The goal of the present proposal is to determine the role of HIV and illicit drugs such as opiates and cocaine in the development of renal injury which manifests itself as focal glomerulosclerosis (FGS) and tubulointerstitial lesions (TIL). We hypothesize that HIV-I in combination with the drugs interacts with monocytes and tubular cells (TC) and mesangial cells (MC) to induce TIL and expansion of the mesangium (precursor of FGS). Tubulo-interstitial lesions, a unique feature of HIV-associated renal injury, set the pace of the progression of renal failure. To examine the role of HIV-I and drugs in both glomerular and interstitial lesions we plan to 1) study the effect of HIV and drugs on the migration of macrophages (Mphi) into the interstitium and mesangium 2) determine the effect of HIV-l/drugs and Mphi interaction products on MC proliferation and matrix accumulation, 3) examine the effect of HIV-1 and drugs on the migrated Mphi and proliferated MC, and 4) study the effect of HIV-l/drugs and tubular cell interaction products on kidney fibroblast (KF) proliferation/apoptosis and matrix accumulation. Transmigration of Mphi across the endothelial cell layer will be determined as well as across a gelatin coated filter. Thymidine incorporation studies will be used to evaluate MC/KF proliferation. Western blots will be used to measure the laminin, fibronectin, proteoglycan and collagen components of matrix and Northern blots to measure mRNA expression for growth/cell death related genes and matrix components. A biotin-avidin assay and zymography will be used in the measurement of gelatinolytic and stromelysin activity. To examine the effect of HIV-1 gene expression, studies for cell proliferation and matrix synthesis will be carried out on MC derived from mice transgenic for HIV-I genes. In addition, these mice will be treated with drugs and acceleration of renal cortical and medullary mRNA expression of matrix components and cytokines will be evaluated. The hypothesis for the role of HIV and drugs in the development of renal injury will be tested based on our preliminary findings of increased MC/KF proliferation, and matrix accumulation when HIV-I proteins, HIV-1 protein-Mphi/TC interaction products are added to MC/KF in culture. Moreover, our results show that HIV and MC secretory/gpl20 and TC products enhance the migration of Mphi into the interstitium and mesangium. We believe that tubulointerstitial lesions determine the accelerated course of renal failure in drug addicts with HIV infection.
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