Agonists of peroxisome-proliferator activated receptor-alpha (clofibrate and WY14643) reduce renal ischemia/reperfusion injury in the rat.
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.


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.
Sivarajah
Ahila
A
Department of Experimental Medicine & Nephrology, The William Harvey Research Institute, Queen Mary - University of London, London, UK.
Chatterjee
Prabal K
PK
Hattori
Yoshiyuki
Y
Brown
Paul A
PA
Stewart
Keith N
KN
Todorovic
Zoran
Z
Mota-Filipe
Helder
H
Thiemermann
Christoph
C
D000818:Animals; D002994:Clofibrate / Q000494:pharmacology*; D015870:Gene Expression; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics; D007668:Kidney / Q000098:blood supply / Q000187:drug effects* / Q000293:injuries* / Q000503:physiopathology; D008297:Male; D011743:Pyrimidines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000235:genetics; D015427:Reperfusion Injury / Q000235:genetics / Q000503:physiopathology / Q000517:prevention & control*; D014157:Transcription Factors / Q000819:agonists* / Q000235:genetics
D011743:Pyrimidines; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D018799:Intercellular Adhesion Molecule-1; C006253:pirinixic acid; D002994:Clofibrate