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

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.