PGC-1α promotes recovery after acute kidney injury during systemic inflammation in mice
PGC-1α promotes recovery after acute kidney injury during systemic inflammation in mice
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DOI：
10.1172/jci58662
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发表时间：
2011-10-01
影响因子：
15.9
通讯作者：
Parikh, Samir M.
中科院分区：
文献类型：
--
作者：
Tran, Mei;Tam, Denise;Parikh, Samir M.
脓毒症相关性急性肾损伤(AM)是一种常见的病态疾病，与典型的缺血性肾损伤不同，它缺乏肾小管上皮细胞的死亡。因此，脓毒症相关性AM患者发生肾功能障碍的机制尚不清楚。在这里，我们已经证明，内毒素血症减少了向肾脏的氧气输送，而不改变组织的氧气水平，这表明肾脏细胞的氧气消耗减少。肾小管线粒体肿胀，功能受损。表达谱显示，氧化磷酸化基因在脓毒症相关AM期间被选择性抑制，并在整体功能正常化时重新激活。PPAR-γ辅活化子-1α(PGC-1α)是线粒体生物发生和代谢的主要调节因子，它不仅遵循这种模式，而且随着肾脏损害的程度成比例地被抑制。此外，肾小管上皮细胞对肿瘤坏死因子-α的反应降低了PGC-1α的表达和氧耗；然而，过量的PGC-1α逆转了后者的作用。全局和小管特异的PGC-1α基因敲除小鼠都有正常的基础肾功能，但内毒素血症后持续损伤。我们的结果证明了一种我们认为是败血症相关AM的新机制，并表明PGC-1α的诱导可能是从这种疾病中恢复所必需的，为未来的治疗研究确定了一个潜在的新靶点。
Sepsis-associated acute kidney injury (AM) is a common and morbid condition that is distinguishable from typical ischemic renal injury by its paucity of tubular cell death. The mechanisms underlying renal dysfunction in individuals with sepsis-associated AM are therefore less clear. Here we have shown that endotoxemia reduces oxygen delivery to the kidney, without changing tissue oxygen levels, suggesting reduced oxygen consumption by the kidney cells. Tubular mitochondria were swollen, and their function was impaired. Expression profiling showed that oxidative phosphorylation genes were selectively suppressed during sepsis-associated AM and reactivated when global function was normalized. PPAR gamma coactivator-1 alpha (PGC-1 alpha), a major regulator of mitochondrial biogenesis and metabolism, not only followed this pattern but was proportionally suppressed with the degree of renal impairment. Furthermore, tubular cells had reduced PGC-1 alpha expression and oxygen consumption in response to TNF-alpha; however, excess PGC-1 alpha reversed the latter effect. Both global and tubule-specific PGC-1 alpha-knockout mice had normal basal renal function but suffered persistent injury following endotoxemia. Our results demonstrate what we believe to be a novel mechanism for sepsis-associated AM and suggest that PGC-1 alpha induction may be necessary for recovery from this disorder, identifying a potential new target for future therapeutic studies.