Platelets (PLTs) are important inflammatory effector cells in glomerulonephritis (GN). Our hypothesis is that PLTs have an important role in mediating glomerular cell proliferation in GN via mechanisms involving release by the PLT of growth factors, as well as stimulation of intrinsic glomerular cells to produce their own (i.e., autocrine) growth factors.
In Specific Aim #1 we will follow up on our observation that PLT- mediated mesangial cell (MC) proliferation in an immune model of GN involves an upregulation of MC to produce the autocrine growth factor, platelet-derived growth factor (PDGF), and PDGF receptor (PDGF-R). Specifically, we will determine if PLTs mediate glomerular cell proliferation in other nonimmune models of proliferative GN (such as induced by toxins or hemodynamic mechanisms) and if this involves stimulation of MC to upregulate PDGF and PDGF-R. Studies will include localization of PDGF and PDGF-R by immunocytochemistry, quantitation of PDGF and PDGF-R in isolated glomeruli, and measurements of glomerular PDGF and PDGF-R mRNA by Northern analysis with localization by in situ hybridization.
In Specific Aim #2, we will determine if PLT-mediated MC proliferation is associated with upregulation by the MC of another autocrine growth factor, interleukin I (IL-1). Studies will be similar to Specific Aim #1 and will involve both localization and quantitation of IL-1 and IL-1 receptor mRNA and protein in an immune model of mesangial proliferative GN.
In Specific Aim #3, we will determine the role of PDGF in mediating MC proliferation in a PLT-mediated model of mesangial proliferation GN by attempting to block in vivo PDGF with a specific anti- PDGF antibody. Finally, in Specific Aim #4, we will pursue our observation that PLTs mediate an upregulation of PDGF-R on MC in GN by determining what PLT factor(s) modulate MC expression of PDGF-R in cell culture. These studies will confirm the importance of the PLT in proliferative GN and will define the mechanisms involved, specifically the importance of PLTs in mediating the MC to produce autocrine growth factors, and the role of PDGF in glomerular disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Modified Research Career Development Award (K04)
Project #
1K04DK002142-01
Application #
3072643
Study Section
Pathology A Study Section (PTHA)
Project Start
1992-08-01
Project End
1997-07-30
Budget Start
1992-08-01
Budget End
1993-07-30
Support Year
1
Fiscal Year
1992
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
Hugo, C P; Pichler, R P; Schulze-Lohoff, E et al. (1999) Thrombospondin peptides are potent inhibitors of mesangial and glomerular endothelial cell proliferation in vitro and in vivo. Kidney Int 55:2236-49
Hugo, C; Shankland, S J; Pichler, R H et al. (1998) Thrombospondin 1 precedes and predicts the development of tubulointerstitial fibrosis in glomerular disease in the rat. Kidney Int 53:302-11
Hugo, C; Nangaku, M; Shankland, S J et al. (1998) The plasma membrane-actin linking protein, ezrin, is a glomerular epithelial cell marker in glomerulogenesis, in the adult kidney and in glomerular injury. Kidney Int 54:1934-44
Nangaku, M; Johnson, R J; Couser, W G (1997) Glomerulonephritis and complement regulatory proteins. Exp Nephrol 5:345-54
Hughes, J; Johnson, R J; Mooney, A et al. (1997) Neutrophil fate in experimental glomerular capillary injury in the rat. Emigration exceeds in situ clearance by apoptosis. Am J Pathol 150:223-34
Floege, J; Hackmann, B; Kliem, V et al. (1997) Age-related glomerulosclerosis and interstitial fibrosis in Milan normotensive rats: a podocyte disease. Kidney Int 51:230-43
Zachem, C R; Alpers, C E; Way, W et al. (1997) A role for P-selectin in neutrophil and platelet infiltration in immune complex glomerulonephritis. J Am Soc Nephrol 8:1838-44
Johnson, R J (1997) Have we ignored the role of oncotic pressure in the pathogenesis of glomerulosclerosis? Am J Kidney Dis 29:147-52
Nangaku, M; Shankland, S J; Kurokawa, K et al. (1997) Cloning of a new human gene with short consensus repeats using the EST database. Immunogenetics 46:99-103
Hugo, C; Shankland, S J; Bowen-Pope, D F et al. (1997) Extraglomerular origin of the mesangial cell after injury. A new role of the juxtaglomerular apparatus. J Clin Invest 100:786-94

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