Studies are proposed to examine if platelet/neutrophil activation and the consequent glomerular binding of released cationic proteins cause altered glomerular permeability to immune complexes during the early pathogenesis of glomerulonephritis. THe studies will utilize the following experimental models: In the first, inflammatory cells will be activated by intrarenal arterial infusions of synthetic platelet-activating factor (PAF) to cause release of endogenous PAF from basophils. The effects of ensuing cationic protein release will be tested by measuring glomerular permeability to macromolecules and pre-formed soluble immune complexes. In the second, BSA will be infused into the renal arteries in BSA immunized rabbits. The immune complexes formed in vivo will act as triggers for cell activation and cationic protein release. In the third, the biology of inflammatory cell activation, cationic protein binding and immune complex deposition in glomeruli will be studied in the rabbit model of acute serum sickness. Pharmacologic interventions will be employed to blunt inflammatory cell activation by prostacyclin-theophylline, ticlopidine, or anti-platelet/anti-neutrophil sera or neutralize cationic preoteins (by heparins) and thus attempt to decrease immune complex deposition. In addition, a common feature of glomerulonephritis is the development of hypercellularity as the result of infiltration of blood-borne inflammatory cells and/or the proliferation of resident glomerular cells. Studies are proposed to examine the potential roles of biologically active platelet cationic proteins in the recruitment of inflammatory cells to glomerular structures and/or the proliferation of resident glomerular cells in immune and non-immune models of progressive glomerular disease. Glomerular hypercellularity will be induced by: (1) Formation of large intraglomerular immune complexes and by infusion of BSA in preimmunized rabbit as outlined above; (2) Surgical ablation of 1 and 5/6 of the total renal mass leading to hyperfiltration of the remnant kidney; (3) Desoxycorticosterose-salt induced hypertension; and (4) Intravenous administration of Habu snake venom. Therapeutic interventions with the anti-platelet drug ticlopidine, anti-platelet serum and heparin will be employed to blunt platelet activation and attempt to ameliorate glomerular hypercellularity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
7R01DK038758-01
Application #
3238234
Study Section
Pathology A Study Section (PTHA)
Project Start
1986-09-01
Project End
1989-06-30
Budget Start
1986-09-01
Budget End
1987-06-30
Support Year
1
Fiscal Year
1986
Total Cost
Indirect Cost
Name
Rhode Island Hospital (Providence, RI)
Department
Type
DUNS #
161202122
City
Providence
State
RI
Country
United States
Zip Code
02903
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Barnes, V L; Musa, J; Mitchell, R J et al. (1999) Expression of embryonic fibronectin isoform EIIIA parallels alpha-smooth muscle actin in maturing and diseased kidney. J Histochem Cytochem 47:787-98
Barnes, J L; Woodruff, K A; Levine, S P et al. (1996) Inhibition of mesangial cell proliferation by platelet factor 4. J Am Soc Nephrol 7:991-8
Barnes, J L; Torres, E S; Mitchell, R J et al. (1995) Expression of alternatively spliced fibronectin variants during remodeling in proliferative glomerulonephritis. Am J Pathol 147:1361-71
Barnes, J L; Mitchell, R J; Torres, E S (1995) Expression of plasminogen activator-inhibitor-1 (PAI-1) during cellular remodeling in proliferative glomerulonephritis in the rat. J Histochem Cytochem 43:895-905
Barnes, J L; Hastings, R R; De la Garza, M A (1994) Sequential expression of cellular fibronectin by platelets, macrophages, and mesangial cells in proliferative glomerulonephritis. Am J Pathol 145:585-97
Barnes, J L; Hevey, K A (1991) Glomerular mesangial cell migration. Response to platelet secretory products. Am J Pathol 138:859-66
Barnes, J L; Hevey, K A (1990) Glomerular mesangial cell migration in response to platelet-derived growth factor. Lab Invest 62:379-82
Barnes, J l; Camussi, G; Tetta, C et al. (1990) Glomerular localization of platelet cationic proteins after immune complex-induced platelet activation. Lab Invest 63:755-61
Barnes, J L (1989) Amelioration of habu venom-induced glomerular lesions: potential role for platelet secretory proteins. J Lab Clin Med 114:200-6