Abstract:
:Nephrotoxicity associated with cyclosporine A (CsA) administration is characterized by marked renal vasoconstriction, interstitial fibrosis and arteriolar hypertrophy. The molecular mechanisms of CsA nephrotoxicity are not well characterized, but previous studies have demonstrated that angiotensin II (Ang II), the primary mediator of renin-angiotensin system (RAS) cascade plays a role in its pathogenesis. Recent studies also suggest an involvement of reactive oxygen species (ROS) in CsA nephrotoxicity. There is emerging evidence that Ang II induces oxidative stress in vitro and in vivo. The aims of this study were to investigate the role of Ang II-induced oxidative stress in CsA nephrotoxicity, and to examine the effects of the insurmountable Ang II type 1 (AT (1)) receptor antagonist, candesartan on CsA-induced nephrotoxicity in rats. Candesartan cilexetil (1.0 mg kg (-1), perorally (p.o.), once a day) was administered 24 h before and 21 days concurrently with CsA (20 mg kg(-1), subcutaneously (s.c.)). Tissue lipid peroxidation was measured as thiobarbituric acid reacting substances (TBARS). Renal function was assessed by estimating serum creatinine, blood urea nitrogen (BUN), creatinine and urea clearance. Renal morphological alterations were assessed by histopathological examination of Haematoxylin-Eosin, PAS and Mason's trichome stained sections of the kidneys. CsA (20 mg kg (-1), s.c.) administration for 21 days produced elevated levels of TBARS and deteriorated the renal function as assessed by increased serum creatinine, BUN and decreased creatinine and urea clearance as compared to vehicle treated rats. The kidneys of CsA-treated rats showed severe striped interstitial fibrosis, arteriolopathy, glomerular basement thickening, tubular vacuolisation and hyaline casts. Candesartan cilexetil (1.0 mg kg (-1)) markedly reduced elevated levels of TBARS, significantly attenuated renal dysfunction and morphological changes in CsA-treated rats. These results clearly demonstrate the pivotal role of Ang II-induced oxidative stress and the therapeutic potential of AT (1)receptor antagonists in ameliorating CsA-induced nephrotoxicity.
journal_name
Pharmacol Resjournal_title
Pharmacological researchauthors
Padi SS,Chopra Kdoi
10.1006/phrs.2002.0959keywords:
subject
Has Abstractpub_date
2002-05-01 00:00:00pages
413-20issue
5eissn
1043-6618issn
1096-1186pii
S104366180290959Xjournal_volume
45pub_type
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