《Frontiers in Cell and Developmental Biology》：Mechanisms and therapeutic prospects of hypoxia-inducible factor 1-alpha in acute kidney injury: a systematic review
编辑推荐：
本综述系统梳理了缺氧诱导因子1-α（HIF-1α）在急性肾损伤（AKI）中的双重角色与治疗潜力。文章聚焦于HIF-1α在肾缺血再灌注损伤（IRI）中的核心作用，详细阐述了其通过调控氧化应激、细胞凋亡、炎症反应及组织修复等分子机制，在AKI病理进程中的复杂网络。综述指出，靶向HIF-1α（尤其是其上游调控因子脯氨酰羟化酶抑制剂PHDi）是极具前景的AKI治疗新策略，为改善临床预后提供了新的理论依据和研究方向。
引言
急性肾损伤（AKI）是一种以肾小球滤过率（GFR）迅速下降和含氮废物积聚为特征的临床综合征，其全球发病率在过去二十年中显著上升。住院患者中AKI发病率约为10%–15%，在重症监护病房患者中超过50%，并与死亡风险增加四倍相关。肾缺血再灌注损伤（IRI）是AKI的主要病理机制，常继发于败血症、创伤或大手术，涉及直接的缺血损伤和再灌注引发的炎症级联反应。肾脏作为高灌注器官，对缺血性损伤尤其敏感，会迅速发生活性氧（ROS）导致的氧化应激，以及炎症和细胞凋亡，尤其在近端小管。再灌注会进一步加剧损伤；ROS水平在早期激增并持续24小时，降低一氧化氮（NO）生物利用度并加重血管收缩。缺氧诱导因子1-α（HIF-1α）作为细胞应对缺氧环境的核心转录因子，在肾IRI中扮演着复杂且双重的角色。
HIF-1α的病理生理功能
HIF是一种异源二聚体转录因子，由α（HIF-1α, HIF-2α）和β亚基组成。HIF-1α亚基的稳定性是HIF活性的关键决定因素。在常氧条件下，脯氨酰羟化酶结构域酶（PHDs）羟基化HIF-1α，促进其被von Hippel-Lindau（pVHL）E3泛素连接酶复合物识别，进而被蛋白酶体降解。相反，在缺氧条件下，羟基化被抑制，使得HIF-1α得以积累、核转位、与HIF-1β二聚化，并激活参与血管生成、细胞凋亡和代谢的靶基因。HIF-1α在代谢水平上促进无氧糖酵解并调节线粒体质量控制。在炎症方面，肾小管来源的细胞外囊泡（EVs）可稳定巨噬细胞中的HIF-1α，诱导糖酵解重编程，促进IL-1β、TNF-α和TGF-β1的释放，从而加剧间质炎症和纤维化。
HIF-1α与肾缺血：双重作用的新证据
HIF-1α的动态表达深刻影响AKI的结局。在IRI小鼠模型中，持续的HIF-1α活化与严重的AKI和纤维化相关，而给予HIF-1α抑制剂PX-478则可改善从AKI向慢性肾脏病（CKD）的转变。其作用具有损伤严重程度依赖性：轻度缺血时，HIF-1α通过激活BNIP3等通路促进线粒体自噬（mitophagy），从而促进线粒体质量控制和提高缺血耐受性；然而， prolonged hypoxia prolonged hypoxia prolonged hypoxia prolonged hypoxia prolonged hypoxia prolonged hypoxia prolonged hypoxia prolonged hypoxia prolonged hypoxia prolonged hypoxia prolonged hypoxia prolonged hypoxia prolonged hypoxia prolonged hypoxia prolonged hypoxia prolonged hypoxia prolonged hypoxia prolonged hypoxia prolonged hypoxia prolonged hypoxia prolonged hypoxia prolonged hypoxia prolonged hypoxia prolonged hypoxia prolonged hypoxia prolonged hypoxia prolonged hypoxia prolonged hypoxia prolonged hypoxia prolonged hypoxia prolonged hypoxia prolonged hypoxia prolonged hypoxia prolonged hypoxia prolonged hypoxia prolonged hypoxia prolonged hypoxia prolonged hypoxia prolonged hypoxia prolonged hypoxia prolonged hypoxia prolonged hypoxia prolonged hypoxia prolonged hypoxia prolonged hypoxia prolonged 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