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 #
1R01DK098074-01A1
Application #
8542375
Study Section
NeuroAIDS and other End-Organ Diseases Study Section (NAED)
Program Officer
Kimmel, Paul
Project Start
2013-06-01
Project End
2017-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
1
Fiscal Year
2013
Total Cost
$618,034
Indirect Cost
$248,065
Name
Feinstein Institute for Medical Research
Department
Type
DUNS #
110565913
City
Manhasset
State
NY
Country
United States
Zip Code
11030
Pan, Yangbin; Wan, Jianxin; Liu, Yipeng et al. (2014) sPLA2 IB induces human podocyte apoptosis via the M-type phospholipase A2 receptor. Sci Rep 4:6660
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
Chandel, Nirupama; Sharma, Bipin; Husain, Mohammad et al. (2013) HIV compromises integrity of the podocyte actin cytoskeleton through downregulation of the vitamin D receptor. Am J Physiol Renal Physiol 304:F1347-57
Cheng, Kang; Rai, Partab; Lan, Xiqian et al. (2013) Bone-derived mesenchymal stromal cells from HIV transgenic mice exhibit altered proliferation, differentiation capacity and paracrine functions along with impaired therapeutic potential in kidney injury. Exp Cell Res 319:2266-74
Lan, Xiqian; Cheng, Kang; Chandel, Nirupama et al. (2013) High glucose enhances HIV entry into T cells through upregulation of CXCR4. J Leukoc Biol 94:769-77
Cheng, Kang; Rai, Partab; Plagov, Andrei et al. (2013) Rapamycin-induced modulation of miRNA expression is associated with amelioration of HIV-associated nephropathy (HIVAN). Exp Cell Res 319:2073-80