Neat1 promotes acute kidney injury to chronic kidney disease by facilitating tubular epithelial cells apoptosis via sequestering miR-129-5p.

Abstract

Acute kidney injury (AKI) is increasingly identified as a crucial risk factor for progression to CKD. However, the factors governing AKI to CKD progression remain largely unknown. By high-throughput RNA sequencing, we found that Neat1_2, a transcript variant of Neat1, was upregulated in 40-min ischemia/reperfusion injury (IRI), which resulted in the development of renal fibrotic lesions. The upregulation of Neat1_2 in hypoxia-treated TECs was attributed to p53 transcriptional regulation. Gain- and loss-of-function studies, both in vitro and in vivo, demonstrated that Neat1_2 promoted apoptosis of injured TECs induced by IRI and caused tubulointerstitial inflammation and fibrosis. Mechanistically, Neat1_2 shares miRNA response elements with FADD, CASP-8, and CASP-3. Neat1_2 competitively binds to miR-129-5p and prevents miR-129-5p from decreasing the levels of FADD, CASP-8, and CASP-3, and ultimately facilitates TEC apoptosis. Increased expression of Neat1_2 associated with kidney injury and TEC apoptosis was recapitulated in human AKI, highlighting its clinical relevance. These findings suggest that preventing TEC apoptosis by hindering Neat1_2 expression may be a potential therapeutic strategy for AKI to CKD progression.

• Authors: Tongtong Ma, Hongwei Li, Hui Liu, Yili Peng, Tong Lin, Zhiya Deng, Nan Jia, Zhongqing Chen, Peng Wang
• Journal: Molecular therapy : the journal of the American Society of Gene Therapy (Mol Ther) Vol. 30 Issue 10 Pg. 3313-3332 (10 05 2022) ISSN: 1525-0024 [Electronic] United States
• PMID: 35619557 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.

Chemical References

• MicroRNAs
• Mirn129 microRNA, human
• NEAT1 long non-coding RNA, human
• RNA, Long Noncoding
• Tumor Suppressor Protein p53

Topics

• Acute Kidney Injury (genetics, metabolism)
• Apoptosis (genetics)
• Epithelial Cells (metabolism)
• Fibrosis
• Humans
• MicroRNAs (genetics, metabolism)
• RNA, Long Noncoding (genetics, metabolism)
• Renal Insufficiency, Chronic (genetics, metabolism, pathology)
• Tumor Suppressor Protein p53 (metabolism)