Human immunodeficiency virus-associated nephropathy (HIVAN) is a distinct clinico-pathological entity that is characterized by focal segmental glomerular sclerosis (FSGS) and tubulointerstitial lesions. Preliminary studies by others and us have indicated that many of the effects of HIV-1 infection are mediated via oxidative stress which results from the generation of reactive oxygen species (ROS). Recently, pivotal role of p66ShcA proteins have been identified in the generation of oxidative stress. The long term objective of the present proposal is to develop novel therapeutic strategies, targeting mutant genes or dysfunctional gene products, to arrest or prevent the development of HIVAN. Our recent preliminary studies in Tg26 (a mouse model of HIVAN) animals have shown that both glomerular and tubular cells showed enhanced generation of ROS. In addition, in in vitro studies, podocytes-transduced with HIV-1 not only showed enhanced expression of p66ShcA but also demonstrated increased generation of ROS;whereas, p66ShcA-deficient podocytes showed attenuated generation of ROS. Based on these results we hypothesize that in HIV-1 infection, inhibition of p66ShcA activates a Foxo3A- dependent stress program that promotes the survival phenotype. We further hypothesize that deletion of p66ShcA from the genome of Tg26 mice will not only attenuate or prevent HIV-1-induced oxidative stress, but also delay or prevent the progression of renal lesions. In the present proposal we will 7 Test the hypothesis that inhibition of p66ShcA in HIV-1-infected podocytes activates a Foxo3-dependent stress program that promotes the survival phenotype 7 Test the hypothesis that deletion of p66ShcA from the genome of Tg26 mice will delay or prevent the progression of renal lesions 7 Test the hypothesis that HIV-1-induced p66ShcA redox function and dysregulation of the mTOR pathway leads to renal pathogenesis associated with HIVAN The outcome of these studies will help us in the development of therapeutic strategies to treat this devastating renal disease.

Public Health Relevance

Patients infected with HIV-1 are prone to a rapidly progressing kidney disease termed HIV-associated nephropathy (HIVAN). There is high incidence of this kidney disease in young black African-American men. HIVAN is the third leading cause of End-stage renal disease among young black individuals, and is associated with the highest rates of hospitalizations in this population. At present, there is no specific treatment to cure this disease. Our long term research goal is to develop strategies to slow down the progression and/or cure of this devastating kidney disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK083931-04
Application #
8440810
Study Section
NeuroAIDS and other End-Organ Diseases Study Section (NAED)
Program Officer
Kimmel, Paul
Project Start
2010-03-15
Project End
2014-02-28
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
4
Fiscal Year
2013
Total Cost
$577,092
Indirect Cost
$208,423
Name
Feinstein Institute for Medical Research
Department
Type
DUNS #
110565913
City
Manhasset
State
NY
Country
United States
Zip Code
11030
Haque, Shabirul; Lan, Xiqian; Wen, Hongxiu et al. (2016) HIV Promotes NLRP3 Inflammasome Complex Activation in Murine HIV-Associated Nephropathy. Am J Pathol 186:347-58
Chandel, Nirupama; Ayasolla, Kameshwar S; Lan, Xiqian et al. (2015) Epigenetic Modulation of Human Podocyte Vitamin D Receptor in HIV Milieu. J Mol Biol 427:3201-15
Rai, Partab; Singh, Tejinder; Lederman, Rivka et al. (2015) Hyperglycemia enhances kidney cell injury in HIVAN through down-regulation of vitamin D receptors. Cell Signal 27:460-9
Lan, Xiqian; Wen, Hongxiu; Saleem, Moin A et al. (2015) Vascular smooth muscle cells contribute to APOL1-induced podocyte injury in HIV milieu. Exp Mol Pathol 98:491-501
Singh, Tejinder; Ayasolla, Kamesh; Rai, Partab et al. (2015) AT1R blockade in adverse milieus: role of SMRT and corepressor complexes. Am J Physiol Renal Physiol 309:F189-203
Ayasolla, Kamesh R; Rai, Partab; Rahimipour, Shai et al. (2015) Tubular cell phenotype in HIV-associated nephropathy: role of phospholipid lysophosphatidic acid. Exp Mol Pathol 99:109-15
Lan, Xiqian; Wen, Hongxiu; Lederman, Rivka et al. (2015) Protein domains of APOL1 and its risk variants. Exp Mol Pathol 99:139-44
Chandel, Nirupama; Ayasolla, Kamesh; Lan, Xiqian et al. (2014) Renin modulates HIV replication in T cells. J Leukoc Biol 96:601-9
Rai, Partab; Lederman, Rivka; Haque, Shabirul et al. (2014) Renin angiotensin system modulates mTOR pathway through AT2R in HIVAN. Exp Mol Pathol 96:431-7
Lan, Xiqian; Jhaveri, Aakash; Cheng, Kang et al. (2014) APOL1 risk variants enhance podocyte necrosis through compromising lysosomal membrane permeability. Am J Physiol Renal Physiol 307:F326-36

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