Objectives are (1) to further develop diabetic nephropathy (DN) risk markers based on in vitro studies of cells derived from type 1 D patients (pts), (b) to ask if these markers represent genetically determined processes and (c) to determine if these predictors are dependent on in vivo cellular exposure to D. These markers will be searched for by (i) their relevance to known pathophysiologic patterns and by (ii) microarray screening for candidate molecules and discriminant expression patterns. Five groups will be studied: (1) early (10 yrs) and (2) long-term (20 yrs) D duration pts dichotomized into 2 groups with slow or rapid development of DN lesions and albuminuria, (3) sibling pairs concordant for type 1 D, (4) type 1 D kidney transplant recipients and their living donors, (5) type 1 D pts with rapid development of DN who have been cured of D by successful pancreas transplant for at least 5 yrs. DN will be quantitated morphometrically, and factored for duration or expressed as a rate determined by 2 biopsies 5 yrs apart. The primary endpoint will be mesangial volume fraction [Vv(Mes/glom)]. Cross-sectional studies of long-term pts will allow the identification of markers associated with DN risk. Longitudinal studies (5 yr) in shorter-term will determine if these markers are present before any increase in albuminuria is detectable. Skin fibroblasts (SF) were selected since differences in their phenotype occur between """"""""slow-track,"""""""" """"""""fast-track"""""""" and controls and their phenotypes are correlated in sibling pairs. Proximal tubular epithelial cells (PTEC) are selected because tubular basement membrane changes in D parallel those in glomeruli. These studies will determine the relationship of DN to SF and PTEC behaviors (gene expression levels and patterns; cell proliferation cell cycle), and evaluate whether these behaviors are genetically regulated. These studies will provide markers and predictors of DN risk, determine if these are genetically regulated or dependent on prior exposure to D, and identify DN pathogenetic pathways.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK054638-07
Application #
6852700
Study Section
Epidemiology and Disease Control Subcommittee 2 (EDC)
Program Officer
Flessner, Michael Francis
Project Start
1998-08-14
Project End
2008-02-29
Budget Start
2005-03-01
Budget End
2006-02-28
Support Year
7
Fiscal Year
2005
Total Cost
$643,489
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Pediatrics
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Najafian, Behzad; Mauer, Michael (2013) Predilection of segmental glomerulosclerosis lesions for the glomerulotubular junction area in type 1 diabetic patients: a novel mapping method. PLoS One 8:e69253
Najafian, Behzad; Mauer, Michael (2012) Morphologic features of declining renal function in type 1 diabetes. Semin Nephrol 32:415-22
Alvarez-Muñoz, Patricia; Mauer, Michael; Kim, Youngki et al. (2010) Cellular basis of diabetic nephropathy: V. Endoglin expression levels and diabetic nephropathy risk in patients with Type 1 diabetes. J Diabetes Complications 24:242-9
Fioretto, P; Caramori, M L; Mauer, M (2008) The kidney in diabetes: dynamic pathways of injury and repair. The Camillo Golgi Lecture 2007. Diabetologia 51:1347-55
Fioretto, Paola; Mauer, Michael (2007) Histopathology of diabetic nephropathy. Semin Nephrol 27:195-207
Huang, Chunmei; Kim, Youngki; Caramori, M Luiza et al. (2006) Diabetic nephropathy is associated with gene expression levels of oxidative phosphorylation and related pathways. Diabetes 55:1826-31
Caramori, Maria Luiza; Kim, Youngki; Fioretto, Paola et al. (2006) Cellular basis of diabetic nephropathy: IV. Antioxidant enzyme mRNA expression levels in skin fibroblasts of type 1 diabetic sibling pairs. Nephrol Dial Transplant 21:3122-6
Najafian, Behzad; Crosson, John T; Kim, Youngki et al. (2006) Glomerulotubular junction abnormalities are associated with proteinuria in type 1 diabetes. J Am Soc Nephrol 17:S53-60
Caramori, M Luiza; Fioretto, Paola; Mauer, Michael (2006) Enhancing the predictive value of urinary albumin for diabetic nephropathy. J Am Soc Nephrol 17:339-52
Huang, C; Kim, Y; Caramori, M L et al. (2004) Cellular basis of diabetic nephropathy: III. In vitro GLUT1 mRNA expression and risk of diabetic nephropathy in type 1 diabetic patients. Diabetologia 47:1789-94

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