Childhood HIV-associated nephropathy (HIVAN) is characterized by the presence of renal epithelial proliferative lesions that cause focal segmental glomerulosclerosis (FSGF), glomerular collapse, and microcystic transformation of renal tubules leading to heavy proteinuria, renal enlargement, and rapid chronic renal failure. African Americans show a unique susceptibility to develop this renal disease. During the last period of the grant we found that HIV-Tat and heparin binding growth factors (HBGF) accumulated in the kidney bound to heparan sulfate proteglycans (HSPG) precipitate the development of HIV-collapsing glomerulopathy in HIV-Tg mice. We also found that HBGF release in the urine of HIV-infected children can become promising biomarkers to follow the clinical outcome of childhood HIVAN. Based on data generated by others and our own preliminary data, we hypothesize that renal HSPG, alone or in combination with the glycosphingolipid Gb3, increase the binding, attachment, and entry of HIV-1 to renal epithelial cells (REc), causing chronic renal injury and renal accumulation of circulating viral proteins and HBGF. A second corollary of this hypothesis, is that these changes induce persistent growth, contractility, and permeabiliy changes in REc, and facilitate the release of HBGF in the urine of children with HIVAN. These HBGF become then reliable biomarkers to follow the progression of HIVAN in children. This hypothesis will be tested in threee specific aims: (1) To define how HSPG and Gb3 modulate the attachment, entry and or fusion of HIV-1 to cultured REc harvested from children with HIVAN;(2) To determine how viral proteins, alone or in combination with HBGF, modulate the growth, contractilty, and permeability behaviors of cultured REc harvested from the urine of children with HIVAN. These cells will be screened for the presence of the HIV-genome, HBGF, HSPG, and genotyped to characterize a genetic variation in the MYH9 gene, encoding the non-muscle myosin IIA heavy chain, that is associated with HIV-collapsing glomerulopathy in adults. (3) To determine the clinical value of a new panel of urinary biomarkers, and a podocyte-permeability assay developed in our lab, to follow the clinic outcome of childhood HIVAN. We are confident that these studies will generate fundamental new knowledge to improve our understanding of the pathogenesis of childhood HIVAN and identify new biomarkers to follow the outcome of this disease in HIV-infected children.

Public Health Relevance

Black children infected with HIV-1 can develop a lethal renal disease named HIV- associated nephropathy (HIVAN). Very few studies have been done in HIV-infected children to determine how they develop renal disease. This proposal will close a critical knowledge gap related to our understanding of how HIV-1, alone or in combination with circulating viral proteins and heparin binding growth factors, causes kidney injury in HIV-infected children. We will also test the role of new urinary biomarkers to identify children at high risk of developing HIVAN, and to follow the clinical outcome and treatment of HIV-associated renal diseses using their clincial samples and HIV-transgenic mice.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK049419-14
Application #
8317716
Study Section
NeuroAIDS and other End-Organ Diseases Study Section (NAED)
Program Officer
Moxey-Mims, Marva M
Project Start
2010-09-01
Project End
2014-08-31
Budget Start
2012-09-01
Budget End
2014-08-31
Support Year
14
Fiscal Year
2012
Total Cost
$284,061
Indirect Cost
$118,909
Name
Children's Research Institute
Department
Type
DUNS #
143983562
City
Washington
State
DC
Country
United States
Zip Code
20010
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-García, Ángel 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
Hoffman, Suma Bhat; Massaro, An N; Soler-Garcia, Angel A et al. (2013) A novel urinary biomarker profile to identify acute kidney injury (AKI) in critically ill neonates: a pilot study. Pediatr Nephrol 28:2179-88
Wai, Kitman; Soler-García, Angel A; Perazzo, Sofia et al. (2013) A pilot study of urinary fibroblast growth factor-2 and epithelial growth factor as potential biomarkers of acute kidney injury in critically ill children. Pediatr Nephrol 28:2189-98

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