The objective is to study and resolve the riddles of certain diseases in childhood, specifically those associated with abnormalities of the glomerular capillary filter. The grant focuses on research that will help us understand the pathogenesis of familial forms of renal disease including Alport-type familial nephritis, nephrotic syndrome, and glomerulonephritis. This proposal is predicated on observations that an antigenic determinant(s) on the non-collagenous domain (NC1) of type IV collagen is not detected on the glomerular basement (GBM) membrane and epidermal basement membrane (EBM) of males with Alport-type familial nephritis whereas in affected females the EBM shows zones of reactivity separated by gaps of non-reactivity, supporting X-linked dominant inheritance. Direct analysis of Alport kidney basement membrane by PAGE and 2-dimensional gel analysis demonstrates absence of a normally-occurring 28 kDa antigenic component. Studies include further antigenic analysis of affected kindreds; development of highly specific and informative monoclonal antibodies; detailed analyses of NC1 monomers and dimers; and development of cDNA probes to the NC1 component. The proposal is concerned with components of the human glomerular visceral epithelium and basement membrane. We will characterize the role of a previously unrecognized component of human GBM - MBM15 antigen - which appears early in ontogeny, is a component of epithelial spikes in membranous nephropathy; is synthesized by human glomerular epithelial cells in culture, and is a normal urinary constituent. Studies will be carried out on human glomerular polyanion (GPA) (podocalyxin), a negatively-charged sialoprotein that covers the surface of viscerel eplithelial cells, and proteoglycan located in the lamina rara of the GBM--in order to define further their role in human disease. We have shown that human glomerular epithelium in culture synthesize a variety of components including proteoglycans, MBM15 antigen, collagen IV, laminin, fibronectin, and certain lymphohemopoietic antigens. The role of the epithelial cell in modulating and controlling components of the glomerular capillary will be addressed. The methods used include cell culture, immunohistochemistry, morphology, biochemistry, immunology, and cDNA technology.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI010704-29
Application #
3124772
Study Section
Pathology A Study Section (PTHA)
Project Start
1976-12-01
Project End
1991-11-30
Budget Start
1988-12-01
Budget End
1989-11-30
Support Year
29
Fiscal Year
1989
Total Cost
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Type
Schools of Medicine
DUNS #
168559177
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
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Lenkkeri, U; Mannikko, M; McCready, P et al. (1999) Structure of the gene for congenital nephrotic syndrome of the finnish type (NPHS1) and characterization of mutations. Am J Hum Genet 64:51-61
Kashtan, C E (1999) Alport syndrome. An inherited disorder of renal, ocular, and cochlear basement membranes. Medicine (Baltimore) 78:338-60
Yi, X Y; Wayner, E A; Kim, Y et al. (1998) Adhesion of cultured human kidney mesangial cells to native entactin: role of integrin receptors. Cell Adhes Commun 5:237-48
Kashtan, C E (1998) Alport syndrome and thin glomerular basement membrane disease. J Am Soc Nephrol 9:1736-50
Kashtan, C E; Gubler, M C; Sisson-Ross, S et al. (1998) Chronology of renal scarring in males with Alport syndrome. Pediatr Nephrol 12:269-74
Sasaki, S; Zhou, B; Fan, W W et al. (1998) Expression of mRNA for type IV collagen alpha1, alpha5 and alpha6 chains by cultured dermal fibroblasts from patients with X-linked Alport syndrome. Matrix Biol 17:279-91
Wu, K; Setty, S; Mauer, S M et al. (1997) Altered kidney matrix gene expression in early stages of experimental diabetes. Acta Anat (Basel) 158:155-65
Kashtan, C E (1997) Alport syndrome. Kidney Int Suppl 58:S69-71

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