Novel Mechanisms of Hypertensive Kidney Injury and Fibrosis

高血压肾损伤和纤维化的新机制

• 批准号: 9206079
• 负责人: YANLIN WANG
• 金额: --
• 依托单位: MICHAEL E DEBAKEY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-10-01 至 2019-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9206079
• 关键词: 1-Phosphatidylinositol 3-Kinase; Adaptor Signaling Protein; Affect; Alpha Cell; American; Angiotensin II; Atrophic; Biological Pharmacology; Bone Marrow; CXCR6 gene; Cells; Chromosomes; Chronic Kidney Failure; Clinical; Deposition; Development; Dialysis procedure; Employee Strikes; End stage renal failure; Epithelial Cells; Extracellular Matrix; Fibroblasts; Fibrosis; Genetic; Health; Homologous Gene; Hypertension; Immune; In Vitro; Infiltration; Inflammatory; Injury; Kidney; Kidney Diseases; Kidney Transplantation; Lead; Leucine Zippers; Leukocytes; Military Personnel; Minority; Modeling; Molecular; Mononuclear; Myelogenous; PH Domain; PTB Domain; PTEN gene; PTEN protein; PTPRC gene; Pathogenesis; Pathologic; Phosphoric Monoester Hydrolases; Population; Production; Public Health; Recruitment Activity; Regulation; Renal function; Research; Role; Signal Transduction; T-Lymphocyte; Testing; Therapeutic; Tubular formation; United States; Veterans; base; cGMP-dependent protein kinase Ibeta; cell motility; chemokine; genetic approach; in vivo; interstitial; macrophage; migration; monocyte; mortality; novel; novel therapeutics; prevent; public health relevance; receptor; response; tensin; treatment strategy; uptake

 DESCRIPTION (provided by applicant): Hypertension is a major cause of chronic kidney disease in the Veterans that leads to end stage renal disease. The current therapeutic options in the clinical settings for this devastating condition are limited and often ineffective except dialysis or kidney transplantation. Therefore, a better understanding of the cellular and molecular mechanisms underlying the pathogenesis of hypertensive kidney disease is essential for developing effective strategies for the treatment of this progressive kidney disorder. We have studied the factors initiating and controlling the development of hypertensive kidney disease in a model of angiotensin II-induced hypertension and have discovered a critical and obligate role for immune-inflammatory dysregulation in the initiation of hypertensive kidney disease. We have found that the development of hypertensive kidney disease arises from the infiltration of mononuclear cells (monocytes/macrophage, T cells, and bone marrow-derived fibroblasts) into the kidney. The presence and activation of these cells from a CD45+ mononuclear population appear to be driven by and dependent upon induction of the chemokine, CXCL16, in renal tubular epithelial cells and is prevented by genetic disruption of CXCL16. Our preliminary studies have shown that induction of CXCL16 is associated with striking activation of PI3 kinase signaling in vivo, which is regulated by p PTEN) and the adaptor protein containing a PH domain, PTB domain, and leucine zipper motif 1 (APPL1) in vitro. Therefore, we hosphatase and tensin homologue deleted on chromosome ten (hypothesize that pathologic renal injury and fibrosis arises from immune-inflammatory dysregulation associated with induction of CXCL16 and subsequent activation of PI3 kinase /Akt. We propose that CXCL16 triggers PI3 kinase /Akt activation, initiating the uptake of circulating mononuclear cell population obligate to the resultant kidney injury and fibrosis, which is regulated by PTEN and APPL1. To test our hypothesis, we will pursue the following Specific Aims: Specific Aim 1 is to determine the role of PI3K in the recruitment of bone marrow-derived mononuclear cells in vitro and in vivo. Specific Aim 2 is to examine whether PTEN regulates PI3K/Akt signaling and inflammatory cell migration in vitro and in vivo. Specific Aim 3 is to evaluate whether APPL1 function as a negative regulator of PI3K/Akt signaling and inflammatory cell migration in vitro and in vivo. In summary, we plan to utilize biological, pharmacological, and genetic approaches to study the signaling mechanisms underlying immune-inflammatory dysregulation in the pathogenesis of Ang II- induced renal injury and fibrosis. Results from our studies will provide a new understanding of the molecular and cellular bases of hypertensive kidney disease and could lead to the development of novel therapeutic strategies for the treatment of hypertensive kidney disease.

 描述（由申请人提供）： 高血压是退伍军人慢性肾脏疾病的主要原因，导致终末期肾脏疾病。目前在临床环境中对这种破坏性疾病的治疗选择是有限的，除了透析或肾移植外，通常无效。因此 更好地理解高血压肾病发病机制的细胞和分子机制对于开发治疗这种进行性肾病的有效策略是至关重要的。 我们在血管紧张素II诱导的高血压模型中研究了引发和控制高血压肾病发展的因素，并发现免疫炎症失调在高血压肾病的引发中起着关键性和专性作用。我们已经发现，高血压肾病的发展是由单核细胞（单核细胞/巨噬细胞、T细胞和骨髓来源的成纤维细胞）浸润到肾脏中引起的。这些来自CD 45+单核细胞群的细胞的存在和活化似乎是由肾小管上皮细胞中趋化因子CXCL 16的诱导驱动和依赖的，并且通过CXCL 16的遗传破坏来阻止。我们的初步研究表明，CXCL 16的诱导与体内PI 3激酶信号传导的显著激活有关，其在体外由pPTEN和含有PH结构域、PTB结构域和亮氨酸拉链基序1的衔接蛋白（APPL 1）调节。因此，我们在染色体10上缺失磷酸酶和张力蛋白同源物（假设病理性肾损伤和纤维化由与CXCL 16诱导和随后的PI 3激酶/Akt活化相关的免疫炎症失调引起）。我们提出CXCL 16触发PI 3激酶/Akt激活，启动对所产生的肾损伤和纤维化的专性循环单核细胞群体的摄取，其由PTEN和APPL 1调节。为了验证我们的假设，我们将追求以下具体目标：具体目标1是确定PI 3 K在体外和体内骨髓来源的单核细胞募集中的作用。具体目的2是检查PTEN是否在体外和体内调节PI 3 K/Akt信号传导和炎症细胞迁移。具体目标3是评估APPL 1是否在体外和体内作为PI 3 K/Akt信号传导和炎性细胞迁移的负调节剂发挥作用。 总之，我们计划利用生物学、药理学和遗传学方法来研究血管紧张素II诱导的肾损伤和纤维化发病机制中免疫炎症失调的信号传导机制。我们的研究结果将为高血压肾病的分子和细胞基础提供新的认识，并可能导致高血压肾病治疗新的治疗策略的发展。