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作者

Ziyang Wang Ying Chang Yue Liu Bing Liu Junhui Zhen Xiaobing Li Jiangong Lin Qun Yu Zhimei Lv Rong Wang

作者单位

Institute of Basic Medicine, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong 250062, China Department of Pathology, School of Medicine, Shandong University, Jinan, Shandong 250012, China Department of Nephrology, Shandong Provincial Hospital, Shandong University, Jinan, Shandong 250021, China Department of Geriatrics, Chongqing General Hospital, Chongqing 401147, China Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250117, China

刊名

Molecular Therapy - Nucleic Acids

年份

2022

卷号

Vol.28

页码

136-153

ISSN

2162-2531

关键词

MT diabetic nephropathy MIAT podocyte mitotic catastrophe Sox4 p53 miR-130b-3p ubiquitination acetylation

摘要

Podocyte damage is strongly associated with the progression of diabetic nephropathy. Mitotic catastrophe plays an essential role in accelerating podocyte loss and detachment from the glomerular basement membrane. In the current study, we observed that the long non-coding RNA MIAT was noticeably upregulated in the plasma and kidney tissues of patients with diabetic nephropathy, and this upregulation was accompanied by higher albumin/creatinine ratios and serum creatinine levels. By generating CR...更多

Podocyte damage is strongly associated with the progression of diabetic nephropathy. Mitotic catastrophe plays an essential role in accelerating podocyte loss and detachment from the glomerular basement membrane. In the current study, we observed that the long non-coding RNA MIAT was noticeably upregulated in the plasma and kidney tissues of patients with diabetic nephropathy, and this upregulation was accompanied by higher albumin/creatinine ratios and serum creatinine levels. By generating CRISPR-Cas9 Miat-knockout mice in vivo and employing vectors in vitro, we found that the depletion of Miat expression significantly restored slit-diaphragm integrity, attenuated foot process effacement, prevented dedifferentiation, and suppressed mitotic catastrophe in podocytes during hyperglycemia. The mechanistic investigation revealed that Miat increased Sox4 expression and subsequently regulated p53 ubiquitination and acetylation, thereby inhibiting the downstream factors CyclinB/cdc2 by enhancing p21 cip1/waf1 activity, and that Miat interacted with Sox4 by sponging miR-130b-3p. Additionally, the inhibition of miR-130b-3p with an antagomir in vivo effectively enhanced glomerular podocyte injury and mitotic dysfunction, eventually exacerbating proteinuria. Based on these findings, MIAT may represent a therapeutic target for diabetic nephropathy.收起

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