The complement (C) system is a well established mediator of immune renal injury. Previously the only role of C was believed to be an indirect one involving attraction of effector inflammatory cells. In recent preliminary studies we have identified a new direct role for C in mediating glomerualr injury due to subepithelia immune deposit formation in rats and provided evidence that C6 is required for C-mediated membranous nephropathy and anti-GBM nephritis in rabbits. In this proposal we will test the hypothesis that a distal C mechanism is a major component of C-mediated renal injury by: 1) looking for deposition of distal C components and neoantigens of the membrane attack complex (MAC) in models of C-dependent renal injury due to the spectrum of immune glomerular diseases seen in man associated with subeptithelial, intramembranous and mesanglial immune deposits induced with antibodies to fixed and planted glomerular antigens, 2) quantitating the capacity of glomerular immune deposits at various sites to activate distal C components in vitro, 3) determining the capacity of perfusates selectively sufficient of deficient in individual C components to mediate capillary wall injury when exposed to in vivo formed glomerular immune deposits, 4) testing the effect of several modulators of C5b-9 assembly on various C-dependent and independent forms of immune glomerular disease, 5) studying the effect of genetic or induced deficiencies in distal C components on development of various types of experimental glomerulonephritis, and 6) testing the ability of antibody to proximal tubular epithelial cell brush border membranes to alter tubular transport functions in the presence or absence of fixation of selected components of the C5b-9 complex using tubular microperfusion techniques. 7) We will also asses the capacity of C to solubilize various types of glomerular immune deposits and determine the C components required.

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National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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University of Washington
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Petermann, Arndt T; Pippin, Jeffrey; Durvasula, Raghu et al. (2005) Mechanical stretch induces podocyte hypertrophy in vitro. Kidney Int 67:157-66
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
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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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