The goal of the present proposal is to determine the mechanism of glomerular injury (focal glomerulosclerosis) in patients with opioid abuse. Since expansion of mesangium is considered a precursor of glomerulosclerosis, the objective of the present application is to examine whether opioid use is associated with mesangial expansion, and if it is, is it caused by an increased delivery of macromolecules into the mesangium or by an increased synthesis of mesangial matrix or both. To determine the role of mesangial cells (MC) in this lesion we intend to a) study the presence of opioid receptors on mesangial cells; b) determine the effect of opioids on uptake of IgG complexes and associated release of lipid mediators of inflammation and reactive oxygen species by MC and macrophages; c) evaluate opioid induced cytoskeletal changes in mesangial cells and matrix. A number of methods will be used. These include quantification of IgG complex uptake by mesangial cells using reflectance microscopy and radiolabeling; determination of lipid mediators of inflammation (PGE2,PAF) and reactive oxygen species (superoxide and hydroxyl radicals); morphometric analysis of the size of mesangium (in vivo); mesangial localization of cytoskeletal changes by fluorescence technique using video enhancement and the confocal microscope to determine structural changes at high resolution. The hypothesis for opioid action will be tested based on preliminary findings that MC have receptors for opioids and opioids cause attenuation of growth of MC and may thus cause accumulation of phlogogenic macromolecules in the glomerular mesangium. This may lead to an initial mesangial expansion and subsequent sclerosis. These findings will increase the understanding of glomerular lesions in patients with drug abuse, where little work has been done. It will increase our understanding of the response of the mesangial cells, and important contribution of renal function.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
2R01DA006753-04
Application #
2119055
Study Section
Sociobehavioral Subcommittee (DAAR)
Project Start
1991-09-30
Project End
1998-07-31
Budget Start
1994-09-01
Budget End
1995-07-31
Support Year
4
Fiscal Year
1994
Total Cost
Indirect Cost
Name
Long Island Jewish Medical Center
Department
Type
DUNS #
City
New Hyde Park
State
NY
Country
United States
Zip Code
11040
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Singhal, P C; Gibbons, N; Franki, N et al. (1998) Simulated glomerular hypertension promotes mesangial cell apoptosis and expression of cathepsin-B and SGP-2. J Investig Med 46:42-50
Bank, N; Kiroycheva, M; Ahmed, F et al. (1998) Peroxynitrite formation and apoptosis in transgenic sickle cell mouse kidneys. Kidney Int 54:1520-8
Singhal, P C; Franki, N; Kumari, S et al. (1998) Extracellular matrix modulates mesangial cell apoptosis and mRNA expression of cathepsin-B and tissue transglutaminase. J Cell Biochem 68:22-30
Mattana, J; Margiloff, L; Sharma, P et al. (1998) Oxidation of the mesangial matrix metalloproteinase-2 impairs gelatinolytic activity. Inflammation 22:269-76
Margiloff, L; Chaplia, L; Chow, A et al. (1998) Metal-catalyzed oxidation of immunoglobulin G impairs Fc receptor-mediated binding to macrophages. Free Radic Biol Med 25:780-5
Kapasi, A; Bhat, P; Singhal, P C (1998) Tubular cell and HIV-1 gp120 interaction products promote migration of monocytes. Inflammation 22:137-44
Mattana, J; Margiloff, L; Chaplia, L et al. (1998) Metal-catalyzed oxidation of extracellular matrix increases macrophage nitric oxide generation. Kidney Int 54:1581-92
Singhal, P C; Sharma, P; Reddy, K et al. (1997) HIV-1 gp160 envelope protein modulates proliferation and apoptosis in mesangial cells. Nephron 76:284-95
Mattana, J; Effiong, C; Kapasi, A et al. (1997) Leukocyte-polytetrafluoroethylene interaction enhances proliferation of vascular smooth muscle cells via tumor necrosis factor-alpha secretion. Kidney Int 52:1478-85

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