Neutrophils (PMN) are established mediators of immune renal injury. Our objective is to test a new hypothesis to explain how PMNs cause renal damage. New evidence strongly suggests that PMN-derived reactive oxygen species (ROS), particularly H2O2, are the major mediators of tissue injury. However, how H2O2 in physiologic concentration causes tissue injury is not known. We hypothesize that the cationic PMN enzyme myeloperoxidase (MPO) binds on a charge basis to the glomerular capillary wall and catalyzes the reaction of H2O2 with a halide (C1, I) to form highly toxic hypohalous acids and halogens. We have now shown that MPO and H2O2 can interact to produce severe glomerular injury and that a similar mechanism may be operative in a model of immune complex nephritis. We now wish to expand these preliminary observations in three areas. First, we will establish the importance of the MPO system in PMN-mediated injury by studying glomerular injury in PMN- depleted rats with immune complex nephritis (GN) that are reconstituted with normal or MPO deficient human PMNs. Second, we will study the effects of the MPO-H2O2-halide system in vitro on resident glomerular cells and glomerular basement membrane (GBM) which may account for its nephritogenicity. This would include examining the ability of the system to cause hydroxyproline release from GBM collagen and the lethal and sublethal effects of the MPO system on the mesangial cell. Finally, we will pursue some interesting preliminary data which suggests that platelets may play an important role in PMN/MPO mediated GN by studying rats depleted of platelets and by performing kinetic studies with isotopic labelled platelets and PMNs in PMN-mediated immune complex GN.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29DK039068-03
Application #
3462983
Study Section
General Medicine B Study Section (GMB)
Project Start
1987-08-01
Project End
1992-07-31
Budget Start
1989-08-01
Budget End
1990-07-31
Support Year
3
Fiscal Year
1989
Total Cost
Indirect Cost
Name
University of Washington
Department
Type
Schools of Medicine
DUNS #
135646524
City
Seattle
State
WA
Country
United States
Zip Code
98195
Floege, J; Radeke, H R; Johnson, R J (1994) Glomerular cells in vitro versus the glomerulus in vivo. Kidney Int 45:360-8
Floege, J; Eng, E; Young, B A et al. (1993) Factors involved in the regulation of mesangial cell proliferation in vitro and in vivo. Kidney Int Suppl 39:S47-54
Floege, J; Eng, E; Young, B A et al. (1993) Heparin suppresses mesangial cell proliferation and matrix expansion in experimental mesangioproliferative glomerulonephritis. Kidney Int 43:369-80
Floege, J; Johnson, R J; Alpers, C E et al. (1993) Visceral glomerular epithelial cells can proliferate in vivo and synthesize platelet-derived growth factor B-chain. Am J Pathol 142:637-50
Couser, W G (1993) Pathogenesis of glomerulonephritis. Kidney Int Suppl 42:S19-26
Floege, J; Johnson, R J; Gordon, K et al. (1992) Altered glomerular extracellular matrix synthesis in experimental membranous nephropathy. Kidney Int 42:573-85
Floege, J; Eng, E; Lindner, V et al. (1992) Rat glomerular mesangial cells synthesize basic fibroblast growth factor. Release, upregulated synthesis, and mitogenicity in mesangial proliferative glomerulonephritis. J Clin Invest 90:2362-9
Floege, J; Burns, M W; Alpers, C E et al. (1992) Glomerular cell proliferation and PDGF expression precede glomerulosclerosis in the remnant kidney model. Kidney Int 41:297-309
Floege, J; Alpers, C E; Burns, M W et al. (1992) Glomerular cells, extracellular matrix accumulation, and the development of glomerulosclerosis in the remnant kidney model. Lab Invest 66:485-97
Johnson, R J; Raines, E W; Floege, J et al. (1992) Inhibition of mesangial cell proliferation and matrix expansion in glomerulonephritis in the rat by antibody to platelet-derived growth factor. J Exp Med 175:1413-6

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