The long-term goal of our study is to clarify the pathogenesis of the proliferative lesions in HIV-1 associated nephropathy (HIVAN). Based on previous work done by others and our preliminary data using an HIV-1 transgenic murine model of HIVAN, we hypothesize that the proliferative changes present in HIVAN are partially related to alterations in bFGF released by injured cells. The strong binding affinity of bFGF to heparin, suggest that bFGF released by injured cells could be bound to renal heparin-like molecules such as heparan sulfate proteoglycans (HSPG) located on the cell surface or extracellular matrix. HSPG may affect bFGF interaction with its high affinity receptors potentiating its mitogenic effects. Thus, renal HSPG could play a dual role in HIVAN: 1) increasing virus adsorption and possible infection of renal cells, and 2) inducing proliferation by facilitating bFGF storage in renal tissue.
The specific aims of this study are: 1. Determine whether HSPG located on renal proximal tubular epithelial cells (RPTEc) interact with HIV envelope protein gp120 facilitating virus binding and entry. a) Characterize the proteoglycan content of human RPTEc. b) Define binding interactions between gp120 and HSPG on the cell surface of RPTEc. c) Determine whether RPTEc could be infected by macrophage-tropic or T cell tropic HIV-1 viruses, and evaluate the role of HSPG on this process. We expect to define the role of HSPG on HIV-1 virus attachment and entry to RPTEc. 2. Define whether HIV-1 viral products influence bFGF activity and cell growth. a) Identify renal cell types producing, releasing, and responding to bFGF mitogenic effects. b) Evaluate the role of HIV-1 viral products tat and gp120 on renal growth, bFGF synthesis and release. c) Define whether proteolytic enzymes induced by HIV infection, may facilitate bFGF release from renal cells and extracellular matrix. We expect to determine how HIV-1 viral products influence bFGF activity and cell growth in renal tissue. 3. Determine the role of bFGF and its receptors in the pathogenesis of HIVAN in HIV transgenic mice. a) Define topographical distribution and number of bFGF low and high affinity binding sites in control and transgenic kidneys. b) Identify novel bFGF binding proteins in transgenic RTEc. c) Determine renal gene expression of bFGF high affinity receptors (FGFR-1, FGFR-2). d) Define in vivo effects of bFGF on renal growth and HIV expression. e) Evaluate therapies to block bFGF low affinity receptors or bFGF gene expression in renal tissue. We expect these experiments to define the interrelationships between bFGF accumulation in renal tissue and kidney growth, and to test potential therapies to prevent the progression of HIVAN.
Showing the most recent 10 out of 55 publications
