Department of Pharmacology and Toxicology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA 23298, USA.
Hypertension. 2011 Oct;58(4):657-64. doi: 10.1161/HYPERTENSIONAHA.111.177626. Epub 2011 Sep 6.
Although it has been shown that upregulation of hypoxia-inducible factor (HIF)-1α is protective in acute ischemic renal injury, long-term overactivation of HIF-1α is implicated to be injurious in chronic kidney diseases. Angiotensin II (Ang II) is a well-known pathogenic factor producing chronic renal injury and has also been shown to increase HIF-1α. However, the contribution of HIF-1α to Ang II-induced renal injury has not been evidenced. The present study tested the hypothesis that HIF-1α mediates Ang II-induced renal injury in Sprague-Dawley rats. Chronic renal injury was induced by Ang II infusion (200 ng/kg per minute) for 2 weeks in uninephrectomized rats. Transfection of vectors expressing HIF-1α small hairpin RNA into the kidneys knocked down HIF-1α gene expression by 70%, blocked Ang II-induced HIF-1α activation, and significantly attenuated Ang II-induced albuminuria, which was accompanied by inhibition of Ang II-induced vascular endothelial growth factor, a known glomerular permeability factor, in glomeruli. HIF-1α small hairpin RNA also significantly improved the glomerular morphological damage induced by Ang II. Furthermore, HIF-1α small hairpin RNA blocked Ang II-induced upregulation of collagen and α-smooth muscle actin in tubulointerstitial region. There was no difference in creatinine clearance and Ang II-induced increase in blood pressure. HIF-1α small hairpin RNA had no effect on Ang II-induced reduction in renal blood flow and hypoxia in the kidneys. These data suggested that overactivation of HIF-1α-mediated gene regulation in the kidney is a pathogenic pathway mediating Ang II-induced chronic renal injuries, and normalization of overactivated HIF-1α may be used as a treatment strategy for chronic kidney damages associated with excessive Ang II.
虽然已经表明缺氧诱导因子 (HIF)-1α 的上调在急性缺血性肾损伤中具有保护作用，但长期过度激活 HIF-1α 被认为在慢性肾脏病中是有害的。血管紧张素 II (Ang II) 是一种众所周知的产生慢性肾损伤的致病因子，也已被证明会增加 HIF-1α。然而，HIF-1α 对 Ang II 诱导的肾损伤的贡献尚未得到证实。本研究检验了以下假设：HIF-1α 介导 Ang II 诱导的 Sprague-Dawley 大鼠肾损伤。在单侧肾切除大鼠中，用 Ang II 输注（200 ng/kg/min）诱导慢性肾损伤 2 周。将表达 HIF-1α 短发夹 RNA 的载体转染到肾脏中，使 HIF-1α 基因表达降低 70%，阻断了 Ang II 诱导的 HIF-1α 激活，并显著减轻了 Ang II 诱导的白蛋白尿，同时抑制了血管内皮生长因子（一种已知的肾小球通透性因子）在肾小球中的表达。HIF-1α 短发夹 RNA 还显著改善了 Ang II 诱导的肾小球形态损伤。此外，HIF-1α 短发夹 RNA 阻断了 Ang II 诱导的肾小管间质区域胶原和α-平滑肌肌动蛋白的上调。肌酐清除率和 Ang II 诱导的血压升高没有差异。HIF-1α 短发夹 RNA 对 Ang II 诱导的肾血流量减少和肾脏缺氧没有影响。这些数据表明，肾脏中 HIF-1α 介导的基因调控过度激活是介导 Ang II 诱导的慢性肾损伤的发病途径，正常化过度激活的 HIF-1α 可能可用于治疗与过量 Ang II 相关的慢性肾脏损害。
