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-? facilitates the establishment of a low level productive infection of cultured podocytes and human glomerular endothelial cells (HGEc) through a trans-membrane TNF-?-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 -? (TNF-?) 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-? 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-? 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-? + 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.

Public Health Relevance

A large number of HIV-infected children and young adults of African ancestry are at high risk of developing chronic kidney disease and hypertension. This proposal will close a critical knowledge gap to understand how HIV-1 injures and impairs the regeneraiton of podocytes and glomerular endothelial cells. In addition, it will identify a new mechanism through which HIV-1 induces vascular contractlity changes leading to the development of chronic kidney injury and hypertension in HIV-infected children and young adults.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
3R01DK108368-05S1
Application #
9951166
Study Section
Special Emphasis Panel (ZDK1)
Program Officer
Chan, Kevin E
Project Start
2015-09-18
Project End
2020-07-31
Budget Start
2019-08-01
Budget End
2020-07-31
Support Year
5
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Virginia
Department
Pediatrics
Type
Schools of Medicine
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
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Tassi, Elena; Lai, En Yin; Li, Lingli et al. (2018) Blood Pressure Control by a Secreted FGFBP1 (Fibroblast Growth Factor-Binding Protein). Hypertension 71:160-167
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Fu, Yulong; Zhu, Jun-Yi; Richman, Adam et al. (2017) APOL1-G1 in Nephrocytes Induces Hypertrophy and Accelerates Cell Death. J Am Soc Nephrol 28:1106-1116
Das, Jharna R; Gutkind, J Silvio; Ray, Patricio E (2016) Circulating Fibroblast Growth Factor-2, HIV-Tat, and Vascular Endothelial Cell Growth Factor-A in HIV-Infected Children with Renal Disease Activate Rho-A and Src in Cultured Renal Endothelial Cells. PLoS One 11:e0153837
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