Peroxisome proliferator-activated receptor β/δ agonism protects the kidney against ischemia/reperfusion injury in diabetic rats

• Published in: Free radical biology & medicine Vol. 50; no. 2; pp. 345 - 353
• Main Authors: Collino, Massimo, Benetti, Elisa, Miglio, Gianluca, Castiglia, Sara, Rosa, Arianna Carolina, Aragno, Manuela, Thiemermann, Christoph, Fantozzi, Roberto
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15-01-2011
• Subjects: agonistic behavior; agonists; Animals; antagonists; Blotting, Western; Cells, Cultured; Diabetes; Diabetes Mellitus, Experimental - drug therapy; Diabetes Mellitus, Experimental - metabolism; Free radicals; GSK0660; GW0742; inflammation; interleukin-6; ischemia; Ischemia/reperfusion; Kidney; Kidney - cytology; Kidney - drug effects; Kidney - metabolism; kidneys; leukocytes; Male; necrosis; Peroxidase; PPAR delta - agonists; PPAR delta - metabolism; PPAR-beta - agonists; PPAR-beta - metabolism; PPARβ/δ; Rats; Rats, Wistar; Reperfusion Injury - metabolism; Reperfusion Injury - prevention & control; Reverse Transcriptase Polymerase Chain Reaction; risk factors; RNA, Messenger - genetics; signal transduction; SOCS-3; Thiazoles - pharmacology; tumor necrosis factor-alpha; Kim-1; AST; ED-1; IL; Free radicals; SOCS-3; ICAM-1; SOCS; GSK0660; I/R; MPO; Ischemia/reperfusion; Kidney; PPAR; TNF-α; PPARβ/δ; Diabetes; GW0742; AKI
• ISSN: 0891-5849; 1873-4596
• DOI: 10.1016/j.freeradbiomed.2010.10.710

Diabetes is an important risk factor for ischemic acute kidney injury, whose pharmacological treatment remains an unmet medical need. The peroxisome proliferator-activated receptor (PPAR) β/δ is highly expressed in the kidney, although its role has not yet been elucidated. Here, we used an in vivo model of renal ischemia/reperfusion (I/R) in streptozotocin-induced diabetic rats (i) to evaluate whether diabetes increases kidney susceptibility to I/R injury and (ii) to investigate the effects of PPARβ/δ activation. The degree of renal injury (1
h ischemia/6
h reperfusion) was significantly increased in diabetic rats compared with nondiabetic littermates. PPARβ/δ expression was increased after I/R, with the highest levels in diabetic rats. Administration of the selective PPARβ/δ agonist GW0742 attenuated the renal dysfunction, leukocyte infiltration, and formation of interleukin-6 and tumor necrosis factor-α. These effects were accompanied by an increased expression of the suppressor of cytokine signaling (SOCS)-3, which plays a critical role in the cytokine-activated signaling pathway. The beneficial effects of GW0742 were attenuated by the selective PPARβ/δ antagonist GSK0660. Thus, we report herein that PPARβ/δ activation protects the diabetic kidney against I/R injury by a mechanism that may involve changes in renal expression of SOCS-3 resulting in a reduced local inflammatory response.