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 (HIF)-1α 是一种转录因子，已被证明在几乎所有细胞中都会上调 慢性肾脏病（CKD）的类型。 HIF-1α 通过激活纤维生成来刺激胶原蛋白积累 因素。有证据表明 HIF-1α 的长期激活对 CKD 是有害的，尽管 HIF-1α 的上调对急性肾损伤具有保护作用。合并高血压占主导地位 CKD 进展中的作用。尽管发现肾脏自动调节受损会传递升高的 肾灌注压（RPP）进入肾脏微血管，引起 RPP 诱导的 CKD 肾损伤，但很少 关于介导 RPP 诱导损伤的分子机制是已知的。我们的初步数据表明 沉默 HIF-1α 可减轻大鼠 5/6 肾消融/梗塞中的肾损伤，但对高血压没有影响 型号（5/6 A/I）；维持正常的 RPP 可阻止肾 HIF-1α 的增加，并抑制肾功能 CKD 模型中的损伤，表明 HIF-1α 可能介导 RPP 诱导的肾损伤。 HIF 脯氨酰- 羟化酶（含脯氨酰羟化酶结构域的蛋白质，PHD）是促进 HIF-1α 的降解并存在于肾脏中以调节肾 HIF-1α。我们最近展示了 PHD 玩 在 TGF-β 和 ANG II 诱导的 HIF-1α 激活以及随后的肾细胞损伤中发挥着关键作用。我们的 初步数据表明，升高的 RPP 会抑制肾脏 PHD 活性，而升高的 RPP 会激活 PHD 活性。 减轻 5/6 A/I 大鼠的肾损伤。因此，PHD 介导的 HIF-1α 调节可能是一个重要的机制。 介导 RPP 诱导损伤的机制。此外，PHD 活性受到 TRPC6 激活的抑制，TRPC6 是一种 瞬时受体电位通道的成员。已知 TRPC6 的激活会产生肾 受伤。此外，TRPC6 参与多种细胞类型的机械/压力感觉，包括 足细胞。因此，TRPC6可能是将RPP应力传递给下游的上游中介。 引起 RPP 诱导损伤的分子途径。我们的初步数据显示肾脏 TRPC6 水平 增加，通过伺服控制来抑制，以阻断 5/6 A/I 大鼠 RPP 的增加。在 此外，TRPC6 shRNA 阻断了 5/6 A/I 大鼠肾脏中 HIF-1α 的增加。以上信息 导致一个假设：RPP 升高会激活 TRPC6，从而抑制 PHD 活性以诱导 HIF-1α- 介导的促纤维化基因，从而导致 CKD 肾损伤。提出了三个具体目标。 目标 1：检验 HIF-1α 过度激活介导 CKD 中 RPP 诱导的慢性肾损伤的假设。 目标 2：检验 RPP 升高抑制 PHD 活性上调 HIF-1α 的假设，从而产生 CKD 中的慢性肾损伤。目标 3：检验 TRPC6 是上游调节器传感的假设 压力应激在 RPP 诱导的 CKD 肾损伤中调节 PHD/HIF-1α 通路。这些结果 拟议的研究将定义与 TRPC6/PHD/HIF-1α 通路相关的重要分子机制 RPP 诱导的 CKD 损伤，最终将为 CKD 提出新的治疗靶点。