Renal tubular Bim mediates the tubule-podocyte crosstalk via NFAT2 to induce podocyte cytoskeletal dysfunction
Renal tubular Bim mediates the tubule-podocyte crosstalk via NFAT2 to induce podocyte cytoskeletal dysfunction
复制标题
肾小管 Bim 通过 NFAT2 介导肾小管-足细胞串扰诱导足细胞骨架功能障碍
DOI：
10.7150/thno.43145
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发表时间：
2020-01-01
期刊：
影响因子：
12.4
通讯作者：
Dong, Jianjun
中科院分区：
文献类型：
--
作者：
Xu, Chunmei;Zhou, Xiaojun;Dong, Jianjun
糖尿病肾病主要被认为是糖尿病肾小球病变，其进展与肾小管上皮病变密切相关。然而，肾小管损伤和肾小球病变之间的潜在分子机制却知之甚少。方法：我们先前报道Bim上调介导了近端肾小管上皮细胞(PTEC)的凋亡，并在糖尿病肾病的早期阶段起关键作用。在此，我们通过在高糖(HG)中建立Transwell共培养体系来调节PTECs中Bim的表达，并随后确定了足细胞(PC)的细胞骨架排列。结果：与正常葡萄糖相比，40 mM汞暴露48h可显著诱导PTECs表达Bim，并使PC细胞骨架解体。在HG中与PTECs共同培养时，PCs的丝状肌动蛋白(F-肌动蛋白)重排加剧，突触素水平降低。相反，PTECs中Bim的基因敲除与PC细胞骨架紊乱的缺失相关。抑制Bim表达可降低PTECs中NFAT2的水平及其核转位。上调NFAT2阻断了通过抑制Bim而获得的对PC中F-肌动蛋白组织的有益影响。LncRNA芯片分析证实，NONHSAT179542.1与Bim介导的PC细胞骨架紊乱有关。结论：我们的研究阐明了Bim的功能作用，它是一种促凋亡因子，参与了PTECs和PC之间的串扰。BIM促进PTECs中NFAT2的激活，诱导PCs中lncRNA NONHSAT179542.1的下调，从而导致细胞骨架的损伤。识别Bim/NFAT2通路的作用可能是更好地了解糖尿病肾病发生发展的一个有前途的研究方向。
Diabetic nephropathy (DN) is mainly regarded as diabetic glomerulopathy, and its progression is tightly correlated with tubular epithelial lesions. However, the underlying molecular mechanisms linking tubular damage and glomerulopathy are poorly understood. Methods: We previously reported that the upregulation of Bim mediated proximal tubular epithelial cell (PTEC) apoptosis and was crucial in the early stages of DN. Herein we modulated Bim expression in PTECs and subsequently determined podocyte (PC) cytoskeletal arrangement by building a Transwell co-culture system in high glucose (HG). Results: Compared to normal glucose, exposure to 40 mM of HG for 48 h induced significant expression of Bim in PTECs and disorganization in the PC cytoskeleton. When cocultured with PTECs in HG, exacerbated filamentous actin (F-actin) rearrangement and reduced synaptopodin levels were detected in PCs. In contrast, gene knockdown of Bim in PTECs was correlated with the absence of PC cytoskeletal disorganization. NFAT2 level and its nuclear translocation in PTECs were decreased by suppressing Bim expression. Upregulating NFAT2 disrupted the beneficial effects on F-actin organization in PCs obtained by inhibiting Bim. LncRNA microarray analysis identified NONHSAT179542.1, which was implicated in Bim-mediated PC cytoskeletal disorder. Conclusion: Our study clarified the functional role of Bim, a pro-apoptotic factor, which is involved in the crosstalk between PTECs and PCs. Bim promotes NFAT2 activation in PTECs, inducing the downregulation of lncRNA NONHSAT179542.1 in PCs, contributing to the cytoskeletal damage. Identification of the role of the Bim/NFAT2 pathway may represent a promising research direction for a better understanding of DN development.