PPAR-α ligand ameliorates acute renal failure by reducing cisplatin-induced increased expression of renal endonuclease G
PPAR-α ligand ameliorates acute renal failure by reducing cisplatin-induced increased expression of renal endonuclease G
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DOI：
10.1152/ajprenal.00206.2004
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发表时间：
2004-11-01
影响因子：
4.2
通讯作者：
Portilla, D
中科院分区：
文献类型：
--
作者：
Li, SY;Bhatt, R;Portilla, D
顺铂对肾脏的损伤的部分特征在于抑制底物氧化、炎症以及以细胞凋亡和坏死形式出现的肾小管细胞死亡。最近，我们证明顺铂诱导的底物氧化抑制可以通过给予过氧化物酶体增殖物激活受体-α（PPAR-α）配体来逆转，从而改善肾功能。因此，我们假设通过改善体内脂肪酸氧化可能通过减少顺铂治疗小鼠的细胞凋亡和坏死来保护肾功能。单次腹腔注射顺铂的小鼠在第 3 天和第 4 天出现急性肾衰竭 (ARF)。在注射顺铂后的第 4 天，与盐水处理的小鼠相比，促凋亡肾内切酶 G (Endo G) 的 mRNA、蛋白水平和酶活性有所增加。原位杂交和免疫组织化学研究发现，在顺铂治疗的小鼠中，Endo G mRNA 的表达增加位于胞质区室，Endo G 蛋白的表达增加位于近端小管的核区室。用 PPAR-α 配体 WY-14643 预处理 PPAR-α 野生型小鼠，显着降低顺铂诱导的 Endo G 蛋白表达和酶活性增加，并阻止线粒体 Endo G 的核转位。接受 PPAR-α 配体和顺铂的 PPAR-α 野生型小鼠肾小管损伤的形态学检查确实显示急性肾小管坏死显着改善，近端凋亡细胞数量显着减少与顺铂治疗组相比。相反，在用配体和顺铂治疗的 PPAR-α 缺失小鼠中，Endo G 蛋白表达没有减少，并且缺乏对肾功能的保护。我们得出的结论是，PPAR-α 配体通过 PPAR-α 依赖性机制，通过降低近端小管 Endo G 的表达和酶活性，防止顺铂诱导的肾损伤，从而改善近端肾小管细胞凋亡和坏死。
Cisplatin injury to the kidney is characterized, in part, by inhibition of substrate oxidation, inflammation, and tubular cell death in the form of apoptosis and necrosis. Recently, we demonstrated that cisplatin-induced inhibition of substrate oxidation can be reversed by the administration of peroxisome proliferator-activated receptor-alpha (PPAR-alpha) ligands, resulting in amelioration of renal function. We therefore hypothesize that by improving fatty acid oxidation in vivo might protect renal function by reducing both apoptosis and necrosis in cisplatin-treated mice. Mice subjected to a single intraperitoneal injection of cisplatin developed acute renal failure (ARF) at days 3 and 4. At day 4 after cisplatin injection mRNA, protein levels and enzyme activity of proapoptotic renal endonuclease G (Endo G) were increased compared with saline-treated mice. In situ hybridization and immunohistochemical studies localized the increased expression of Endo G mRNA to the cytosolic compartment and Endo G protein to the nuclear compartment of proximal tubules in cisplatin-treated mice. Pretreatment of PPAR-alpha wild-type mice with PPAR-alpha ligand WY-14643 reduced significantly cisplatin-induced increased protein expression and enzyme activity of Endo G and prevented the nuclear translocation of mitochondrial Endo G. Morphological examination of tubular injury in the PPAR-alpha wild-type mice that received PPAR-alpha ligand and cisplatin did show significant amelioration of acute tubular necrosis, as well as a significant reduction in the number of apoptotic cells in the proximal tubule when compared with the cisplatin-treated group. In contrast, in PPAR-alpha-null mice treated with the ligand and cisplatin, Endo G protein expression was not reduced and this was accompanied by lack of protection of kidney function. We conclude that PPAR-alpha ligand protects against cisplatin-induced renal injury via a PPAR-alpha-dependent mechanism by reducing the expression and enzyme activity of proximal tubule Endo G, which results in amelioration of both proximal tubule cell apoptosis and necrosis.