Heme Oxygenase-1 Inhibits Renal Tubular Macroautophagy in Acute Kidney Injury
Heme Oxygenase-1 Inhibits Renal Tubular Macroautophagy in Acute Kidney Injury
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DOI：
10.1681/asn.2010030238
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发表时间：
2010-10-01
影响因子：
13.6
通讯作者：
Agarwal, Anupam
中科院分区：
文献类型：
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作者：
Bolisetty, Subhashini;Traylor, Amie M.;Agarwal, Anupam
自噬是一种严格调控的程序化机制，可以清除细胞中受损的细胞器和蛋白质，以维持体内平衡。顺铂是一种化疗药物，聚集在肾脏近端小管上，引起剂量依赖性的肾毒性，这可能涉及自噬。在肾脏中，顺铂诱导保护性抗氧化剂血红素加氧酶-1(HO-1)。在这项研究中，我们研究了顺铂介导的急性肾损伤(AKI)过程中自噬与HO-1的关系。在野生型原代近端小管细胞(PTC)中，我们观察到顺铂后自噬的时间依赖性增加。然而，在HO-1 PTC中，我们观察到基础自噬水平显著升高，自噬进展受阻，顺铂治疗后细胞凋亡增加。恢复HO-1的表达逆转了顺铂处理后的自噬反应并抑制了细胞的凋亡。在体内，尽管野生型和HO-1缺陷小鼠对顺铂的反应都在肾脏近端小管中显示了自噬小体，但HO-1缺陷小鼠的自噬小体明显更多，即使在生理盐水处理的小鼠中也是如此。此外，蜕皮激素诱导的HO-1在细胞中的过表达导致自噬进程的延迟，产生的活性氧水平显著降低，并保护细胞免受顺铂的细胞毒性。这些发现表明，HO-1抑制自噬，提示血红素加氧酶系统可能包含AKI的治疗靶点。
Autophagy is a tightly regulated, programmed mechanism to eliminate damaged organelles and proteins from a cell to maintain homeostasis. Cisplatin, a chemotherapeutic agent, accumulates in the proximal tubules of the kidney and causes dose-dependent nephrotoxicity, which may involve autophagy. In the kidney, cisplatin induces the protective antioxidant heme oxygenase-1 (HO-1). In this study, we examined the relationship between autophagy and HO-1 during cisplatin-mediated acute kidney injury (AKI). In wild-type primary proximal tubule cells (PTC), we observed a time-dependent increase in autophagy after cisplatin. In HO-1 PTC, however, we observed significantly higher levels of basal autophagy, impaired progression of autophagy, and increased apoptosis after cisplatin. Restoring HO-1 expression in these cells reversed the autophagic response and inhibited apoptosis after treatment with cisplatin. In vivo, although both wild-type and HO-1 deficient mice exhibited autophagosomes in the proximal tubules of the kidney in response to cisplatin, HO-1 deficient mice had significantly more autophagosomes, even in saline-treated animals. In addition, ecdysone-induced overexpression of HO-1 in cells led to a delay in autophagy progression, generated significantly lower levels of reactive oxygen species, and protected against cisplatin cytotoxicity. These findings demonstrsate that HO-1 inhibits autophagy, suggesting that the heme oxygenase system may contain therapeutic targets for AKI.