Diabetic nephropathy (DN) is the leading cause of renal failure, yet pathogenetic understanding remains limited. Objectives of these studies are the following: a) to develop risk markers based on in vitro studies of cells derived from individual IDDM patients, which are related to renal biopsy endpoints; b) to ask if these markers represent genetically determined processes; and c) to define relationships between cellular (in vitro) expression of mRNA for extracellular matrix (ECM) molecules, their enzymes and enzyme regulators, growth factors, glucose transporters, and sodium/hydrogen antiporter and renal structural and functional endpoints in order to explore basic pathogenic mechanisms in DN. Also, to develop a repository of DNA and cultured cells that will allow evaluation of the cellular functional consequences of genetic variations shown to be linked to DN risk. Three patient groups will be studied: a) early (10 years) and long-term (20 years) IDDM duration patients dichotomized into two groups with slow or rapid development of DN lesions; b) sibling pairs concordant for IDDM; and c) identical twins discordant for IDDM. Diabetic nephropathy will be quantitated morphometrically and factored for duration or expressed as rate determined by two biopsies five years apart. The primary endpoint will be mesangial volume fraction (Vv Mes/glom) measured be electron microscopic morphometric analysis. Cross-sectional studies of long-term IDDM patients will allow the identification of cellular markers associated with rapid or very slow development of DN lesions and clinical renal abnormalities. Longitudinal studies (five years) in shorter-term """"""""fast"""""""" and """"""""slow-track"""""""" patients and IDDM sibling pairs will allow factoring for glycemia and blood pressure and other """"""""environmental variables."""""""" Cultured skin fibroblasts (SF) from individual patients will be evaluated for mRNA expression for the above listed molecules using reverse transcriptase polymerase chain reaction. Skin fibroblasts are selected since changes in their phenotype occur in """"""""fast-track"""""""" IDDM patients and are correlated in sibling pairs. These studies will determine the relationship of DN lesions to SF behavior and evaluate whether this behavior is concordant in IDDM sibling pairs who are concordant for DN lesions. Skin fibroblasts from nondiabetic identical twins will answer whether hyperglycemia is necessary for the expression of cellular markers of DN risk.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
3R01DK054638-05S1
Application #
6802177
Study Section
Special Emphasis Panel (ZDK1)
Program Officer
Flessner, Michael Francis
Project Start
1998-08-14
Project End
2004-02-29
Budget Start
2002-08-01
Budget End
2004-02-29
Support Year
5
Fiscal Year
2003
Total Cost
$61,229
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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