The proposal attempts to integrate the roles of circulating factors such as hormones and immunecomplexes with locally generated responses and mediators in the control of renal function. Circulating agents will include vasoactive hormones, and IgG complexes. Local mediators encompass eicosanoids, platelet activating factor and cytokines. The long-term objectives are to expand our understanding of the cellular mechanisms involved in the regulation of glomerular function in the kidney and their contributions to glomerular disease. This will be essential for the rational design of therapeutic interventions for kidney diseases. Two major specific aims are envisioned: 1) To elucidate the interaction of IgG complexes, vasoactive agents, autacoids, and cytokines with mesangial cells and the resulting consequences on mesangial cell biology in order to understand their roles in glomerular physiology and pathophysiology. 2) To determine the cellular mechanisms by which the above agents influence mesangial cells. In order to achieve these goals, we will use cultured mesangial cells, J774 macrophages, and S49.1 T cells. We have identified a specific Fc receptor for IgG on rat mesangial cells. We will now examine factors controlling the expression of the Fc receptors using binding studies, immunoprecipitation, Northern blotting, and in situ hybridization with specific cDNA and RNA probes for the Fc receptor. These studies will then be expanded to in vivo studies to evaluate the Fc receptor function in vivo. We will also examine the consequences of Fc receptor occupancy on mesangial cells. This will be accomplished by determining phospholipid turnover, arachidonic acid metabolism inositol phosphates, cyclic nucleotides, cell proliferation and cytokine generation matrix production. Overall, the proposed studies represent an extension of our current research on the biology of the glomerular mesangial cell and their control mechanisms in the context of glomerular function in general.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK022036-12A1
Application #
3227186
Study Section
General Medicine B Study Section (GMB)
Project Start
1978-09-30
Project End
1995-06-30
Budget Start
1990-07-01
Budget End
1991-06-30
Support Year
12
Fiscal Year
1990
Total Cost
Indirect Cost
Name
Albert Einstein College of Medicine
Department
Type
Schools of Medicine
DUNS #
009095365
City
Bronx
State
NY
Country
United States
Zip Code
10461
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Neugarten, J; Feith, G W; Assmann, K J et al. (1995) Role of macrophages and colony-stimulating factor-1 in murine antiglomerular basement membrane glomerulonephritis. J Am Soc Nephrol 5:1903-9
Schlondorff, D (1995) The role of chemokines in the initiation and progression of renal disease. Kidney Int Suppl 49:S44-7
Schlondorff, D (1994) Cellular mechanism of glomerular injury: metabolic factors in progressive renal injury. Kidney Int Suppl 45:S54-5
Satriano, J; Schlondorff, D (1994) Activation and attenuation of transcription factor NF-kB in mouse glomerular mesangial cells in response to tumor necrosis factor-alpha, immunoglobulin G, and adenosine 3':5'-cyclic monophosphate. Evidence for involvement of reactive oxygen species. J Clin Invest 94:1629-36
Satriano, J A; Shuldiner, M; Hora, K et al. (1993) Oxygen radicals as second messengers for expression of the monocyte chemoattractant protein, JE/MCP-1, and the monocyte colony-stimulating factor, CSF-1, in response to tumor necrosis factor-alpha and immunoglobulin G. Evidence for involvement of reduced J Clin Invest 92:1564-71
Schlondorff, D (1993) Cellular mechanisms of lipid injury in the glomerulus. Am J Kidney Dis 22:72-82
Satriano, J A; Hora, K; Shan, Z et al. (1993) Regulation of monocyte chemoattractant protein-1 and macrophage colony-stimulating factor-1 by IFN-gamma, tumor necrosis factor-alpha, IgG aggregates, and cAMP in mouse mesangial cells. J Immunol 150:1971-8
Hora, K; Satriano, J A; Santiago, A et al. (1992) Receptors for IgG complexes activate synthesis of monocyte chemoattractant peptide 1 and colony-stimulating factor 1. Proc Natl Acad Sci U S A 89:1745-9
Singhal, P C; Gupta, S; Shen, Z et al. (1991) Effects of PGE2 and a thromboxane A2 analogue on uptake of IgG complexes and LDL by mesangial cells. Am J Physiol 261:F537-44

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