Molecular mechanism of hypertension-induced renal injury: the role of HIF-1alpha

高血压肾损伤的分子机制：HIF-1α的作用

• 批准号: 9383995
• 负责人: Ningjun Li
• 金额: $ 23.25万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-16 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9383995
• 关键词: Ablation; Acute Renal Failure with Renal Papillary Necrosis; Angiotensin II; Animal Model; Animals; Applications Grants; Attenuated; Blood Pressure; Cells; Chronic; Chronic Kidney Failure; Collagen; Data; Disease model; Doctor of Philosophy; Enzymes; Esthesia; Fibrosis; Gene Expression Regulation; Genes; Homeostasis; Human; Hypertension; Hypoxia Inducible Factor; Impairment; Infarction; Injury; Kidney; Lead; Mechanics; Mediating; Mediator of activation protein; Modeling; Molecular; Mus; Oxygen; Pathogenicity; Pathway interactions; Patients; Perfusion; Plasminogen Inactivators; Play; Procollagen-Proline Dioxygenase; Proteins; Rattus; Regulation; Role; Stress; Techniques; Testing; Tissue Inhibitor of Metalloproteinases; Tissues; Up-Regulation; Work; cell type; connective tissue growth factor; glomerulosclerosis; hypertension treatment; hypoxia inducible factor 1; interstitial; kidney cell; mechanical pressure; member; new therapeutic target; podocyte; pressure; receptor; renal hypoxia; sensor; slit diaphragm; small hairpin RNA; transcription factor; transmission process

Hypoxia inducible factor (HIF)-1α is a transcription factor that has been shown to be up-regulated in almost all types of chronic kidney diseases (CKD). HIF-1α stimulates the collagen accumulation by activating fibrogenic factors. There is evidence suggesting that the long-term activation of HIF-1α is injurious in CKD, although upregulation of HIF-1α is protective in acute kidney injury. The coexistent hypertension plays a predominant role in the progression of CKD. Despite the findings that impaired renal autoregulation transmits the elevated renal perfusion pressure (RPP) into the renal microvasculature, causing RPP-induced renal injury in CKD, little is known regarding the molecular mechanism mediating RPP-induced injury. Our preliminary data showed that silencing of HIF-1α attenuated renal injury without effect on hypertension in a rat 5/6 renal ablation/infarction model (5/6 A/I); maintaining a normal RPP blocked the increase of renal HIF-1α and suppressed the renal injury in this CKD model, indicating that HIF-1α may mediate RPP-induced renal injury. HIF prolyl- hydroxylases (prolyl hydroxylase domain-containing proteins, PHDs) are the major enzymes to promote the degradation of HIF-1α and present in the kidneys to regulate renal HIF-1α. We recently showed that PHDs play a critical role in TGF-- and ANG II-induced activation of HIF-1α and consequent injuries in renal cells. Our preliminary data showed that renal PHD activity was inhibited by elevated RPP and that activating PHD activity attenuated renal injury in 5/6 A/I rats. Thus, PHD-mediated regulation of HIF-1α could be an important mechanism mediating RPP-induced injury. Further, the PHD activity is inhibited by the activation of TRPC6, a member of the Transient Receptor Potential Channels. The activation of TRPC6 is known to produce renal injury. Moreover, TRPC6 participates in the mechanical/pressure sensation in various cell types, including podocytes. Therefore, TRPC6 may be the upstream mediator that transmits the RPP stress into downstream molecular pathways to cause RPP-induced injury. Our preliminary data showed that the levels of renal TRPC6 was increased, which was inhibited by servo-control to block the increase of RPP in rats with 5/6 A/I. In addition, TRPC6 shRNA blocked the increase of HIF-1α in the kidneys of 5/6 A/I rats. The above information leads to a hypothesis that the elevated RPP activates TRPC6, which inhibits PHD activity to induce HIF-1α- mediated profibrogenic genes, consequently causing renal injuries in CKD. Three specific aims are proposed. Aim 1: To test the hypothesis that over-activation of HIF-1α mediates RPP-induced chronic renal injury in CKD. Aim 2: To test the hypothesis that elevated RPP inhibits PHD activity to up-regulate HIF-1α, thereby producing chronic renal injury in CKD. Aim 3: To test the hypothesis that TRPC6 is the upstream regulator sensing pressure stress to regulate PHD/HIF-1α pathway in RPP-induced renal injury in CKD. The results from these proposed studies will define an important molecular mechanism associated with TRPC6/PHD/HIF-1α pathway in RPP-induced injury in CKD, which will ultimately suggest new therapeutic targets for CKD.

缺氧诱导因子（Hypoxia inducible factor， HIF）-1α是一种在几乎所有疾病中均上调的转录因子