Agonists of Peroxisome-Proliferator Activated Receptor-Gamma Reduce Renal Ischemia/Reperfusion Injury

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-γ 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-α, PPAR-β and PPAR-γ1 (but not PPAR-γ2) was observed in kidneys with down-regulation of PPAR-α 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-γ 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.

Protective Effects of Nigella sativa against Ischemia-Reperfusion Injury of Kidneys

“…[2] However, reperfusion can paradoxically create more tissue injury by initiating the complex cellular events that result in renal injury and the concluding death of renal cells due to a combination of apoptosis and necrosis. High levels of oxygen free radicals produced on reperfusion play a critical role in the injury caused by I/R.…”

Mechanisms of anti-inflammatory and neuroprotective actions of PPAR-gamma agonists

“…The observed protection has been attributed to improved insulin sensitivity and glucose metabolism and reduced inflammation and apoptosis in the kidneys. 15d-PGJ2 was also shown to protect the kidneys from ischemic injury by inhibiting NF-kappaB activation and other pro-inflammatory proteins like AP-1, ICAM1 and iNOS, thereby decreasing oxidative stress (23,95,96) (Table 3). …”

Amelioration of anti-Thy1-glomerulonephritis by PPAR-γ agonism without increase of endothelial progenitor cell homing

“…Several experimental studies in rats showed favorable effects of PPAR-␥ agonism on nondiabetic renal pathology (24), including anti-glomerular basement membrane antibody-induced crescentic glomerulonephritis (8), passive Heymann nephritis (2), the development of glomerulosclerosis after 5/6 nephrectomy (12), and renal ischemia-reperfusion induced damage (26). The course of anti-Thy1-glomerulonephritis is determined by the degree of inflammatory cell invasion and inflammatory damage (4), as well as by the degree of endothelial repair (15).…”