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.
Showing the most recent 10 out of 37 publications
