Li Shenyang, Gokden Neriman, Okusa Mark D, Bhatt Renu, Portilla Didier
Division of Nephrology, Department of Internal Medicine, University of Arkansas for Medical Sciences, Little Rock, 72205, USA.
Am J Physiol Renal Physiol. 2005 Aug;289(2):F469-80. doi: 10.1152/ajprenal.00038.2005. Epub 2005 Apr 5.
Recently, we demonstrated that peroxisome proliferator-activated receptor-alpha (PPARalpha) ligand ameliorates cisplatin-induced acute renal failure (ARF) by preventing inhibition of substrate oxidation, and also by preventing apoptosis and necrosis of the proximal tubule (Li S, Bhatt R, Megyesi J, Gokden N, Shah SV, and Portilla D. Am J Physiol Renal Physiol 287: F990-F998, 2004). In the following studies, we examined the protective effect of PPARalpha ligand on cisplatin-induced inflammatory responses during ARF. Mice subjected to a single intraperitoneal injection of cisplatin developed ARF at day 3. Cisplatin increased mRNA and protein expression of TNF-alpha, RANTES, and also upregulated endothelial adhesion molecules ICAM-1/VCAM-1 and chemokine receptors CCR1/CCR5. Cisplatin also led to neutrophil infiltration in the corticomedullary region. Pretreatment of wild-type mice with WY-14,643, a fibrate class of PPARalpha ligands, before cisplatin significantly suppressed cisplatin-induced upregulation of cytokine/chemokine expression, prevented neutrophil accumulation, and ameliorated renal dysfunction. In contrast, treatment with PPARalpha ligand before cisplatin did not prevent cytokine/chemokine production, neutrophil accumulation, and did not protect kidney function in PPARalpha null mice. In addition, we observed that cisplatin-induced NF-kappaB binding activity in nuclear extracts from wild-type mice was markedly reduced by treatment with PPARalpha ligand. These results demonstrate that PPARalpha exerts an anti-inflammatory effect in kidney tissue by a mechanism that includes inhibition of NF-kappaB DNA binding activity, and this effect results in inhibition of neutrophil infiltration, cytokine/chemokine release, and amelioration of cisplatin-induced ARF.
最近，我们证明过氧化物酶体增殖物激活受体-α（PPARα）配体可通过防止底物氧化受到抑制，以及防止近端小管细胞凋亡和坏死，来改善顺铂诱导的急性肾衰竭（ARF）（Li S、Bhatt R、Megyesi J、Gokden N、Shah SV和Portilla D。《美国生理学杂志：肾脏生理学》287：F990 - F998，2004年）。在接下来的研究中，我们检测了PPARα配体对ARF期间顺铂诱导的炎症反应的保护作用。单次腹腔注射顺铂的小鼠在第3天出现ARF。顺铂增加了TNF-α、RANTES的mRNA和蛋白表达，还上调了内皮黏附分子ICAM - 1/VCAM - 1以及趋化因子受体CCR1/CCR5。顺铂还导致中性粒细胞浸润到皮质髓质区域。在顺铂给药前，用PPARα配体类贝特药物WY - 14,643预处理野生型小鼠，可显著抑制顺铂诱导的细胞因子/趋化因子表达上调，防止中性粒细胞积聚，并改善肾功能障碍。相比之下，在顺铂给药前用PPARα配体处理，并不能防止PPARα基因敲除小鼠产生细胞因子/趋化因子、中性粒细胞积聚，也不能保护其肾功能。此外，我们观察到，用PPARα配体处理可显著降低野生型小鼠核提取物中顺铂诱导的NF-κB结合活性。这些结果表明，PPARα通过抑制NF-κB DNA结合活性的机制在肾脏组织中发挥抗炎作用，这种作用导致中性粒细胞浸润、细胞因子/趋化因子释放受到抑制，以及顺铂诱导的ARF得到改善。
