Abstract

Human immunodeficiency virus-associated nephropathy (HIVAN) is a distinct clinico-pathological entity that is characterized by rapidly progressive renal failure. HIVAN is predominantly a disease of young African American men. In addition, intravenous drug addiction has been considered a risk factor for the development of HIVAN. The long-term goal of our research is to understand and develop strategies to modulate the progression of HIVAN in drug addicts. The rationale for the present proposal is based on studies that have demonstrated: 1. Drugs (morphine and cocaine) and HIV-1 proteins (gp120 and tat) have a bimodal effect on mesangial, glomerular and tubular epithelial cell proliferation. These effects of the drugs and HIV-1 proteins are mediated by oxidative stress. 2. Promotion of HIV-1 replication by both morphine and cocaine in peripheral blood mononuclear cells coupled to the recent detection of HIV-1 in podocytes and renal tubular epithelial cells despite eradication of viremia. 3. Amplification of the effect of HIV-1 protein-induced monocyte/mesangial cell injury by Angiotensin II (Ang II), a key mediator of focal glomerulosclerosis. We have also shown that both morphine and cocaine increase the level of angiotensinogen, the precursor of Ang II and tubular cell expression of AT1 receptor. The objective of the present proposal is to determine the effect and molecular mechanism involved in the drug associated progression of HIVAN. The PI hypothesizes that drugs and Ang II accelerate the progression and severity of HIVAN by modulating oxidative stress caused by HIV-1 proteins. The hypotheses to be tested are: 1. Drugs accelerate the deterioration of renal function in humans and mice with HIVAN. 2. Oxidative stress modulated by drugs accelerates the progression of renal injury in a mouse model of HIVAN. 3. Drugs modulation of the renin-angiotensin system contributes to the progression of renal lesions in mice with HIVAN. ? ? ?

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA012111-07
Application #
6805648
Study Section
NeuroAIDS and other End-Organ Diseases Study Section (NAED)
Program Officer
Khalsa, Jagjitsingh H
Project Start
2003-09-30
Project End
2008-06-30
Budget Start
2004-07-01
Budget End
2005-06-30
Support Year
7
Fiscal Year
2004
Total Cost
$552,982
Indirect Cost

  Institution

Name
Feinstein Institute for Medical Research
Department
Type
DUNS #
110565913
City
Manhasset
State
NY
Country
United States
Zip Code
11030

  Publications

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
Kumar, Dileep; Bhaskaran, Madhu; Alagappan, Lakshmi et al. (2010) Heme oxygenase-1 modulates mesangial cell proliferation by p21 Waf1 upregulation. Ren Fail 32:254-8
Mikulak, Joanna; Teichberg, Saul; Faust, Thomas et al. (2009) HIV-1 harboring renal tubular epithelial cell interaction with T cells results in T cell trans-infection. Virology 385:105-14
Husain, Mohammad; Meggs, Leonard G; Vashistha, Himanshu et al. (2009) Inhibition of p66ShcA longevity gene rescues podocytes from HIV-1-induced oxidative stress and apoptosis. J Biol Chem 284:16648-58
Vashistha, Himanshu; Husain, Mohammed; Kumar, Dileep et al. (2009) Tubular cell HIV-1 gp120 expression induces caspase 8 activation and apoptosis. Ren Fail 31:303-12
Chen, Cheng; Liang, Wei; Jia, Junya et al. (2009) Aldosterone induces apoptosis in rat podocytes: role of PI3-K/Akt and p38MAPK signaling pathways. Nephron Exp Nephrol 113:e26-34
Mathew, Jayant T; Patni, Hitesh; Chaudhary, Ahmad N et al. (2008) Aldosterone induces mesangial cell apoptosis both in vivo and in vitro. Am J Physiol Renal Physiol 295:F73-81
Vashistha, Himanshu; Husain, Mohammad; Kumar, Dileep et al. (2008) HIV-1 expression induces tubular cell G2/M arrest and apoptosis. Ren Fail 30:655-64
Jia, Junya; Ding, Guohua; Zhu, Jili et al. (2008) Angiotensin II infusion induces nephrin expression changes and podocyte apoptosis. Am J Nephrol 28:500-7
Hatsukari, Ikusuke; Singh, Priyanka; Hitosugi, Naoko et al. (2007) DEC-205-mediated internalization of HIV-1 results in the establishment of silent infection in renal tubular cells. J Am Soc Nephrol 18:780-7

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