Role of PPAR-gamma on the pathogenesis and vascular changes in glycerol-induced acute renal failure.

Peroxisome proliferator activated receptor-gamma (PPAR-gamma), a nuclear transcription factor, modulates angiotensin II (AII) or thromboxane A(2) (TxA(2)) response in the vasculature via transcriptional regulation of their gene or receptor expression. Increased AII or TxA(2) vasoconstriction and deteriorating renal function observed in glycerol-induced acute renal failure (ARF) may be attributed to a down-regulated PPAR-gamma expression/activity probably via an increased free radical generation. In this study, we investigated the effect of PPAR-gamma induction in glycerol-induced ARF by examining renal vascular reactivity to AII and TxA(2) and by renal expression/activity of PPAR-gamma. Vascular responses to AII or U46619, a TxA(2) mimetic were determined in rat isolated perfused kidney following induction of ARF with glycerol (50%, v/v, i.m.). Extent of renal damage and function were assessed with or without pre-treatment with ciglitazone (9 nmol kg(-1) x 21 days), a PPAR-gamma inducer. In ARF, vasoconstriction was enhanced to AII (three-fold; p<0.05) and U46619 (82%; p<0.05). Ciglitazone reduced AII and U46619 vasoconstriction by 59+/-1% (p<0.05) and 56+/-1% (p<0.05), respectively. Ciglitazone reduced proteinuria (38+/-3%) which was two-fold higher in ARF. Similarly, ciglitazone enhanced Na(+) excretion by 1.5 times while reducing BUN by 49+/-6%. On the contrary, ciglitazone did not change plasma creatinine which was significantly higher in ARF rats. Ciglitazone reduced free radical generation by 30+/-3% while elevating nitrite excretion approximately 2-fold. PPAR-gamma expression and activity were significantly lower in ARF rats and ciglitazone enhanced PPAR-gamma protein expression and activity by 45+/-3% and 52+/-4%, respectively. Data from this study suggest that reduced PPAR-gamma expression and activity may be involved in the pathology of glycerol-induced ARF and induction of PPAR-gamma by ciglitazone confers protection through reduced AII and TxA(2) vasoconstriction and/or enhanced renal function via reducing free radical generation.