Peroxisome proliferator-activated receptor β/δ agonism protects the kidney against ischemia/reperfusion injury in diabetic rats
Peroxisome proliferator-activated receptor β/δ agonism protects the kidney against ischemia/reperfusion injury in diabetic rats
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DOI：
10.1016/j.freeradbiomed.2010.10.710
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发表时间：
2011-01-15
影响因子：
7.4
通讯作者：
Fantozzi, Roberto
中科院分区：
文献类型：
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作者：
Collino, Massimo;Benetti, Elisa;Fantozzi, Roberto
糖尿病是缺血性急性肾损伤的重要危险因素，其药物治疗仍然是未满足的医疗需求。过氧化物酶体增殖物激活受体（PPAR）β/δ在肾脏中高度表达，尽管其作用尚未阐明。在此，我们使用链脲佐菌素诱导的糖尿病大鼠的肾缺血/再灌注（I/R）体内模型（i）评估糖尿病是否增加肾脏对I/R损伤的易感性和（ii）研究PPAR β/δ激活的影响。与非糖尿病同窝仔相比，糖尿病大鼠的肾损伤程度（1小时缺血/6小时再灌注）显著增加。I/R后，PPAR β/δ表达增加，其中糖尿病大鼠的水平最高。选择性pPAR β/δ激动剂GW 0742的给药减轻了肾功能障碍、白细胞浸润以及白细胞介素-6和肿瘤坏死因子-α的形成。这些作用伴随着细胞因子信号传导抑制因子（SOCS）-3的表达增加，SOCS-3在精氨酸激活的信号传导途径中起着关键作用。GW 0742的有益作用被选择性PPAR β/δ拮抗剂GSK 0660减弱。因此，我们在此报告，过氧化物酶体增殖物激活受体β/δ激活保护糖尿病肾脏免受I/R损伤的机制，可能涉及SOCS-3的肾脏表达的变化，导致减少局部炎症反应。(C)2010年爱思唯尔公司All rights reserved.
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) beta/delta 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 PPAR beta/delta activation. The degree of renal injury (1 h ischemia/6 h reperfusion) was significantly increased in diabetic rats compared with nondiabetic littermates. PPAR beta/delta expression was increased after I/R, with the highest levels in diabetic rats. Administration of the selective pPAR beta/delta agonist GW0742 attenuated the renal dysfunction, leukocyte infiltration, and formation of interleukin-6 and tumor necrosis factor-alpha. 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 PPAR beta/delta antagonist GSK0660. Thus, we report herein that PPAR beta/delta 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. (C) 2010 Elsevier Inc. All rights reserved.