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

基本信息

  • 批准号:
    9383995
  • 负责人:
  • 金额:
    $ 23.25万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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

项目成果

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Ningjun Li其他文献

Ningjun Li的其他文献

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{{ truncateString('Ningjun Li', 18)}}的其他基金

Inhibition of fatty acid amide hydrolase as a novel strategy to prevent nephrotoxicity of cisplatin.
抑制脂肪酸酰胺水解酶作为预防顺铂肾毒性的新策略。
  • 批准号:
    10684803
  • 财政年份:
    2022
  • 资助金额:
    $ 23.25万
  • 项目类别:
Inhibition of fatty acid amide hydrolase as a novel strategy to prevent nephrotoxicity of cisplatin.
抑制脂肪酸酰胺水解酶作为预防顺铂肾毒性的新策略。
  • 批准号:
    10513011
  • 财政年份:
    2022
  • 资助金额:
    $ 23.25万
  • 项目类别:
Renal sphingosine-1-phosphate receptor 1 in salt-sensitive hypertension
盐敏感性高血压中的肾 1-磷酸鞘氨醇受体 1
  • 批准号:
    10319594
  • 财政年份:
    2019
  • 资助金额:
    $ 23.25万
  • 项目类别:
Renal sphingosine-1-phosphate receptor 1 in salt-sensitive hypertension
盐敏感性高血压中的肾 1-磷酸鞘氨醇受体 1
  • 批准号:
    10064007
  • 财政年份:
    2019
  • 资助金额:
    $ 23.25万
  • 项目类别:
Renal Medullary Stem Cell Niche in Salt Sensitive Hypertension
盐敏感性高血压中的肾髓质干细胞生态位
  • 批准号:
    8207205
  • 财政年份:
    2011
  • 资助金额:
    $ 23.25万
  • 项目类别:
Renal Medullary Stem Cell Niche in Salt Sensitive Hypertension
盐敏感性高血压中的肾髓质干细胞生态位
  • 批准号:
    8386965
  • 财政年份:
    2011
  • 资助金额:
    $ 23.25万
  • 项目类别:
Renal Medullary Stem Cell Niche in Salt Sensitive Hypertension
盐敏感性高血压中的肾髓质干细胞生态位
  • 批准号:
    8024001
  • 财政年份:
    2011
  • 资助金额:
    $ 23.25万
  • 项目类别:
Renal Medullary Stem Cell Niche in Salt Sensitive Hypertension
盐敏感性高血压中的肾髓质干细胞生态位
  • 批准号:
    8584315
  • 财政年份:
    2011
  • 资助金额:
    $ 23.25万
  • 项目类别:
Renal medullary HIF prolyl hydroxylases and salt sensitivity of blood pressure
肾髓质HIF脯氨酰羟化酶与血压盐敏感性
  • 批准号:
    7841255
  • 财政年份:
    2009
  • 资助金额:
    $ 23.25万
  • 项目类别:
Renal medullary HIF prolyl hydroxylases and salt sensitivity of blood pressure
肾髓质HIF脯氨酰羟化酶与血压盐敏感性
  • 批准号:
    7481007
  • 财政年份:
    2007
  • 资助金额:
    $ 23.25万
  • 项目类别:
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