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Theranostics 2020; 10(15):6806-6824. doi:10.7150/thno.43145 This issue Cite

Research Paper

Renal tubular Bim mediates the tubule-podocyte crosstalk via NFAT2 to induce podocyte cytoskeletal dysfunction

Chunmei Xu^1,2#, Xiaojun Zhou^3,1#, Tianyue Xie^4,5, Yuan Zhou³, Qian Zhang⁶, Shan Jiang⁶, Rui Zhang⁶, Lin Liao^1,3✉, Jianjun Dong^6✉

1. Department of Endocrinology and Metabology, Shandong Provincial Qianfoshan Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.
2. Laboratory of Endocrinology, Medical Research Center, the First Affiliated Hospital of Shandong First Medical University, Jinan, Shandong, China.
3. Department of Endocrinology and Metabology, the First Affiliated Hospital of Shandong First Medical University, Jinan, Shandong, China.
4. First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China.
5. Department of Endocrinology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China.
6. Department of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.
#co-first authors

✉ Corresponding authors: Lin Liao, PhD, Department of Endocrinology and Metabology, Shandong Provincial Qianfoshan Hospital, Cheeloo College of Medicine, Shandong University, the First Affiliated Hospital of Shandong First Medical University, Jinan, Shandong, People's Republic of China, 250014E-mail: liaolinedu.cn, Phone: 15168888260; Jianjun Dong, PhD, Department of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, People's Republic of China, 250012, E-mail: cwc_lledu.cn., Phone: 13791122910. More

Abstract

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.

Keywords: diabetic nephropathy, communication, cytoskeleton, Bim, coculture

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