HIV-associated nephropathy (HIVAN) is a renal disease almost exclusively seen in people of African ancestry. It is caused directly by the infection and injury of podocytes and renal tubular epithelial cells (RTEc) by HIV-1. While the mechanism for renal epithelial cell infection by HIV-1 in vivo has not been elucidated, endogenous host factors are believed to play a crucial role in this process. Additionally variants in the APOL1 gene (G1/G2) were recently identified as a major risk for developing HIVAN in adults. Identifying the mechanism by which APOL1 variants precipitate the development of HIVAN can provide insights into the underlying mechanism involved in the pathogenesis of HIVAN. Recently we identified tumor necrosis factor alpha (TNF-a) as a critical host factor that facilitates the infection of podocytes cultured from children with HIVAN. TNF-a, in presence of infectious HIV-1, also increases the expression of ApoL-1, a protein that at physiological levels regulates autophagy. We hypothesize that TNF-a is the host factor that plays a critical role in the pathogenesis of childhood HIVAN by facilitatin infection of renal epithelial cells and increasing ApoL-1expression. In HIV-1 infected podocytes, over expression of the APOL1 risk variants, tip the balance to increased podocyte death triggering renal epithelial injury, which precipitates in the development of HIVAN. This hypothesis will be tested in three aims.
In aim 1, we will define how TNF-a affects viral entry and infection of podocytes and RTEc cultured from children with HIVAN, and identify the TNF-a domain involved in this process.
In aim 2, we will determine how ApoL-1 modulates the survival of infected podocytes in culture by interacting with TNF-a, viral proteins, and endocytic or autophagic pathways for viral entry and degradation.
In aim 3, we will define how APOL1 and TNF-a affect the renal outcome of young wild type and HIV-Tg26 mice, and validate relevant clinical findings in renal sections, cells, and urine samples collected from children with HIVAN. These experiments will generate highly relevant clinical information to understand how children develop HIVAN.
Children of African ancestry infected with HIV-1 can develop a lethal renal disease named HIV- associated nephropathy (HIVAN). This proposal will close a critical knowledge gap related to the understanding of how cytokines that are increased in the circulation of HIV-infected children (TNF-apha in particular) modulate the pathogenesis of childhood HIVAN. More specifically, we propose that these cytokines act as a major risk factor ( 2nd hit) precipitating the development of HIVAN, by facilitating the infection of renal epithelial cells and inducing the renal expression of the APOL1, a gene, considered to play a critical role as a risk factor for the development of HIVAN. This proposal will also have clinical implications to understand the pathogenesis of focal segmental glomerulosclerosis in HIV- negative children, and will generate information that is critical for African American children.
|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|
|Hu, Chien-An A; Ray, Patricio E (2016) How complicated can it be? The link between APOL1 risk variants and lipoprotein heterogeneity in kidney and cardiovascular diseases. Nephrol Dial Transplant 31:509-11|
|Gupta, Charu; Massaro, An N; Ray, Patricio E (2016) A new approach to define acute kidney injury in term newborns with hypoxic ischemic encephalopathy. Pediatr Nephrol 31:1167-78|
|Perazzo, Sofia; Soler-GarcÃa, Ãngel A; Hathout, Yetrib et al. (2015) Urinary biomarkers of kidney diseases in HIV-infected children. Proteomics Clin Appl 9:490-500|
|Jerebtsova, Marina; Das, Jharna R; Tang, Pingtao et al. (2015) Angiopoietin-1 prevents severe bleeding complications induced by heparin-like drugs and fibroblast growth factor-2 in mice. Am J Physiol Heart Circ Physiol 309:H1314-25|
|Zhang, Aiping; Uaesoontrachoon, Kitipong; Shaughnessy, Conner et al. (2015) The use of urinary and kidney SILAM proteomics to monitor kidney response to high dose morpholino oligonucleotides in the mdx mouse. Toxicol Rep 2:838-849|
|Lucas, Gregory M; Ross, Michael J; Stock, Peter G et al. (2014) Clinical practice guideline for the management of chronic kidney disease in patients infected with HIV: 2014 update by the HIV Medicine Association of the Infectious Diseases Society of America. Clin Infect Dis 59:e96-138|
|Xie, Xuefang; Colberg-Poley, Anamaris M; Das, Jharna R et al. (2014) The basic domain of HIV-tat transactivating protein is essential for its targeting to lipid rafts and regulating fibroblast growth factor-2 signaling in podocytes isolated from children with HIV-1-associated nephropathy. J Am Soc Nephrol 25:1800-13|