Membranous nephropathy (MN) is the commonest cause of idiopathic nephrotic syndrome in adults and is a prototype of immune complex induced glomerulonephropathy. The subepithelial deposits which characterize MN in vivo form locally as a consequence of A) antibody binding to antigen(s) on the glomerular epithelial cell (GEC) surface, or B) charge interaction between cationic antigens or antibodies and glomerular anionic sites followed by in situ immune complex formation. The consequences of subepithelial immune deposit formation by both mechanisms include a marked increase in glomerular permeability accompanied by an increase in basement membrane (GBM) thickness due to accumulation of excess normal matrix components produced by the GEC, particularly laminin. Studies in experimental models of MN induced by both of these mechanisms have documented that the complement membrane attack complex, C5b-9, mediates proteinuria in MN, presumably through insertion into the GEC membrane. This project will examine the cellular and molecular consequences of C5b-9 attack on the GEC which may lead to the functional and structural glomerular abnormalities of MN. Three hypotheses will be tested. 1) That GEC C5b-9 attack results in altered synthesis of extracellular matrix components. The effect of C5b-9 attack on GEC in culture on GEC synthesis of type IV collagen, laminin, heparan sulfate proteoglycans and entactin will be studied utilizing metabolic labeling, direct measurement of product in cell supernatant and cell layer/matrix and measurement of GEC mRNA encoding for type IV collagen and laminin. C5b-9 attack on antibody sensitized cultured GEC (analogous the autoimmune mechanism of MN) will be compared to C5b-9 attack on non-sensitized GEC (analogous to exogenous antigen induced MN). 2) The hypothesis that altered GBM permeability in MN results from GEC production of a neutral serine proteinase will be tested by isolating and characterizing a proteinase produced by GEC and measuring the effect of GEC C5b-9 attack on production of this proteinase. 3) The hypothesis that C5b-9 attack on GEC induces proteinuria by causing GEC detachment from basement membrane will be tested by studying the effect of C5b-9 attack initiated by the two mechanisms above on GEC attachment to, or detachment from, various extracellular matrices, and by examining the effect of C5b-9 attack on GEC membrane attachment receptors. The results of these studies should clarify the cellular and molecular basis for glomerular injury induced by C5b-9 in MN as well as in other antibody initiated glomerular diseases.
| 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 |
| 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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