The complement membrane attack complex (C5b-9) is a major mediator of antibody-induced glomerular diseases. Progression is often characterized by mesangial matrix expansion in the glomerulus which is tightly linked to glomerular mesangial cell (MC) proliferation and by interstitial fibrosis which is often linked to proteinuria. The focus of this project is on two proposed new roles for C5b-9 in mediating progressive renal disease.
Specific Aim 1 tests the hypothesis that C5b-9 is a mitogen for glomerular mesangial cells. Experiments proposed test the hypothesis that at low doses C5b-9 augments the mesangial cell response to growth factors, while at higher doses it has a direct mitogenic effect mediated a) through changes in mesangial cells expression of cyclin kinase inhibitors and, b) by stimulating the release of mesangial cell-derived growth factors and oxidants. Experiments will quantify C5b-9 insertion into mesangial cells and examine effects on proliferation, growth factor and H2O2 release and expression of cell cycle regulatory proteins (CDK2, CDK4, p21 and p27) and anti-proliferative molecules (TGF-b, SPARC). To confirm a functional role for cell cycle kinase inhibitors p21 and p27 in C5b-9 induced proliferation, the proliferative response to C5b-9 will be studied in mesangial cells derived from p21 and p27 knockout mice compared to wildtype controls, and mesangial cell proliferation induced by antibody and complement will also be studied in these animals in vivo.
In Specific Aim 2, experiments proposed will test the hypothesis that the interstitial lesions which characterize proteinuric glomerular diseases derive in part from complement activation in proteinuric urine with sublytic effects of C5b-9 on proximal tubular epithelial cells to stimulate production of inflammatory mediators and matrix components that lead to fibrosis. Studies will test this hypothesis by comparing tubular injury and proliferation, apoptosis, macrophage infiltration, macrophage adhesion molecules, myofibroblasts, matrix components and renal function in normocomplentemic and C6 deficient PVG rats with proteinuria induced by several different mechanisms. A functional role for C5b-9 will be confirmed by modulating C5b-9 deposition in the proximal tubule utilizing antisense technology to alter CD59 expression on tubular cells. Differences in mediator production by proximal tubular cells in culture to sublytic C5b-9 attack and measuring production of the mediators involved. The data generated may establish a role for C5b-9 in mediating the two principal structural features of progressive renal disease, glomerular matrix expansion and interstitial fibrosis, and will document the mechanisms of these effects. This information should lead to new opportunities for therapeutic intervention in immune renal disease.
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| Nangaku, Masaomi; Shankland, Stuart J; Couser, William G (2005) Cellular response to injury in membranous nephropathy. J Am Soc Nephrol 16:1195-204 |
| Nangaku, Masaomi; Couser, William G (2005) Mechanisms of immune-deposit formation and the mediation of immune renal injury. Clin Exp Nephrol 9:183-91 |
| Rangan, Gopala K; Pippin, Jeffrey W; Coombes, Jason D et al. (2005) C5b-9 does not mediate chronic tubulointerstitial disease in the absence of proteinuria. Kidney Int 67:492-503 |
| Vaughan, Michael R; Pippin, Jeffrey W; Griffin, Sian V et al. (2005) ATRA induces podocyte differentiation and alters nephrin and podocin expression in vitro and in vivo. Kidney Int 68:133-44 |
| Griffin, Sian V; Krofft, Ronald D; Pippin, Jeffrey W et al. (2005) Limitation of podocyte proliferation improves renal function in experimental crescentic glomerulonephritis. Kidney Int 67:977-86 |
| Griffin, Sian V; Hiromura, Keiju; Pippin, Jeffrey et al. (2004) Cyclin-dependent kinase 5 is a regulator of podocyte differentiation, proliferation, and morphology. Am J Pathol 165:1175-85 |
| Rangan, Gopala K; Pippin, Jeffrey W; Couser, William G (2004) C5b-9 regulates peritubular myofibroblast accumulation in experimental focal segmental glomerulosclerosis. Kidney Int 66:1838-48 |
| Durvasula, Raghu V; Petermann, Arndt T; Hiromura, Keiju et al. (2004) Activation of a local tissue angiotensin system in podocytes by mechanical strain. Kidney Int 65:30-9 |
| Petermann, Arndt; Hiromura, Keiju; Pippin, Jeffrey et al. (2004) Differential expression of d-type cyclins in podocytes in vitro and in vivo. Am J Pathol 164:1417-24 |
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