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. ? ? ?

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National Institute on Drug Abuse (NIDA)
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NeuroAIDS and other End-Organ Diseases Study Section (NAED)
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Khalsa, Jagjitsingh H
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Feinstein Institute for Medical Research
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