Ciglitazone, a peroxisome proliferator-activated receptor γ inducer, ameliorates renal preglomerular production and activity of angiotensin II and thromboxane A2 in glycerol-induced acute renal failure

Zivar Yousefipour, Hantz Hercule, Luan Truong, Adebayo Oyekan, Mohammad A. Newaz

Research output: Contribution to journalArticle

15 Scopus citations

Abstract

Peroxisome proliferator-activated receptor γ (PPARγ), a nuclear transcription factor, modulates vascular responses to angiotensin II (AII) or thromboxane A2 (TxA2) via regulation of their gene/receptor. Increased vasoconstriction and deteriorating renal function in glycerol-induced acute renal failure (ARF) may be attributed to down-regulation of PPARγ. In this study, we investigated the effect of ciglitazone (CG), a PPARγ inducer, on AII and TxA2 production and activity in glycerol-induced ARF. Vascular responses to AII or 9,11-dideoxy-11α, 9α-epoxymethano prostaglandin F (U46619), a TxA 2 mimetic, were determined in preglomerular vessels following induction of ARF with glycerol. Renal damage and function were assessed in CG-treated (9 nmol/kg for 21 days) rats. PPARγ protein expression and activity, which were significantly lower in ARF rats, were enhanced by CG (26 and 30%). CG also increased PPARγ mRNA by 67 ± 6%, which was reduced in ARF. In ARF, there was significant tubular necrosis and apoptosis, a 5-fold increase in proteinuria and a 2-fold enhancement in vasoconstriction to AII and U46619. CG reduced proteinuria (49 ± 3%), enhanced Na+ (124 ± 35%) and creatinine excretion (92 ± 25%), markedly diminished tubular necrosis, and reduced ARF-induced increase in AII (40 ± 3%) and TxA2 (39 ± 2%) production, the attending increase in vasoconstriction to AII (36 ± 2%) and U46619 (50 ± 11%), and the increase in angiotensin receptor-1 (AT1) (23 ± 3%) or thromboxane prostaglandin (TP) receptor (13 ± 1%). CG reduced free radical generation by 55 ± 14% while elevating nitrite excretion (65 ± 13%). Our results suggest that enhanced activity of AII and TxA 2, increased AT1 or TP receptor expression, and renal injury in glycerol-induced ARF are consequent to down-regulation of PPARγ gene. CG ameliorated glycerol-induced effects through maintaining PPARγ gene.

Original languageEnglish (US)
Pages (from-to)461-468
Number of pages8
JournalJournal of Pharmacology and Experimental Therapeutics
Volume322
Issue number2
DOIs
StatePublished - Aug 1 2007

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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