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

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 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.