HIV-associated nephropathy (HIVAN) is an important complication of acquired immunodeficiency syndrome (AIDS).Its manifestation requires presence of specific ancestry (APOL1 gene), environmental (HIV infection), and host factors. Although significant research has been done to identify and to delineate the involved genes to correlate with the ancestry but there has been a limited effort to identify subversive activities o HIV, which might be contributing to specific host factors- increased expression of Snail- required for the display of unique phenotype of renal lesions in HIVAN. In preliminary studies, we found that HIV enhanced renal cell expression of Snail (a repressor of E-cadherin transcriptor, and a promoter of proliferative phenotype). Since Snail has been demonstrated to repress transcription of vitamin D receptor (VDR) and nephrin (a podocyte slit diaphragm protein), it carries a potential to alter renal cell phenotype. HIV is known to modulate gene expression by DNA methylation (epigenetic factors). In our laboratory, we observed that both glomerular and tubular epithelial cells in HIVAN mice displayed enhanced expression of Snail and diminished expression of VDR and nephrin. On the basis of these findings we will test the following hypotheses * HIV alters renal cell gene expression through the induction of epigenetic factors * Renal cortical sections of HIVAN mice as well as HIVAN patients would display enhanced Snail expression and diminished expression of E/P-cadherin, VDR, and nephrin * Inhibition of either HIV-induced epigenetic factors, associated downstream signaling, or both would not only attenuate the development of HIVAN phenotype but will also prevent, retard the progression, and/or cause resolution of HIVAN We suggest that testing of these hypotheses will aid in developing therapeutic strategies to prevent, retard the progression, or cause resolution of HIVAN.

Public Health Relevance

HIV-associated nephropathy (HIVAN) is the third leading cause of End-stage renal disease among individuals with African American background, and is associated with the highest rates of hospitalizations in this population. In preliminary studies, w observed that HIV-induced subversion modulated expression of genes which maintain kidney cell phenotypes. We hypothesize that HIV-induced epigenetic factors are playing as the host factors for the initiation as well as progression of HIVAN.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK098074-03
Application #
8845549
Study Section
NeuroAIDS and other End-Organ Diseases Study Section (NAED)
Program Officer
Kimmel, Paul
Project Start
2013-06-01
Project End
2016-05-31
Budget Start
2015-06-01
Budget End
2016-05-31
Support Year
3
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Feinstein Institute for Medical Research
Department
Type
DUNS #
110565913
City
Manhasset
State
NY
Country
United States
Zip Code
11030
Kumar, Vinod; Vashistha, Himanshu; Lan, Xiqian et al. (2018) Role of Apolipoprotein L1 in Human Parietal Epithelial Cell Transition. Am J Pathol 188:2508-2528
Lan, Xiqian; Wen, Hongxiu; Aslam, Rukhsana et al. (2018) Nicotine enhances mesangial cell proliferation and fibronectin production in high glucose milieu via activation of Wnt/?-catenin pathway. Biosci Rep 38:
Wen, Hongxiu; Kumar, Vinod; Lan, Xiqian et al. (2018) APOL1 risk variants cause podocytes injury through enhancing endoplasmic reticulum stress. Biosci Rep 38:
Chandel, Nirupama; Ayasolla, Kamesh; Wen, Hongxiu et al. (2017) Vitamin D receptor deficit induces activation of renin angiotensin system via SIRT1 modulation in podocytes. Exp Mol Pathol 102:97-105
Haque, Shabirul; Patil, Gauri; Mishra, Abheepsa et al. (2017) Effect of APOL1 disease risk variants on APOL1 gene product. Biosci Rep 37:
Lan, Xiqian; Wen, Hongxiu; Cheng, Kang et al. (2017) Hedgehog pathway plays a vital role in HIV-induced epithelial-mesenchymal transition of podocyte. Exp Cell Res 352:193-201
Mikulak, Joanna; Oriolo, Ferdinando; Portale, Federica et al. (2016) Impact of APOL1 polymorphism and IL-1? priming in the entry and persistence of HIV-1 in human podocytes. Retrovirology 13:63
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
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
Khatua, Atanu K; Cheatham, Amber M; Kruzel, Etty D et al. (2015) Exon 4-encoded sequence is a major determinant of cytotoxicity of apolipoprotein L1. Am J Physiol Cell Physiol 309:C22-37

Showing the most recent 10 out of 26 publications