Renal involvement in insulin dependent diabetes is characterized by thickening of the glomerular basement membrane (GBM) and accumulation of GBM-like material in the mesangium. Shortly after the induction of experimental diabetes, uracil ribonucleotide synthesis de novo is increased in the glomerulus resulting in an expansion of the glomerular pool of uridine triphosphate (UTP) and uridine diphosphosugars (UDP-sugars). These are essential precursors for the synthesis of collagenous and non-collagenous components of the GBM and mesangial matrix. Although increased bioavailability of glomerular UTP and UDP-sugars may not be specific for the glomerular hypertrophy characteristic of diabetes, these metabolic changes may have significant consequences by facilitating enhancement of the synthesis and deposition of GBM material in diabetic glomeruli. The major objective of this research is to study the relationships between alterations in glomerular pyrimidine metabolism and the synthesis of GBM and mesangial matrix in streptozotocin-induced diabetes. Glomerular mesangial cells in culture and incubated whole glomeruli isolated from renal cortices of diabetic or control rats will be used to study the synthesis and cellular content of UDP-sugars under conditions of inhibition (treatment with pyrazofurin or PALA) or enhancement (high glucose concentration and orotate in the media) of uracil ribonucleotide formation. The synthesis of the collagenous and non-collagenous components of basement membrane will be studied in cultured mesangial cells after alteration of UDP-sugar synthesis. The effects of diabetes on GBM and mesangial matrix synthesis will be studied in vivo in 3-day to 3-month diabetic rats under control conditions and following induced alterations in pyrimidine metabolism. In these studies, factors influencing the interpretation of results such as the plasma specific radioactivity of infused precursors and the size of the intracellular precursor pools will be evaluated. If the hypothesis on which this research is based is proved to be valid, further insight into the mechanism of experimental diabetic glomerular disease will have been gained.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK028081-05
Application #
3228572
Study Section
General Medicine B Study Section (GMB)
Project Start
1981-07-01
Project End
1988-03-31
Budget Start
1986-04-01
Budget End
1987-03-31
Support Year
5
Fiscal Year
1986
Total Cost
Indirect Cost
Name
Henry Ford Health System
Department
Type
DUNS #
City
Detroit
State
MI
Country
United States
Zip Code
48202
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