, glomerular basement thickening, tubular vacuolization and hyaline casts. TMZ (2.5 mg/kg) markedly reduced elevated levels of TBARS, significantly attenuated renal dysfunction and the morphological changes in CsA treated rats. These results clearly demonstrate the pivotal role of reactive oxygen species and their relation to renal dysfunction and point to the therapeutic potential of an anti-ischemic agent, trimetazidine, in CsA-induced nephrotoxicity.
Satyanarayana
Padi S V
PS
Pharmacology Division, University Institute of Pharmaceutical Sciences, Punjab University, Chandigarh, India.
Chopra
Kanwaljit
K
D000818:Animals; D015415:Biomarkers / Q000032:analysis; D001794:Blood Pressure / Q000187:drug effects; D001806:Blood Urea Nitrogen; D001835:Body Weight / Q000187:drug effects; D003404:Creatinine / Q000097:blood / Q000652:urine; D016572:Cyclosporine / Q000009:adverse effects*; D004195:Disease Models, Animal; D004326:Drinking / Q000187:drug effects; D004359:Drug Therapy, Combination; D005260:Female; D005919:Glomerular Filtration Rate / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000009:adverse effects*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D007674:Kidney Diseases / Q000139:chemically induced* / Q000188:drug therapy / Q000503:physiopathology*; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D013599:Systole / Q000187:drug effects; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D013997:Time Factors; D016896:Treatment Outcome; D014292:Trimetazidine / Q000627:therapeutic use; D014665:Vasodilator Agents / Q000627:therapeutic use
D015415:Biomarkers; D007166:Immunosuppressive Agents; D017392:Thiobarbituric Acid Reactive Substances; D014665:Vasodilator Agents; D016572:Cyclosporine; D003404:Creatinine; D014292:Trimetazidine