Original Article: Basic Sciences

Agonists of Peroxisome-Proliferator Activated Receptor-Gamma Reduce Renal Ischemia/Reperfusion Injury
Ahila Sivarajah^a, Prabal K. Chatterjee^a, Nimesh S.A. Patel^a, Zoran Todorovic^a, Yoshiyuki Hattori^b, Paul A.J. Brown^c, Keith N. Stewart^c, Helder Mota-Filipe^d, Salvatore Cuzzocrea^e, Christoph Thiemermann<sup>a

a</sup>Department of Experimental Medicine and Nephrology, William Harvey Research Institute, Queen Mary - University of London, UK;
^bDepartment of Endocrinology and Metabolism, Dokkyo University School of Medicine, Mibu, Japan;
^cDepartments of Pathology and Medicine and Therapeutics, University of Aberdeen, Aberdeen, UK;
^dLaboratory of Pharmacology, Faculty of Pharmacy, University of Lisbon, Portugal;
^eDepartment of Clinical and Experimental Medicine and Pharmacology, Institute of Pharmacology, School of Medicine, University of Messina, Messina, Italy

Address of Corresponding Author

Am J Nephrol 2003;23:267-276 (DOI: 10.1159/000072088)

  Key Words

• Kidney
• Reperfusion-injury
• Renal dysfunction
• Peroxisome-proliferator activated receptor
• Rosiglitazone
• Ciglitazone
• Intercellular adhesion molecule-1

  Abstract

Background/Aims: Recent evidence indicates that peroxisome-proliferator activated receptor (PPAR) agonists protect against ischemia/reperfusion (I/R) injury. Here we investigate the effects of the PPAR- agonists, rosiglitazone and ciglitazone, on the renal dysfunction and injury caused by I/R of the rat kidney in vivo. Methods: Rosiglitazone or ciglitazone were administered to male Wistar rats prior to and during reperfusion. Biochemical indicators of renal dysfunction and injury were measured and histological scoring of kidney sections was used to assess renal injury. Expression of PPAR isoforms and intercellular adhesion molecule-1 during renal I/R were assessed using RT-PCR and Northern blot, respectively. Myeloperoxidase activity and activation of poly(ADP-ribose) polymerase (PARP) were used as indicators of polymorphonuclear (PMN) cell infiltration and oxidative stress, respectively. Results: Expression of PPAR-, PPAR- and PPAR-1 (but not PPAR-2) was observed in kidneys with down-regulation of PPAR- expression during renal I/R. Rosiglitazone and ciglitazone significantly reduced biochemical and histological signs of renal dysfunction and injury. Renal expression of ICAM-1 caused by I/R was reduced by rosiglitazone and ciglitazone which was reflected by decreased PMN infiltration into reperfused renal tissues. Both rosiglitazone and ciglitazone reduced PARP activation indicating a reduction of oxidative stress. Conclusion: These results suggest that the PPAR- agonists rosiglitazone and ciglitazone reduce the renal dysfunction and injury associated with I/R of the kidney. We propose that one mechanism underlying the protective effects involves inhibition of the expression of ICAM-1, a reduction of PMN infiltration into renal tissues and subsequent reduction of oxidative stress.

Copyright © 2003 S. Karger AG, Basel

  Author Contacts

Prof. Christoph Thiemermann
Department of Experimental Medicine and Nephrology
William Harvey Research Institute, Queen Mary - University of London
Charterhouse Square, London, EC1M 6BQ (UK)
Tel. +44 20 7882 6118, Fax +44 20 7251 1685, E-Mail c.thiemermann@qmul.ac.uk

  Article Information

Received: June 3, 2003
Accepted: May 16, 2003
Published online: July 3, 2003
Number of Print Pages : 10
Number of Figures : 5, Number of Tables : 1, Number of References : 37