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

Abstract

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.

• Authors: Ahila Sivarajah, Prabal K Chatterjee, Yoshiyuki Hattori, Paul A Brown, Keith N Stewart, Zoran Todorovic, Helder Mota-Filipe, Christoph Thiemermann
• Journal: Medical science monitor : international medical journal of experimental and clinical research (Med Sci Monit) Vol. 8 Issue 12 Pg. BR532-9 (Dec 2002) ISSN: 1234-1010 [Print] United States
• PMID: 12503032 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Pyrimidines
• RNA, Messenger
• Receptors, Cytoplasmic and Nuclear
• Transcription Factors
• Intercellular Adhesion Molecule-1
• pirinixic acid
• Clofibrate

Topics

• Animals
• Clofibrate (pharmacology)
• Gene Expression
• Intercellular Adhesion Molecule-1 (genetics)
• Kidney (blood supply, drug effects, injuries, physiopathology)
• Male
• Pyrimidines (pharmacology)
• RNA, Messenger (genetics, metabolism)
• Rats
• Rats, Wistar
• Receptors, Cytoplasmic and Nuclear (agonists, genetics)
• Reperfusion Injury (genetics, physiopathology, prevention & control)
• Transcription Factors (agonists, genetics)