17494862

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2

Peroxisome proliferator-activated receptor gamma (PPARgamma), a nuclear transcription factor, modulates vascular responses to angiotensin II (AII) or thromboxane A(2) (TxA(2)) 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 PPARgamma. In this study, we investigated the effect of ciglitazone (CG), a PPARgamma inducer, on AII and TxA(2) production and activity in glycerol-induced ARF. Vascular responses to AII or 9,11-dideoxy-11alpha,9alpha-epoxymethano prostaglandin F(2alpha) (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. PPARgamma protein expression and activity, which were significantly lower in ARF rats, were enhanced by CG (26 and 30%). CG also increased PPARgamma 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 TxA(2) (39 +/- 2%) production, the attending increase in vasoconstriction to AII (36 +/- 2%) and U46619 (50 +/- 11%), and the increase in angiotensin receptor-1 (AT(1)) (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 AT(1) or TP receptor expression, and renal injury in glycerol-induced ARF are consequent to down-regulation of PPARgamma gene. CG ameliorated glycerol-induced effects through maintaining PPARgamma gene.

eng

IM

MEDLINE

0022-3565

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NLM

461-8

pubmed-meshheading:17494862-15-Hydroxy-11 alpha,9..., pubmed-meshheading:17494862-Acute Kidney Injury, pubmed-meshheading:17494862-Angiotensin II, pubmed-meshheading:17494862-Animals, pubmed-meshheading:17494862-Creatinine, pubmed-meshheading:17494862-Dinoprost, pubmed-meshheading:17494862-Gene Expression, pubmed-meshheading:17494862-Glycerol, pubmed-meshheading:17494862-Hypoglycemic Agents, pubmed-meshheading:17494862-Kidney Glomerulus, pubmed-meshheading:17494862-Male, pubmed-meshheading:17494862-Nitric Oxide, pubmed-meshheading:17494862-Nitrites, pubmed-meshheading:17494862-PPAR gamma, pubmed-meshheading:17494862-Proteinuria, pubmed-meshheading:17494862-Rats, pubmed-meshheading:17494862-Rats, Sprague-Dawley, pubmed-meshheading:17494862-Receptor, Angiotensin, Type 1, pubmed-meshheading:17494862-Receptors, Thromboxane A2, Prostaglandin H2, pubmed-meshheading:17494862-Renal Artery, pubmed-meshheading:17494862-Sodium, pubmed-meshheading:17494862-Thiazolidinediones, pubmed-meshheading:17494862-Thromboxane A2, pubmed-meshheading:17494862-Thromboxane B2, pubmed-meshheading:17494862-Vasoconstriction

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

Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural