MG53-mediated cell membrane repair protects against acute kidney injury.
MG53-mediated cell membrane repair protects against acute kidney injury.
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DOI：
10.1126/scitranslmed.3010755
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发表时间：
2015-03-18
影响因子：
17.1
通讯作者：
Ma J
中科院分区：
文献类型：
--
作者：
Duann P;Li H;Lin P;Tan T;Wang Z;Chen K;Zhou X;Gumpper K;Zhu H;Ludwig T;Mohler PJ;Rovin B;Abraham WT;Zeng C;Ma J
肾近端肾小管上皮细胞（PTE）的损伤是急性肾损伤（阿基）暴露于各种应激因素（包括肾毒素和缺血/再灌注（I/R））后的潜在后果。虽然肾脏在轻度损伤后有自我修复的能力，但PTE细胞的修复不足可能引发炎症和纤维化反应，导致慢性肾衰竭。我们报告说，MG 53，TRIM蛋白家族的成员，参与修复受伤的PTE细胞，并防止阿基的发展。我们发现MG 53易位到PTE细胞上的急性损伤部位并形成修复补丁。MG 53的消融导致有缺陷的膜修复。与野生型小鼠相比，MG 53缺陷型小鼠发生明显的肾小管间质损伤，并增加对I/R诱导的阿基的易感性。重组人MG 53（rhMG 53）蛋白可以靶向PTE细胞上的损伤位点，以促进I/R损伤或肾毒素暴露后的修复。此外，在动物研究中，静脉内递送rhMG 53改善顺铂诱导的阿基，而不影响顺铂的肿瘤抑制功效。这些发现将MG 53确定为肾脏保护的重要组分，靶向MG 53介导的PTE细胞修复代表了预防和治疗阿基的潜在方法。
Injury to the renal proximal tubular epithelium (PTE) represents the underlying consequence of acute kidney injury (AKI) after exposure to various stressors, including nephrotoxins and ischemia/reperfusion (I/R). Although the kidney has the ability to repair itself after mild injury, insufficient repair of PTE cells may trigger inflammatory and fibrotic responses, leading to chronic renal failure. We report that MG53, a member of the TRIM family of proteins, participates in repair of injured PTE cells and protects against the development of AKI. We show that MG53 translocates to acute injury sites on PTE cells and forms a repair patch. Ablation of MG53 leads to defective membrane repair. MG53-deficient mice develop pronounced tubulointerstitial injury and increased susceptibility to I/R-induced AKI compared to wild-type mice. Recombinant human MG53 (rhMG53) protein can target injury sites on PTE cells to facilitate repair after I/R injury or nephrotoxin exposure. Moreover, in animal studies, intravenous delivery of rhMG53 ameliorates cisplatin-induced AKI without affecting the tumor suppressor efficacy of cisplatin. These findings identify MG53 as a vital component of reno-protection, and targeting MG53-mediated repair of PTE cells represents a potential approach to prevention and treatment of AKI.