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GASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Ciglitazone, a Peroxisome Proliferator-Activated Receptor Inducer, Ameliorates Renal Preglomerular Production and Activity of Angiotensin II and Thromboxane A₂ in Glycerol-Induced Acute Renal Failure

Center for Cardiovascular Diseases, Texas Southern University, Houston, Texas (Z.Y., H.H., A.O., M.N.); Department of Pathology, Methodist Hospital, Baylor College of Medicine, Houston, Texas (L.T.); and Department of Pathology, Cornell University, New York, New York (L.T.)

Peroxisome proliferator-activated receptor (PPAR), 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 PPAR. In this study, we investigated the effect of ciglitazone (CG), a PPAR inducer, on AII and TxA₂ production and activity in glycerol-induced ARF. Vascular responses to AII or 9,11-dideoxy-11,9-epoxymethano prostaglandin F₂ (U46619 [GenBank] ), 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. PPAR protein expression and activity, which were significantly lower in ARF rats, were enhanced by CG (26 and 30%). CG also increased PPAR 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. [GenBank] 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 [GenBank] (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 PPAR gene. CG ameliorated glycerol-induced effects through maintaining PPAR gene.

Address correspondence to: Mohammad A. Newaz, Center for Cardiovascular Diseases, Texas Southern University, 3100 Cleburne Avenue, Houston, TX 77004. E-mail: newaz_ma{at}tsu.edu