Submitted on November 10, 2008
Revised on June 3, 2009
Accepted on June 22, 2009
Human Immunodeficiency Virus Down Regulates Podocyte ApoE Expression
Shitij Arora1, Mohammad Husain2, Dileep Kumar2, Hitesh Patni3, Shresh Pathak2, Devi Mehrotra2, Vivek Kathi Reddy2, Lalit Rajeev Reddy2, Divya Salhan2, Anju Yadav2, Peter W Mathieson4, Moin A Saleem5, Praveen N Chander6, and Pravin C. Singhal7*
1 Long Island Jewish Medical Center, New Hyde Park
2 Feinstein Institute for Medical Research
3 Long Island Jewish Medical Center and North Shore Unversity Hospital
4 University of Bristol
5 University of Bristol, UK
6 nymc
7 Feinstein Institute for Medical Research North Shore LIJ Health System
* To whom correspondence should be addressed. E-mail: singhal{at}lij.edu.
ApoE has been demonstrated to play an important role in providing protection against mesangial cell injury. In the present study, we evaluated the role of apoE and its associated downstream effects in HIV-associated nephropathy (HIVAN). Control (n=6) and age and sex matched HIV-1 transgenic mice (Tg26, n=6) were evaluated for their renal cortical expression of apoE. Renal tissue from Tg26 mice not only showed decreased apoE expression but also displayed down regulation of perlecan mRNA expression. In in vitro studies, conditionally immortalized human podocytes (CIHPs) were transduced with either NL4-3HIV (an HIV-1 construct lacking gag and pol, used for the development of Tg26 mouse model; NL4-3/CIHP) or empty vector (EV/CIHP); the NL4-3/CIHPs and EV/CIHPs were studied for apoE mRNA expression. NL4-3/CIHPs showed reduction in apoE expression when compared with EV/CIHPs. To evaluate the role of HIV-1 genes in the modulation of apoE expression, mouse podocytes (CIMPs) were transduced with individual HIV-1 gene constructs. Only nef-transduced CIMPs showed a decrease in apoE expression. To confirm this effect of nef in CIHPs, micro array analysis was performed in stable colonies of nef/CIHPs and EV/CIHPs. Nef/CIHPs showed a 60% decrease in apoE and a 90% reduction in heparan sulfate mRNA expression. Moreover, nef transgenic mice showed a decrease in renal tissue expression of both apoE and perlecan. Both Tg26 and nef transgenic mice also showed areas of mesangial cell proliferation. These findings suggest that HIV-1-induced reduction in podocyte apoE expression and associated down-regulation of podocyte perlecan might be contributing to MC phenotype in HIVAN.
