從急性腎損傷不完全的康復是後續發展出纖維化及慢性腎臟病的高風險因子，並且目前對於慢性腎臟病的有效治療方法非常有限。在缺血-再灌流損傷誘導的急性腎臟病中，缺氧被視為是主要的誘發因素，因此探討缺氧誘導因子在腎臟修復中所扮演的角色是格外重要。Yes-associated protein (YAP)是Hippo pathway 中主要的轉錄因子，其調控了細胞生長、器官修復和抑制細胞凋亡。YAP 在細胞核和細胞質間的分布情況，對於其轉錄活性的平衡有重要影響。一般而言，高密度使YAP 停留在細胞質中並抑制其轉錄活性。令人驚訝的是，我們發現高密度下，缺氧可以誘導YAP 進入細胞核，顯示YAP 的核質轉移可以受缺氧所調控並主導YAP 在缺血-再灌流損傷模式中的影響力。我們的目標是揭示缺氧誘導的YAP 核轉移機制和功能。利用缺氧模擬藥物CoCl2，我們模擬缺氧的環境，並進行免疫沉澱和PLA 實驗和來驗證蛋白質之間的交互作用。我們的研究結果顯示在缺氧環境中，高密度下，HIF-1α 可促進YAP 的核轉移。值得注意的是，缺氧環境下，YAP 的核轉移可以保護細胞並對抗DNA 損傷和細胞凋亡。本篇研究是首次驗證缺氧下HIF-1α 本身足以誘導YAP 入核。這些發現顯示YAP 的轉錄活性可作為標靶來促進細胞在缺氧下的修復，提供像是缺氧、缺血、或纖維化等腎臟病一個潛在的療法。

Inadequate recovery from acute kidney injury (AKI) poses a significant risk of progressing to fibrosis and chronic kidney disease, with limited effective therapies available. Hypoxia serves as a primary trigger for ischemia-reperfusion injury (IRI)-induced AKI, making it crucial to investigate the involvement of hypoxia-inducible factor-1α (HIF-1α) in kidney repair. Yes-associated protein (YAP), a key transcription factor in the Hippo pathway, regulates cell proliferation, organ regeneration, and apoptosis inhibition. YAP's subcellular localization, balancing between the nucleus and cytoplasm, is pivotal for its transcriptional activity. Typically, high cell density inhibits YAP activity, retaining it in the cytoplasm. Surprisingly, our observations reveal YAP nuclear translocation under hypoxic conditions at elevated cell density, indicating that the nucleocytoplasmic shuttling of YAP, modulated by hypoxia, influences its impact on IRI. Our objective is to unravel the mechanism behind hypoxia-induced nuclear translocation of YAP and its implications. Utilizing the hypoxia-mimetic agent CoCl2, we simulated a hypoxia-like environment and conducted immunoprecipitation and proximity ligation assay to validate protein interactions. Our findings demonstrate that HIF-1α actively facilitates the nuclear translocation of YAP at high cell density under hypoxic conditions. Remarkably, YAP's nuclear translocation provides cellular protection against DNA damage and apoptosis in hypoxic settings. Notably, this study is the first to identify that the nuclear entry of HIF-1α alone is sufficient to induce YAP nuclear translocation under hypoxic conditions. These discoveries suggest that targeting YAP activation could be a viable strategy to enhance cell recovery during hypoxic insults, offering potential avenues for the treatment of renal diseases associated with hypoxia, ischemia, and fibrosis.

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