Chang Heng-Ai, Ou Yang Rui-Zhi, Su Jing-Ming, Nguyen Thi My Hang, Sung Junne-Ming, Tang Ming-Jer, Chiu Wen-Tai
Institute of Basic Medical Sciences, National Cheng Kung University, Tainan, 701, Taiwan, ROC.
Department of Biomedical Engineering, National Cheng Kung University, Tainan, 701, Taiwan, ROC.
Cell Death Discov. 2023 Oct 20;9(1):385. doi: 10.1038/s41420-023-01687-5.
Maladaptive repair of acute kidney injury (AKI) is associated with a high risk of developing chronic kidney disease deemed irremediable even in present days. When AKI arises from ischemia-reperfusion injury, hypoxia usually plays a major role. Although both hypoxia-inducible factor-1α (HIF-1α) and yes-associated protein (YAP) have been proven to promote renal cell survival under hypoxia, there is a lack of research that studies the crosstalk of the two and its effect on kidney repair. In studying the crosstalk, CoCl was used to create a mimetic hypoxic environment. Immunoprecipitation and proximity ligation assays were performed to verify protein interactions. The results show that HIF-1α interacts with YAP and promotes nuclear translocation of YAP at a high cell density under hypoxic conditions, suggesting HIF-1α serves as a direct carrier that enables YAP nuclear translocation. This is the first study to identify HIF-1α as a crucial pathway for YAP nuclear translocation under hypoxic conditions. Once translocated into a nucleus, YAP protects cells from DNA damage and apoptosis under hypoxic conditions. Since it is unlikely for YAP to translocate into a nucleus without HIF-1α, any treatment that fosters the crosstalk between the two holds the potential to improve cell recovery from hypoxic insults.
急性肾损伤（AKI）的适应性修复与发展为慢性肾病的高风险相关，即使在当今，这种慢性肾病也被认为是无法治愈的。当AKI由缺血再灌注损伤引起时，缺氧通常起主要作用。尽管缺氧诱导因子-1α（HIF-1α）和Yes相关蛋白（YAP）都已被证明可在缺氧条件下促进肾细胞存活，但缺乏对两者相互作用及其对肾脏修复影响的研究。在研究这种相互作用时，使用氯化钴来创建模拟缺氧环境。进行免疫沉淀和邻近连接分析以验证蛋白质相互作用。结果表明，在缺氧条件下，HIF-1α与YAP相互作用，并在高细胞密度下促进YAP的核转位，这表明HIF-1α作为直接载体促使YAP核转位。这是首次将HIF-1α鉴定为缺氧条件下YAP核转位的关键途径。一旦转位到细胞核中，YAP可在缺氧条件下保护细胞免受DNA损伤和凋亡。由于没有HIF-1α时YAP不太可能转位到细胞核中，任何促进两者相互作用的治疗都有可能改善细胞从缺氧损伤中的恢复。
