Inhibition of the lncRNA MIAT prevents podocyte injury and mitotic catastrophe in diabetic nephropathy

Molecular Therapy: Nucleic Acids

Rong Wang¹  Junhui Zhen¹  Qun Yu²  Ying Chang³  Yue Liu⁴  Zhimei Lv⁴  Bing Liu⁴  Ziyang Wang⁴  Xiaobing Li⁵  Jiangong Lin⁶ 

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

关键词: MT;    diabetic nephropathy;    MIAT;    podocyte;    mitotic catastrophe;    Sox4;   

DOI  :  

来源: DOAJ

【 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 (lncRNA) 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 (KO) 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 p21cip1/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.

【 授权许可】

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