Recently, a leukocyte-independent form of complement (C')-mediated glomerular injury was defined in passive Heymann nephritis (PHN), a rat model that closely resembles human membranous nephropathy which is a common cause of nephrotic syndrome in adults. While further observations have suggested a role for the C5b-9 membrane attack complex (MAC) in this and other forms of tissue injury, this has not been conclusively shown. Variants of PHN and a recently developed model of antibody (Ab)-directed, C'-mediated glomerular injury in the isolated perfused rat kidney (IPRK) will be used to further study this unique form of tissue injury. Kidneys that contain an antigen planted in the subepithelial space are perfused in vitro with a cell-free perfusate containing C'-fixing Ab and various sources of C'=replete and C'-deficient sera. The effects on glomerular function are oserved for up to two hours. With the aid of this model, definitive evidence of a functional role for the MAC will be sought using sera deficient in C6 and C8. Additional studies will examine: the possible role of intermediary systems; C'-mediated alterations in glomerular sieving properties, GBM charge residues, and glomerular podocyte morphology; and localization of the MAC by immunohistological and ultrastructural techniques. The role of the MAC will also be examined in vivo by depleting rats of C8 with a specific antiserum. Similar observations in the IPRK and in vivo will also be made with antiglomerular basement membrane (GBM) antibody. Also to be examined in the IPRK are: a) a potential relationship between immunopathogenetic events, locally-derived vasoactive hormones and disordered renal hemodynamics in PHN; and b) the influence of hemodynamic factors on the binding of Abs to glomerular antigens. An erythrocyte-perfused IPRK, in which hemodynamic variables approach physiological values, will be used for these studies. In addition, the relationship between the density of glomerular antigens and the abilities of their respective antibodies to fix C' and induce glomerular injury will be explored. Sheep antisera to laminin and rat GBM and quantitative in vivo and in vitro glomerular binding techniques will be used for this purpose. The proposed studies will further the long term goals of Investigator, which are to comprehensively analyze the factors that influence Ab deposition in glomeruli and the ways in which such Abs interact with C' and other mediators to induce glomerular injury.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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Pathology A Study Section (PTHA)
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Boston University
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Fan, Xueping; Li, Qinggang; Pisarek-Horowitz, Anna et al. (2012) Inhibitory effects of Robo2 on nephrin: a crosstalk between positive and negative signals regulating podocyte structure. Cell Rep 2:52-61
Bonegio, Ramon; Susztak, Katalin (2012) Notch signaling in diabetic nephropathy. Exp Cell Res 318:986-92
Surindran, Sheena; Ayalon, Rivka; Hasan, Nazia et al. (2012) Coexistence of ANCA-associated glomerulonephritis and anti-phospholipase A(2) receptor antibody-positive membranous nephropathy. Clin Kidney J 5:162-165
George, Britta; Verma, Rakesh; Soofi, Abdulsalam A et al. (2012) Crk1/2-dependent signaling is necessary for podocyte foot process spreading in mouse models of glomerular disease. J Clin Invest 122:674-92
Khosroshahi, Arezou; Ayalon, Rivka; Beck Jr, Laurence H et al. (2012) IgG4-Related Disease Is Not Associated with Antibody to the Phospholipase A2 Receptor. Int J Rheumatol 2012:139409
Bonegio, Ramon G B; Beck, Laurence H; Kahlon, Roopkiranjot K et al. (2011) The fate of Notch-deficient nephrogenic progenitor cells during metanephric kidney development. Kidney Int 79:1099-112
Bollee, Guillaume; Flamant, Martin; Schordan, Sandra et al. (2011) Epidermal growth factor receptor promotes glomerular injury and renal failure in rapidly progressive crescentic glomerulonephritis. Nat Med 17:1242-50
Beck Jr, Laurence H; Fervenza, Fernando C; Beck, David M et al. (2011) Rituximab-induced depletion of anti-PLA2R autoantibodies predicts response in membranous nephropathy. J Am Soc Nephrol 22:1543-50
Qin, Weisong; Beck Jr, Laurence H; Zeng, Caihong et al. (2011) Anti-phospholipase A2 receptor antibody in membranous nephropathy. J Am Soc Nephrol 22:1137-43
Hofstra, Julia M; Beck Jr, Laurence H; Beck, David M et al. (2011) Anti-phospholipase A? receptor antibodies correlate with clinical status in idiopathic membranous nephropathy. Clin J Am Soc Nephrol 6:1286-91

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