J Clin Invest. 2014 Jun;124(6):2396-409. doi: 10.1172/JCI69073. Epub 2014 May 1.
The hypoxia-inducible transcription factors HIF-1 and HIF-2 mediate key cellular adaptions to hypoxia and contribute to renal homeostasis and pathophysiology; however, little is known about the cell type-specific functions of HIF-1 and HIF-2 in response to ischemic kidney injury. Here, we used a genetic approach to specifically dissect the roles of endothelial HIF-1 and HIF-2 in murine models of hypoxic kidney injury induced by ischemia reperfusion or ureteral obstruction. In both models, inactivation of endothelial HIF increased injury-associated renal inflammation and fibrosis. Specifically, inactivation of endothelial HIF-2α, but not endothelial HIF-1α, resulted in increased expression of renal injury markers and inflammatory cell infiltration in the postischemic kidney, which was reversed by blockade of vascular cell adhesion molecule-1 (VCAM1) and very late antigen-4 (VLA4) using monoclonal antibodies. In contrast, pharmacologic or genetic activation of HIF via HIF prolyl-hydroxylase inhibition protected wild-type animals from ischemic kidney injury and inflammation; however, these same protective effects were not observed in HIF prolyl-hydroxylase inhibitor-treated animals lacking endothelial HIF-2. Taken together, our data indicate that endothelial HIF-2 protects from hypoxia-induced renal damage and represents a potential therapeutic target for renoprotection and prevention of fibrosis following acute ischemic injury.
缺氧诱导因子（HIF）-1 和 HIF-2 介导了细胞对缺氧的关键适应，并有助于肾脏的内稳态和病理生理学；然而，对于缺氧性肾损伤中 HIF-1 和 HIF-2 的细胞类型特异性功能知之甚少。在这里，我们使用一种遗传方法，特异性地剖析了内皮细胞 HIF-1 和 HIF-2 在缺血再灌注或输尿管梗阻诱导的缺氧性肾损伤的小鼠模型中的作用。在这两种模型中，内皮细胞 HIF 的失活增加了与损伤相关的肾炎症和纤维化。具体而言，内皮细胞 HIF-2α的失活，而不是内皮细胞 HIF-1α的失活，导致缺血后肾脏中肾损伤标志物的表达增加和炎症细胞浸润，使用单克隆抗体阻断血管细胞黏附分子-1（VCAM1）和非常迟抗原-4（VLA4）可逆转这种情况。相比之下，通过抑制脯氨酰羟化酶使 HIF 药理学或遗传学激活可保护野生型动物免受缺血性肾损伤和炎症的影响；然而，在缺乏内皮细胞 HIF-2 的 HIF 脯氨酰羟化酶抑制剂处理的动物中，没有观察到这些相同的保护作用。总之，我们的数据表明，内皮细胞 HIF-2 可防止缺氧引起的肾损伤，代表了急性缺血损伤后肾保护和预防纤维化的潜在治疗靶点。
