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)
Type
Research Project (R01)
Project #
5R01DK098074-02
Application #
8667436
Study Section
NeuroAIDS and other End-Organ Diseases Study Section (NAED)
Program Officer
Kimmel, Paul
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Feinstein Institute for Medical Research
Department
Type
DUNS #
City
Manhasset
State
NY
Country
United States
Zip Code
11030
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