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

 描述(申请人提供)：全球目前感染HIV-1的350万儿童中，许多人预计将成年并发展为慢性肾脏疾病(CKD)。关于HIV-1如何导致这些儿童的慢性肾损伤我们知之甚少，我们的儿科HIV项目目前处于解决这一问题的独特地位。最近，我们发现，肿瘤坏死因子-α通过跨膜肿瘤坏死因子-α包膜介导的机制，促进了对培养的足细胞和人肾小球内皮细胞的低水平生产性感染，该机制独立于CD_4，并与非洲血统的人慢性肾脏病和高血压相关的APOL-1风险等位基因的上调表达有关。此外，我们还发现：(I)在人类免疫缺陷病毒-1和肿瘤坏死因子-α(nff-α)作用下，足细胞和人肾小管上皮细胞在成纤维细胞生长因子-2(fgf-2)作用下发生矛盾的凋亡或细胞死亡；(Ii)表达人免疫缺陷病毒-1基因的足细胞，单独的nef分泌分子，损害人肾小管上皮细胞的血管生成行为和存活；(Iii)从艾滋病毒-肾脏疾病(HIV-RD)儿童分离的肾小管上皮细胞和巨噬细胞分泌成纤维细胞生长因子结合蛋白(fgf-BP-1)，增强血管紧张素II(Ang II)的血管活性并引起小鼠HTN；和(Iv)HIV-TAT单独或与成纤维细胞生长因子-2结合，加速了HIV-TG26小鼠慢性肾脏病和肾小管性盐耗障碍的发展。基于这些发现，我们推测HIV1和肿瘤坏死因子-α在暴露于成纤维细胞生长因子-2时，损害了肾上皮细胞和HGEc的存活或再生能力，影响了肾小球毛细血管的再生，从而加速了慢性肾脏病和肾炎性肾病的发展。在目标1中，我们将确定当暴露于成纤维细胞生长因子-2时，人类免疫缺陷病毒-1和肿瘤坏死因子-α是否“启动”成熟足细胞和成纤维细胞生长因子c发生凋亡或细胞死亡，并确定足细胞前体细胞是否对艾滋病毒感染更具抵抗力，而对肿瘤坏死因子-α-成纤维细胞生长因子-2介导的细胞死亡的敏感性更低。在目标2中，我们将定义表达HIV基因的足细胞或Nef单独分泌的因子如何影响HGEc的血管生成行为，并确定参与这一过程的最相关的信号通路和可溶性因子。在目标3中，我们将验证这一假设，即HIV-1通过诱导血管内皮细胞慢性损伤和血管平滑肌细胞收缩能力的改变，通过涉及成纤维细胞生长因子-BP-1、成纤维细胞生长因子-2和Rho-A激活的机制来引起HTN。在这里，我们将使用TAT诱导的HIV-TG26来确定HIV-1基因是否会损害肾小管Ang II受体的表达，并导致盐耗障碍，从而延迟HIVAN患者HTN的发生。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HGEc之间的双向串扰，从而导致CKD和HTN的发展。

 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.