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: 9329412
• 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 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9329412
• 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; 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; Muscle Cells; Natural regeneration; Pathogenesis; Patients; Positioning Attribute; Process; Proteomics; Renal tubule structure; Research; Resistance; Risk; Signal Pathway; 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（由适用提供）：预计目前感染HIV-1的350万儿童预计将成年并发展慢性肾脏疾病（CKD）。关于HIV-1如何诱导这些儿童的慢性肾脏损伤，我们的小儿艾滋病毒计划目前处于解决这一问题的独特位置，知之甚少。 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祖先。此外，我们发现（i）足细胞和HGEC被HIV-1和肿瘤坏死因子-α（TNF-α）“启动”，当暴露于成纤维细胞生长因子2（FGFF-2）时，会发生矛盾的凋亡或细胞死亡； （ii）表达HIV-1基因的足细胞和单独表达NEF的秘密分子会损害HGEC的血管生成行为和存活； （iii）从HIV-肾脏疾病儿童（HIV-RD）分离出的肾小管上皮细胞和巨噬细胞秘密A Secret A Secret A FGF结合蛋白（FGF-BP-1），从而增强了血管紧张素II（ANG II）的血管活性并引起小鼠HTN的血管活性； （iv）单独或与FGF-2结合使用HIV-TAT会导致HIV-TG26小鼠中CKD和管状盐浪费障碍的发展。 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 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足细胞前体对HIV感染具有更大的抵抗力，并且不太容易受到TNF-α + FGF-2介导的细胞死亡的影响。在AIM 2中，我们将定义表达艾滋病毒可能的足细胞分泌的因素如何影响HGEC的血管生成行为，并确定最相关的信号通路和此过程中涉及的最相关的信号途径和固体因素。在AIM 3中，我们将通过诱导慢性内皮损伤和血管平滑肌细胞的收缩力变化来检验HIV-1的假设，通过涉及FGF-BP-1，FGFF-2和Rho-A活化的ANG II介导的机制。在这里，我们将使用TAT诱导的HIV-TG26来确定HIV-1基因是否会损害肾脏块茎中Ang II受体的表达，并诱导盐浪费障碍，该盐延迟HIVAN患者的HTN发作。这项研究将填补我们对儿童HIV-RD的了解的独特空白，并定义HIV-1如何影响Podocytes和HGEC之间的双向串扰，从而导致CKD和HTN的发展。