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.

急性肾损伤（AKI）越来越被认为是进展为 CKD 的关键危险因素。然而，控制 AKI 向 CKD 进展的因素仍然很大程度上未知。通过高通量RNA测序，我们发现Neat1_2 （ Neat1的转录变体）在40分钟缺血/再灌注损伤（IRI）中表达上调，从而导致肾纤维化病变的发展。缺氧处理的 TEC 中Neat1_2的上调归因于 p53 转录调控。体外和体内的功能获得和丧失研究表明，Neat1_2促进 IRI 诱导的受损 TEC 细胞凋亡，并引起肾小管间质炎症和纤维化。从机制上讲，Neat1_2与FADD、CASP-8和CASP-3共享 miRNA 响应元件。Neat1_2竞争性地结合miR-129-5p并阻止miR-129-5p降低FADD、CASP-8和CASP-3的水平，最终促进 TEC 凋亡。在人类 AKI 中再现了与肾损伤和 TEC 凋亡相关的Neat1_2表达增加，突出了其临床相关性。这些发现表明，通过阻碍Neat1_2表达来预防 TEC 凋亡可能是 AKI 向 CKD 进展的潜在治疗策略。