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 F2α (U46619), a TxA2 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 TxA2, 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.
Footnotes
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This study was supported by American Heart Association, Texas Affiliate Grant 0365001Y (M.N.) and National Institutes of Health Grant HL03674 (A.O.).
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.107.122473.
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ABBREVIATIONS: ARF, acute renal failure; AII, angiotensin II; ACE, angiotensin-converting enzyme; TxA2, thromboxane A2; PPAR, peroxisome proliferator-activated receptor; CG, ciglitazone, (±)-5-{4-(1-methylcyclohexylmethoxy) benzyl} thiazolidine-2,4-dione; U46619, 9,11-dideoxy-11α,9α-epoxy-methano prostaglandin F2α; ID, intraluminal diameter; UNaV, urinary sodium; UNOxV, urinary nitrite; BUN, blood urea nitrogen; TxB2, thromboxane B2; TBST, Tris-buffered saline/Tween 20; PCR, polymerase chain reaction; ROS, reactive oxygen species; TP, thromboxane prostaglandin; AT1, angiotensin receptor-1.
- Received March 8, 2007.
- Accepted May 8, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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