Elevated Endothelial Hypoxia-Inducible Factor-1α Contributes to Glomerular Injury and Promotes Hypertensive Chronic Kidney Disease.
Elevated Endothelial Hypoxia-Inducible Factor-1α Contributes to Glomerular Injury and Promotes Hypertensive Chronic Kidney Disease.
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升高的内皮缺氧诱导因子1α有助于肾小球损伤，并促进高血压慢性肾脏疾病。
DOI：
10.1161/hypertensionaha.115.05578
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发表时间：
2015-07
期刊：
影响因子：
--
通讯作者：
Xia Y
中科院分区：
文献类型：
--
作者：
Luo R;Zhang W;Zhao C;Zhang Y;Wu H;Jin J;Zhang W;Grenz A;Eltzschig HK;Tao L;Kellems RE;Xia Y
高血压慢性肾病是美国和世界范围内发病率和死亡率最高的疾病之一。然而，启动进展为高血压慢性肾脏病的早期事件知之甚少。我们假设内皮缺氧诱导因子-1 α升高是一种常见的早期损伤，触发初始肾小球损伤，导致高血压慢性肾脏病。为了验证我们的假设，我们使用血管紧张素II输注高血压慢性肾病模型来确定负责HIF-1α升高的特定细胞类型和机制及其在高血压慢性肾病进展中的作用。结合RT-PCR分析的遗传学研究显示，内皮HIF-1α升高是通过转录激活编码多种血管活性蛋白的基因启动肾小球损伤和进展为肾纤维化所必需的。从机制上讲，我们发现血管紧张素Ⅱ以核因子-κ B依赖的方式诱导内皮细胞HIF-1α基因表达。最后，我们发现内皮细胞HIF-1α和NF-κB基因的相互正性转录调控是其持续激活和疾病进展的关键驱动力。总之，我们的研究结果表明，刺激内皮细胞中HIF-1α基因表达对诱导肾损伤、高血压和疾病进展是不利的。我们的研究结果强调了高血压慢性肾脏病的早期诊断机会和治疗方法。
Hypertensive chronic kidney disease is one of the most prevalent medical conditions with high morbidity and mortality in the United States and worldwide. However, early events initiating the progression to hypertensive chronic kidney disease are poorly understood. We hypothesized that elevated endothelial hypoxia-inducible factor-1alpha is a common early insult triggering initial glomerular injury leading to hypertensive chronic kidney disease. To test our hypothesis we used an angiotensin II infusion model of hypertensive chronic kidney disease to determine the specific cell type and mechanisms responsible for elevation of HIF-1α and its role in the progression of hypertensive chronic kidney disease. Genetic studies coupled with RT-PCR profiling revealed that elevated endothelial HIF-1α is essential to initiate glomerular injury and progression to renal fibrosis by the transcriptional activation of genes encoding multiple vasoactive proteins. Mechanistically, we found that endothelial HIF-1α gene expression was induced by Ang II in a nuclear factor-κB-dependent manner. Finally, we discovered reciprocal positive transcriptional regulation of endothelial Hif-1α and Nf-κb genes is a key driving force for their persistent activation and disease progression. Overall, our findings revealed that the stimulation of HIF-1α gene expression in endothelial cells is detrimental to induce kidney injury, hypertension and disease progression. Our findings highlight early diagnostic opportunities and therapeutic approaches for hypertensive chronic kidney disease.