Institute of Medicine Science, University of Toronto, Toronto, Canada.
Am J Physiol Renal Physiol. 2013 Jan 1;304(1):F120-6. doi: 10.1152/ajprenal.00416.2012. Epub 2012 Oct 10.
Deletion of the von Hippel-Lindau tumor suppressor (Vhl) gene from renal podocytes of mice (podVhl KO) leads to rapidly progressive glomerulonephritis (RPGN), a clinical syndrome characterized by rapid loss of renal function and crescents on renal biopsy. Genomic profiling of glomeruli isolated from podVhl knockout (KO) mice and from patients with RPGN identified a fingerprint of genes regulated by hypoxia-inducible factors (HIF), important substrates of the product of the VHL gene. Here, we show that stabilization of Hifs in podocytes is both required and sufficient for the glomerular phenotype observed in podVhl KO mice. Genetic deletion of the obligate dimerization partner Arnt/Hif1b that is essential for Hif transcriptional function rescues the phenotype. Conversely, stabilization of HIF2A alone in podocytes results in crescentic glomerular disease. Together, our results show that the Hif pathway and Hif2a in particular are key players in maintenance of the glomerular barrier.
从小鼠肾足细胞中删除抑血管生成因子-1（VHL）肿瘤抑制基因（podVhl KO）会导致快速进行性肾小球肾炎（RPGN），这是一种以肾功能迅速丧失和肾活检上出现新月体为特征的临床综合征。从 podVhl 敲除（KO）小鼠和 RPGN 患者分离的肾小球的基因组分析确定了缺氧诱导因子（HIF）调节基因的特征，这些基因是 VHL 基因产物的重要底物。在这里，我们表明，足细胞中 HIF 的稳定化对于 podVhl KO 小鼠中观察到的肾小球表型既是必需的也是充分的。必需的 HIF 转录功能的必需二聚体伴侣 Arnt/Hif1b 的基因缺失可挽救该表型。相反，单独在足细胞中稳定 HIF2A 会导致新月体肾小球疾病。总之，我们的结果表明 Hif 通路，特别是 Hif2a，是维持肾小球屏障的关键因素。
