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./nMethods: 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)./nResults: 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./nConclusion: 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.

中文翻译：

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肾小管Bim通过NFAT2介导小管与足细胞的串扰，从而诱发足细胞的细胞骨架功能障碍。

糖尿病肾病（DN）主要被认为是糖尿病性肾小球病，其进展与肾小管上皮病变密切相关。然而，关于肾小管损害和肾小球病变的潜在分子机制了解甚少。/n方法：我们以前报道过Bim介导的近端肾小管上皮细胞（PTEC）凋亡的上调，这在DN的早期至关重要。本文我们调制的PTECs和Bim表达随后确定的足细胞（PC）通过在高浓度葡萄糖（HG）./ n个结构Transwell小共培养系统细胞骨架排列结果：与正常葡萄糖相比，暴露于40 mM HG中48 h诱导PTEC中Bim的显着表达和PC细胞骨架的混乱。与HG中的PTECs共培养时，在PC中检测到加剧的丝状肌动蛋白（F-actin）重排和突触足蛋白水平降低。相反，PTECs中Bim的基因敲低与PC细胞骨架的缺乏相关。通过抑制Bim表达，可降低PTEC中NFAT2的水平及其核易位。上调NFAT2会破坏通过抑制Bim获得的PC对F-肌动蛋白组织的有益作用。LncRNA芯片分析鉴定出NONHSAT179542.1，与Bim介导的PC细胞骨架疾病有关。/n结论：我们的研究阐明了促凋亡因子Bim的功能作用，该因子参与PTEC和PC之间的串扰。Bim促进PTEC中的NFAT2激活，诱导PC上的lncRNA NONHSAT179542.1下调，从而导致细胞骨架损伤。鉴定Bim / NFAT2途径的作用可能代表了对DN发展的更好理解的有前途的研究方向。