| Content Provider |
World Health Organization (WHO)-Global Index Medicus |
| Author |
Jennette, J. Charles Gasim, Adil M. H. Chang, Albert S. Madden, Victoria J. Bagnell, C. Robert Kim, Hyung-suk Hathaway, Catherine K. Smithies, Oliver Grant, Ruriko Kakoki, Masao |
| Description |
Author Affiliation: Hathaway CK ( Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27599.); Gasim AM ( Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27599.); Grant R ( Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27599.); Chang AS ( Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27599.); Kim HS ( Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27599.); Madden VJ ( Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27599.); Bagnell CR ( Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27599.); Jennette JC ( Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27599.); Smithies O ( Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27599 oliver_smithies@med.unc.edu mkakoki@med.unc.edu.); Kakoki M ( Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27599 oliver_smithies@med.unc.edu mkakoki@med.unc.edu.); |
| Abstract |
Nephropathy develops in many but not all patients with long-standing type 1 diabetes. Substantial efforts to identify genotypic differences explaining this differential susceptibility have been made, with limited success. Here, we show that the expression of the transforming growth factor ß1 gene (Tgfb1) affects the development of diabetic nephropathy in mice. To do this we genetically varied Tgfb1 expression in five steps, 10%, 60%, 100%, 150%, and 300% of normal, in mice with type 1 diabetes caused by the Akita mutation in the insulin gene (Ins2(Akita)). Although plasma glucose levels were not affected by Tgfb1 genotype, many features of diabetic nephropathy (mesangial expansion, elevated plasma creatinine and urea, decreased creatinine clearance and albuminuria) were progressively ameliorated as Tgfb1 expression decreased and were progressively exacerbated when expression was increased. The diabetic 10% hypomorphs had comparable creatinine clearance and albumin excretion to wild-type mice and no harmful changes in renal morphology. The diabetic 300% hypermorphs had â ¼1/3 the creatinine clearance of wild-type mice, >20× their albumin excretion, â ¼3× thicker glomerular basement membranes and severe podocyte effacement, matching human diabetic nephropathy. Switching Tgfb1 expression from low to high in the tubules of the hypomorphs increased their albumin excretion more than 10-fold but creatinine clearance remained high. Switching Tgfb1 expression from low to high in the podocytes markedly decreased creatinine clearance, but minimally increased albumin excretion. Decreasing expression of Tgfb1 could be a promising option for preventing loss of renal function in diabetes. |
| ISSN |
00278424 |
| e-ISSN |
10916490 |
| Journal |
Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number |
18 |
| Volume Number |
112 |
| Language |
English |
| Publisher |
National Academy of Sciences |
| Publisher Date |
2015-05-01 |
| Publisher Place |
United States |
| Access Restriction |
Open |
| Subject Keyword |
Diabetes Mellitus, Experimental Metabolism Diabetes Mellitus, Type 1 Diabetic Nephropathies Gene Expression Regulation Transforming Growth Factor Beta1 Albumins Albuminuria Alleles Animals Creatinine Crosses, Genetic Fibrosis Pathology Genotype Glucose Chemistry Kidney Kidney Glomerulus Mice Mice, Inbred C57BL Phenotype Podocytes Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Multidisciplinary |
| Content Type |
Text |
| Resource Type |
Article |
| Subject |
Multidisciplinary |
