The long term objective of the studies proposed in this application is to elucidate the mechanism(s) by which diabetes injures vessels and causes clinically significant vascular disease. A growing body of evidence indicates that: 1) many of the late complications of diabetes are linked to increased metabolism of glucose to sorbitol by the enzyme aldose reductase, and 2) aldose reductase-linked, diabetes-induced vascular damage and sorbitol metabolism are hormonally modulated. The experimental protocols are designed to achieve the following specific aims: 1) to elucidate the role of insulin deficiency independent of hyperglycemia, and vice versa, in the pathogenesis of diabetic vascular disease, 2) to clarify the roles of decreased tissue levels of myo-inositol and Na/K-ATPase activity in mediating diabetes-induced increases in vascular permeability, 3) to assess potential mechanisms by which sex steroids and thyroid hormone may modulate diabetes-induced alterations in polyol metabolism and vascular functional integrity, 4) to identify the mechanism(s) responsible for increased aldo- keto reductase activity in erythrocytes of diabetic rats, 5) to determine whether aldo-keto reductase activity in erythrocytes correlates with aldo-keto reductase activity and/or vascular permeability changes in sciatic nerve, aorta, and eyes in diabetic rats, 6) to investigate the relationship between aldo-keto reductase activity in erythrocytes, puberty, and glycemic control in human diabetics. The studies in rats will make extensive use of new methods and procedures developed in our laboratory which make it possible to assess direct effects of hormones, pharmacologic agents, and metabolic substrates on tissue metabolism and vascular permeability in vivo. Direct effects of hormones and metabolic substrates on these parameters are assessed on new granulation tissue formed in skin chambers in which test substances are applied topically to the tissue. Vascular permeability is assessed by permeation of 125I-albumin. Aldo-keto reductase activity (as opposed to ambient polyol levels) of red cells and tissues is assessed by measurement of galactitol accumulation during incubation with galactose in vitro. Tissue polyols are quantified as their butaneboronate derivatives using electron ionization gas chromatography/mass spectrometry. Na/K-ATPase activity is assessed by use of isotopic method. The information to be gained from these experiments should provide important new insights into the pathogenesis of diabetic vascular disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL039934-03
Application #
3356934
Study Section
Metabolism Study Section (MET)
Project Start
1988-03-01
Project End
1993-02-28
Budget Start
1990-03-01
Budget End
1991-02-28
Support Year
3
Fiscal Year
1990
Total Cost
Indirect Cost
Name
Washington University
Department
Type
Schools of Medicine
DUNS #
062761671
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
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Shao, Baohai; Fu, Xiaoyun; McDonald, Thomas O et al. (2005) Acrolein impairs ATP binding cassette transporter A1-dependent cholesterol export from cells through site-specific modification of apolipoprotein A-I. J Biol Chem 280:36386-96
Pennathur, Subramaniam; Ido, Yasuo; Heller, Jozsef I et al. (2005) Reactive carbonyls and polyunsaturated fatty acids produce a hydroxyl radical-like species: a potential pathway for oxidative damage of retinal proteins in diabetes. J Biol Chem 280:22706-14
Ido, Yasuo; Chang, Katherine; Williamson, Joseph R (2004) NADH augments blood flow in physiologically activated retina and visual cortex. Proc Natl Acad Sci U S A 101:653-8
Nyengaard, Jens R; Ido, Yassuo; Kilo, Charles et al. (2004) Interactions between hyperglycemia and hypoxia: implications for diabetic retinopathy. Diabetes 53:2931-8
Ido, Y; Chang, K C; Lejeune, W S et al. (2001) Vascular dysfunction induced by AGE is mediated by VEGF via mechanisms involving reactive oxygen species, guanylate cyclase, and protein kinase C. Microcirculation 8:251-63
Schmidt, R E; Dorsey, D A; Beaudet, L N et al. (2001) Inhibition of sorbitol dehydrogenase exacerbates autonomic neuropathy in rats with streptozotocin-induced diabetes. J Neuropathol Exp Neurol 60:1153-69
Tilton, R G; Chang, K C; LeJeune, W S et al. (1999) Role for nitric oxide in the hyperpermeability and hemodynamic changes induced by intravenous VEGF. Invest Ophthalmol Vis Sci 40:689-96
Stephan, C C; Chang, K C; LeJeune, W et al. (1998) Role for heparin-binding growth factors in glucose-induced vascular dysfunction. Diabetes 47:1771-8
Nyengaard, J R; Chang, K; Berhorst, S et al. (1997) Discordant effects of guanidines on renal structure and function and on regional vascular dysfunction and collagen changes in diabetic rats. Diabetes 46:94-106

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