RGMb protects against acute kidney injury by inhibiting tubular cell necroptosis via an MLKL- dependent mechanism
RGMb protects against acute kidney injury by inhibiting tubular cell necroptosis via an MLKL- dependent mechanism
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RGMb 通过 MLKL 依赖性机制抑制肾小管细胞坏死性凋亡，从而预防急性肾损伤
DOI：
10.1073/pnas.1716959115
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发表时间：
2018-02-13
影响因子：
11.1
通讯作者：
Xia, Yin
中科院分区：
文献类型：
--
作者：
Liu, Wenjing;Chen, Binbin;Xia, Yin
肾小管细胞坏死是急性肾损伤(AKI)的重要组织学特征。坏死性上睑下垂是一种程序性坏死，它是由混合谱系激酶域样蛋白(MLKL)与质膜结合后发生的。越来越多的证据表明，坏死性下垂在AKI的发展中起着关键作用。然而，目前尚不清楚肾小管细胞是否在体内经历了坏死性下垂，以及在AKI过程中坏死性下垂途径是如何调节的。排斥性导向分子(RGM)-b是RGM家族的一员。我们先前的研究表明，RGMb在肾小管上皮细胞中高表达，但其在肾脏中的生物学作用尚未得到很好的表征。在目前的研究中，我们发现RGMb降低了培养细胞中膜相关的MLKL水平，并抑制了坏死性下垂。在缺血再灌注损伤(IRI)或草酸肾病时，MLKL在近曲小管(PT)细胞的顶膜上被诱导表达。与野生型小鼠相比，肾小管上皮细胞特异性Rgmb基因敲除(Rgmb CKO)增加了肾小管上皮细胞顶膜MLKL的表达，导致肾小管上皮细胞死亡和严重的肾功能障碍。在野生型和Rgmb CKO小鼠中，应用坏死抑制物Necrostatin-1或GSK‘963治疗可减少PT细胞顶膜上MLKL的表达，改善IRI后的肾功能损害。综上所述，我们的结果提示近端肾小管细胞坏死性下垂在AKI中起重要作用，RGMb通过抑制近端肾小管上皮细胞MLKL膜结合和坏死性下垂来保护AKI。
Tubular cell necrosis is a key histological feature of acute kidney injury (AKI). Necroptosis is a type of programed necrosis, which is executed by mixed lineage kinase domain-like protein (MLKL) upon its binding to the plasma membrane. Emerging evidence indicates that necroptosis plays a critical role in the development of AKI. However, it is unclear whether renal tubular cells undergo necroptosis in vivo and how the necroptotic pathway is regulated during AKI. Repulsive guidance molecule (RGM)-b is a member of the RGM family. Our previous study demonstrated that RGMb is highly expressed in kidney tubular epithelial cells, but its biological role in the kidney has not been well characterized. In the present study, we found that RGMb reduced membrane-associated MLKL levels and inhibited necroptosis in cultured cells. During ischemia/reperfusion injury (IRI) or oxalate nephropathy, MLKL was induced to express on the apical membrane of proximal tubular (PT) cells. Specific knockout of Rgmb in tubular cells (Rgmb cKO) increased MLKL expression at the apical membrane of PT cells and induced more tubular cell death and more severe renal dysfunction compared with wild-type mice. Treatment with the necroptosis inhibitor Necrostatin-1 or GSK'963 reduced MLKL expression on the apical membrane of PT cells and ameliorated renal function impairment after IRI in both wild-type and Rgmb cKO mice. Taken together, our results suggest that proximal tubular cell necroptosis plays an important role in AKI, and that RGMb protects against AKI by inhibiting MLKL membrane association and necroptosis in proximal tubular cells.