Tubulointerstitial nephritis (TIN) is characterized by abnormalities of renal tubules and interstitium with infiltration of mononuclear and polymorphonuclear leukocytes. Immunologically mediated forms of TIN have been investigated in animal models induced by immunization with kidney tubular basement membrane (TBM) and crude kidney tissue. Cellular and humoral immune responses are variably involved in the pathogenesis of TIN in these models. While immunopathological mechanisms have been investigated extensively in model systems, little is understood about the identity and roles of kidney components in the disease process. In man, TIN is associated with anti-TBM antibodies and cellular immune elements are thought to play a predominant role. This research program will further characterize a component of TBM (TIN antigen (TA)) that reacts with anti-TBM sera in human TIN and induces TIN in rats. Structural relationships between molecular weight forms of TA will be investigated. Ultrastructural localization of TA will be characterized. Cell binding of TA and its interaction with other matrix components will be studied. Protein sequence of TA will be deduced by sequencing cDNA. Methods include: protein isolation by column chromatography, characterization by electrophoresis, chemical analysis, protein sequencing and immunochemical assays. Monoclonal antibodies will be developed and molecular biology techniques, including screening of a cDNA library, PCR, DNA sequencing and Northern analysis will be employed. Electron microscopy will be used for ultrastructural characterization of antibody binding and to define molecular properties of TA and its interactions with other molecules. The applicant's long-term objectives are to elucidate roles of extracellular matrix components in renal disease, to characterize structure and functions of renal basement membrane components, and to define composition and organization of basement membranes in the kidney.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK036007-06
Application #
2139691
Study Section
Pathology A Study Section (PTHA)
Project Start
1987-08-01
Project End
1997-06-30
Budget Start
1995-07-01
Budget End
1996-06-30
Support Year
6
Fiscal Year
1995
Total Cost
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Pediatrics
Type
Schools of Medicine
DUNS #
168559177
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Zhou, B; Nelson, T R; Kashtan, C et al. (2000) Identification of two alternatively spliced forms of human tubulointerstitial nephritis antigen (TIN-Ag). J Am Soc Nephrol 11:658-68
Nelson, T R; Kim, Y; Michael, A F et al. (1998) Tubulointerstitial nephritis antigen (TIN-ag) is expressed in distinct segments of the developing human nephron. Connect Tissue Res 37:53-60
Nelson, T R; Butkowski, R J; Michael, A F et al. (1997) Detection of tubulointerstitial nephritis antigen (TIN-ag) in Lewis rat. Connect Tissue Res 36:223-9
Hasegawa, G; Hunter, A J; Charonis, A S (1995) Matrix nonenzymatic glycosylation leads to altered cellular phenotype and intracellular tyrosine phosphorylation. J Biol Chem 270:3278-83
Nelson, T R; Charonis, A S; McIvor, R S et al. (1995) Identification of a cDNA encoding tubulointerstitial nephritis antigen. J Biol Chem 270:16265-70
Charonis, A; Kalfa, T; Butkowski, R et al. (1994) Interactions between tubulointerstitial nephritis antigen and laminin or type IV collagen. Contrib Nephrol 107:180-7
Kalfa, T A; Thull, J D; Butkowski, R J et al. (1994) Tubulointerstitial nephritis antigen interacts with laminin and type IV collagen and promotes cell adhesion. J Biol Chem 269:1654-9
Hagen, S G; Michael, A F; Butkowski, R J (1993) Immunochemical and biochemical evidence for distinct basement membrane heparan sulfate proteoglycans. J Biol Chem 268:7261-9
Katz, A; Fish, A J; Santamaria, P et al. (1992) Role of antibodies to tubulointerstitial nephritis antigen in human anti-tubular basement membrane nephritis associated with membranous nephropathy. Am J Med 93:691-8
Butkowski, R J; Kleppel, M M; Katz, A et al. (1991) Distribution of tubulointerstitial nephritis antigen and evidence for multiple forms. Kidney Int 40:838-46

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