Agonists of peroxisome-proliferator activated receptor-α (clofibrate and WY14643) reduce renal ischemia/reperfusion injury in the rat.
Ahila Sivarajah, Prabal K. Chatterjee, Yoshiyuki Hattori, Paul AJ. Brown, Keith N. Stewart, Zoran Todorovic, Helder Mota-Filipe, Christoph Thiemermann
Med Sci Monit 2002; 8(12): BR532-539
Available online: 2002-12-27
BACKGROUND: The aim of this study was to investigate the effects of peroxisome-proliferator activated receptor-alpha (PPAR-alpha) agonists, clofibrate and WY14643 on the renal dysfunction and injury caused by bilateral ischemia/reperfusion (I/R) of rat kidneys in vivo. MATERIAL/METHODS: Male Wistar rats were anesthetized with sodium thiopentone (120 mg/kg i.v.) and subjected to bilateral renal ischemia (45 min) followed by reperfusion (6 h). Serum and urinary biochemical indicators of renal dysfunction and injury were measured; serum creatinine (sCr, glomerular dysfunction), fractional excretion of Na+ (FENa, tubular dysfunction), and urinary N-acetyl-b-D-glucosaminidase (uNAG, tubular injury). Additionally, renal sections were used for histological grading of renal injury and for RT-PCR analysis of the expression of PPAR-isoforms in kidneys obtained from rats prior to or after I/R. In addition, expression of intercellular adhesion molecule-1 (ICAM-1) was determined using Northern blot analysis. RESULTS: Using RT-PCR, we document here the expression of PPAR-alpha, PPAR-beta and PPAR-gamma1 (but not PPAR-gamma2) in the kidney of the rat. I/R resulted in the down-regulation of PPAR-alpha without modulation of any other PPAR. Clofibrate and WY14643 significantly reduced the increases in sCr, FENa and uNAG caused by renal I/R, indicating attenuation of renal dysfunction and injury. Expression of ICAM-1 caused by I/R of the kidney was not modulated by PPAR-alpha agonists. CONCLUSIONS: We show here that (i) renal I/R results in the down-regulation of PPAR-alpha in the kidney, and (ii) that the PPAR-alpha agonists clofibrate and WY14643 reduce the renal dysfunction and injury associated with I/R of the kidney.
Keywords: Clofibrate - pharmacology, Reperfusion Injury - genetics