Department of Nephrology and Hypertension, Friedrich-Alexander-University, Erlangen-Nuremberg, Krankenhausstrasse 12, 91054 Erlangen, Germany.
J Am Soc Nephrol. 2011 Nov;22(11):2004-15. doi: 10.1681/ASN.2010121249. Epub 2011 Sep 15.
Hypoxia-inducible transcription factors (HIF) protect cells against oxygen deprivation, and HIF stabilization before ischemia mitigates tissue injury. Because ischemic acute kidney injury (AKI) often involves the thick ascending limb (TAL), modulation of HIF in this segment may be protective. Here, we generated mice with targeted TAL deletion of the von Hippel-Lindau protein (Vhl), which mediates HIF degradation under normoxia, using Tamm-Horsfall protein (Thp)-driven Cre expression. These mice showed strong expression of HIF-1α in TALs but no changes in kidney morphology or function under control conditions. Deficiency of Vhl in the TAL markedly attenuated proximal tubular injury and preserved TAL function following ischemia-reperfusion, which may be partially a result of enhanced expression of glycolytic enzymes and lactate metabolism. These results highlight the importance of the thick ascending limb in the pathogenesis of AKI and suggest that pharmacologically targeting the HIF system may have potential to prevent and mitigate AKI.
缺氧诱导转录因子 (HIF) 可保护细胞免受缺氧的影响，在缺血前稳定 HIF 可减轻组织损伤。因为缺血性急性肾损伤 (AKI) 常涉及到升支粗段 (TAL)，因此对该节段的 HIF 进行调节可能具有保护作用。在这里，我们使用 Tamm-Horsfall 蛋白 (Thp) 驱动的 Cre 表达，在 VHL 介导的 HIF 降解的正常条件下，生成了 TAL 中靶向 VHL 缺失的小鼠。这些小鼠在 TAL 中表现出强烈的 HIF-1α 表达，但在对照条件下，肾脏形态或功能没有变化。TAL 中 VHL 的缺失显著减轻了缺血再灌注后的近端肾小管损伤，并维持了 TAL 功能，这可能部分是由于糖酵解酶和乳酸代谢的表达增强所致。这些结果强调了升支粗段在 AKI 发病机制中的重要性，并表明药物靶向 HIF 系统可能具有预防和减轻 AKI 的潜力。
