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

Peroxisome proliferator activated receptor-γ (PPAR-γ), a nuclear transcription factor, modulates angiotensin II (AII) or thromboxane A2 (TxA2) response in the vasculature via transcriptional regulation of their gene or receptor expression. Increased AII or TxA2 vasoconstriction and deteriorating renal function observed in glycerol-induced acute renal failure (ARF) may be attributed to a down-regulated PPAR-γ expression/activity probably via an increased free radical generation. In this study, we investigated the effect of PPAR-γ induction in glycerol-induced ARF by examining renal vascular reactivity to AII and TxA2 and by renal expression/activity of PPAR-γ. Vascular responses to AII or U46619, a TxA2 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 × 21 days), a PPAR-γ 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 ∼2-fold. PPAR-γ expression and activity were significantly lower in ARF rats and ciglitazone enhanced PPAR-γ protein expression and activity by 45 ± 3% and 52 ± 4%, respectively. Data from this study suggest that reduced PPAR-γ expression and activity may be involved in the pathology of glycerol-induced ARF and induction of PPAR-γ by ciglitazone confers protection through reduced AII and TxA2 vasoconstriction and/or enhanced renal function via reducing free radical generation.