; This is a once revised application for a competitive renewal of an R01 with the overall objective of testing the hypothesis that the pathogenesis of vascular complications experienced by patients with end stage renal disease (ESRD) is linked to the binding and activation of redox active transition metals by AGE proteins. Uremic patients have evidence of increased oxidative stress and markedly elevated levels of AGEs on tissue and circulating proteins. Because AGEs bind metal ions, creating a highly oxidizing metal-protein complex, oxidant stress in uremia may be caused by increased AGE formation on proteins. A good marker of uremic toxicity has yet been defined. The concept that increased levels of AGEs on proteins induce oxidant stress through transition metal binding has the potential to unify previously formulated mechanisms of uremic toxicity, which by themselves were not sufficient to explain the accelerated atherosclerosis and vascular complications seen in patients with ESRD. All of the proposed experiments will be based on the measurement of two specific end points: AGE-induced alterations in proteins, and the effect of these alterations on cellular oxidant stress. We propose (1) to define the source and mechanism of formation of glucoxidation products in ESRD; (2) to delineate the structural nature, properties and consequences of metal coordination by AGE proteins in ESRD; and (3) to characterize the biologic properties of synthetic and naturally occurring AGEs in the induction of oxidative stress and the activation of phagocytic cells; and (4) to examine in vivo mechanisms of action of pharmacologic agents with demonstrated effectiveness in slowing the formation of AGEs. This application is based on the clinical reality of accelerated formation of AGEs in real failure. The results of the proposed experiments are expected to yield novel insights which will better define uremic toxicity and suggest new approaches to the treated of ESRD.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK045619-06
Application #
6177236
Study Section
Pathology A Study Section (PTHA)
Program Officer
Eggers, Paul Wayne
Project Start
1992-09-30
Project End
2002-03-31
Budget Start
2000-04-01
Budget End
2002-03-31
Support Year
6
Fiscal Year
2000
Total Cost
$234,126
Indirect Cost
Name
Case Western Reserve University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
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Lu, Liang; Erhard, Penny; Salomon, Robert G et al. (2007) Serum vitamin E and oxidative protein modification in hemodialysis: a randomized clinical trial. Am J Kidney Dis 50:305-13
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Mustata, Georgian T; Rosca, Mariana; Biemel, Klaus M et al. (2005) Paradoxical effects of green tea (Camellia sinensis) and antioxidant vitamins in diabetic rats: improved retinopathy and renal mitochondrial defects but deterioration of collagen matrix glycoxidation and cross-linking. Diabetes 54:517-26
Schwing, William D; Erhard, Penny; Newman, Lynda N et al. (2004) Assessing 24-hour blood glucose patterns in diabetic paitents treated by peritoneal dialysis. Adv Perit Dial 20:213-6
Bayazit, Aysun K; Vogt, Beth A; Dell, Katherine M et al. (2003) Effect of the peritoneal dialysis prescription on pentosidine in children. Pediatr Nephrol 18:1049-54
Fan, X; Subramaniam, R; Weiss, M F et al. (2003) Methylglyoxal-bovine serum albumin stimulates tumor necrosis factor alpha secretion in RAW 264.7 cells through activation of mitogen-activating protein kinase, nuclear factor kappaB and intracellular reactive oxygen species formation. Arch Biochem Biophys 409:274-86
Kern, Elizabeth O; Newman, Lynda N; Cacho, Carolyn P et al. (2002) Abdominal catastrophe revisited: the risk and outcome of enteric peritoneal contamination. Perit Dial Int 22:323-34

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