Pathogenesis of chronic renal injury and hypertension in HIV-infected children

HIV感染儿童慢性肾损伤和高血压的发病机制

• 批准号: 9547378
• 负责人: PATRICIO E RAY
• 金额: $ 28.44万
• 依托单位: CHILDREN'S RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-18 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9547378
• 关键词: AIDS-Associated Nephropathy; Address; Adult; Affect; African; Amino Acids; Angiotensin II; Angiotensin II Receptor; Apoptosis; Apoptotic; Behavior; Binding Proteins; Blood Vessels; Cardiovascular system; Cell Culture Techniques; Cell Death; Cells; Child; Childhood; Childhood Injury; Chronic; Chronic Kidney Failure; Development; Disease; Early identification; Early treatment; End stage renal failure; Endothelial Cells; Epithelial Cells; Exposure to; FGF2 gene; Fibroblast Growth Factor; Genes; Glomerular Capillary; Growth Factor; HIV; HIV Infections; HIV-1; Human; Hypertension; Impairment; Infection; Inflammation; Injury; Kidney; Kidney Diseases; Knowledge; Mediating; Mus; Natural regeneration; Pathogenesis; Patients; Positioning Attribute; Process; Proteomics; Renal tubule structure; Research; Resistance; Risk; Signal Pathway; Smooth Muscle Myocytes; Sodium; Sodium Chloride; Stable Isotope Labeling; TNF gene; Testing; Therapeutic Intervention; Tubular formation; Urine; Vascular Smooth Muscle; antiretroviral therapy; base; blood pressure regulation; experimental study; high risk; inhibitor/antagonist; injured; macrophage; mouse model; pediatric human immunodeficiency virus; podocyte; programs; public health relevance; release factor; response; rho; risk variant; wasting; young adult

 DESCRIPTION (provided by applicant): Many of the 3.5 million children currently infected with HIV-1 worldwide are expected to reach adulthood and develop chronic kidney disease (CKD). Very little is known about how HIV-1 induces chronic renal injury in these children, and our pediatric HIV-program is currently in a unique position to address this problem. Recently we found that TNF-α facilitates the establishment of a low level productive infection of cultured podocytes and human glomerular endothelial cells (HGEc) through a trans-membrane TNF-α-envelope- mediated mechanism that is independent of CD4, and is associated with an up-regulated expression of the ApoL-1 risk alleles that are associated with CKD and hypertension (HTN) in people of African ancestry. Furthermore, we found that (i) podocytes and HGEc that are "primed" by HIV-1 and Tumor Necrosis Factor -α (TNF-α) undergo paradoxical apoptosis or cell death when exposed to Fibroblast Growth Factor-2 (FGF-2); (ii) podocytes expressing HIV-1 genes, and Nef alone, secrete molecules that impair the angiogenic behavior and survival of HGEc; (iii) Renal tubular epithelial cells and macrophages isolated from children with HIV- renal diseases (HIV-RD) secrete an FGF binding protein (FGF-BP-1) that enhances the vascular activity of Angiotensin II (Ang II) and causes HTN in mice; and (iv) HIV-Tat, alone or in combination with FGF-2, precipitates the development of CKD and tubular salt wasting disorders in HIV-Tg26 mice. Based on these findings, we hypothesize that HIV-1 and TNF-α impair the ability of renal epithelial cells and HGEc to survive or regenerate when exposed to FGF-2, affecting the regeneration of glomerular capillaries, and precipitating the development of CKD and HTN. In aim 1, we will define whether HIV-1 and TNF-α "prime" mature podocytes and HGEc to undergo apoptosis or cell death when exposed to FGF-2, and define whether podocyte precursors are more resistant to HIV-infection and less susceptible to TNF-α + FGF-2 mediated cell death. In aim 2 we will define how factors secreted by podocytes expressing HIV-genes, or Nef alone, affect the angiogenic behavior of HGEc, and identify the most relevant signaling pathways and soluble factors involved in this process. In aim 3 we will test the hypothesis that HIV-1 can cause HTN through the induction of chronic endothelial injury and contractility changes in vascular smooth muscle cells, via an Ang II- mediated mechanism that involves FGF-BP-1, FGF-2 and Rho-A activation. Here, we will use Tat-inducible HIV-Tg26 to determine whether HIV-1 genes impair the expression of Ang II receptors in renal tubules and induce a salt wasting disorder that delays the onset of HTN in patients with HIVAN. This study will fill a unique gap in our knowledge of childhood HIV-RD, and define how HIV-1 affects the bidirectional crosstalk between podocytes and HGEc precipitating the development of CKD and HTN.

 描述（由申请人提供）：目前全世界有 350 万感染 HIV-1 的儿童，其中许多人预计将在成年后患上慢性肾病 (CKD)，但人们对 HIV-1 如何在这些儿童中引起慢性肾损伤知之甚少。 ，我们的儿科 HIV 项目目前处于解决这一问题的独特位置，最近我们发现 TNF-α 有助于培养的足细胞和人肾小球内皮细胞建立低水平的生产性感染。 (HGEc) 通过跨膜 TNF-α 包膜介导的机制，该机制独立于 CD4，并且与与人类 CKD 和高血压 (HTN) 相关的 ApoL-1 风险等位基因表达上调相关此外，我们发现 (i) 由 HIV-1 和肿瘤坏死因子 -α (TNF-α)“引发”的足细胞和 HGEc 会发生矛盾的细胞凋亡或细胞凋亡。暴露于成纤维细胞生长因子-2 (FGF-2) 时死亡；(ii) 表达 HIV-1 基因的足细胞和单独的 Nef 会分泌损害 HGEc 的血管生成行为和存活的分子；从患有 HIV 肾病 (HIV-RD) 的儿童中分离出的一种 FGF 结合蛋白 (FGF-BP-1) 可增强血管紧张素 II (Ang II) 的血管活性，并导致小鼠中的 HTN；以及 (iv) HIV-Tat 单独或与 FGF-2 联合使用，可促进 HIV-Tg26 小鼠中 CKD 和肾小管盐消耗性疾病的发生。基于这些发现，我们追踪了 HIV-1 和 TNF。当暴露于 FGF-2 时，-α 会损害肾上皮细胞和 HGEc 的存活或再生能力，影响肾小球毛细血管的再生，并加速 CKD 的发展在目标 1 中，我们将确定 HIV-1 和 TNF-α 在暴露于 FGF-2 时是否“引发”成熟足细胞和 HGEc 发生凋亡或细胞死亡，并确定足细胞前体是否对 HIV 感染具有更强的抵抗力。且不易受 TNF-α + FGF-2 介导的细胞死亡影响 在目标 2 中，我们将定义表达 HIV 基因的足细胞分泌的因子或单独的 Nef 如何影响血管生成行为。 HGEc，并确定该过程中最相关的信号传导途径和可溶性因子。在目标 3 中，我们将测试 HIV-1 可以通过诱导血管平滑肌细胞的慢性内皮损伤和收缩性变化来引起 HTN 的假设。 Ang II 介导的机制涉及 FGF-BP-1、FGF-2 和 Rho-A 激活 在这里，我们将使用 Tat 诱导的 HIV-Tg26 来确定 HIV-1 基因是否损害 Ang II 的表达。这项研究将填补我们对儿童 HIV-RD 知识的独特空白，并确定 HIV-1 如何影响足细胞和足细胞之间的双向串扰。 HGEc 促进了 CKD 和 HTN 的发展。