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

作者：Ma, Tongtong; Li, Hongwei; Liu, Hui; Peng, Yili; Lin, Tong; Deng, Zhiya; Jia, Nan; Chen, Zhongqing; Wang, Peng^*

来源：Molecular Therapy, 2022, 30(10): 3313-3332.

DOI：10.1016/j.ymthe.2022.05.019

• REPERFUSION INJURY
• RENAL FIBROSIS
• NONCODING RNAS
• PROTECTS MICE
• FAS
• DEATH
• EXPRESSION
• CARCINOMA
• NETWORKS
• CANCER

Acute kidney injury (AKI) is increasingly identified as a crucial risk factor for progression to CKD. However, the factors gov-erning 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 devel-opment 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 po-tential therapeutic strategy for AKI to CKD progression.

• 单位
  南方医科大学; 1; 广州医学院