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Robert C. Stanton, M.D.

Dr. Stanton is a Principal Investigator in the Section on Vascular Cell Biology and the Chief of the Nephrology Section at Joslin Clinic, as well as an Associate Professor of Medicine at Harvard Medical School. He received his medical degree from Hahnemann Medical College in Philadelphia and completed residency training at the Oregon Health and Science University, where he was the Chief Resident in Internal Medicine. He completed his fellowship in Nephrology at Harvard Medical School and Brigham and Women’s Hospital and postdoctoral training in Physiology at Tufts University School of Medicine. Dr. Stanton is involved with teaching at all levels (student, resident, fellow, and faculty) as an original member of the Academy at Harvard Medical School and as a director of courses for second-year students.

Diabetes is associated with increased levels of oxidants (toxic forms of oxygen that cause cells to die). For patients with diabetes, complications associated with increased oxidant damage include diseases of the heart, eye, kidney and blood vessels. The principal antioxidant, or reducing agent, in cells is the compound NADPH, which is produced by the pentose phosphate pathway. Thus, maintaining healthy cells requires appropriate regulation of this pathway. Although researchers traditionally believed that this pathway was not regulated, the laboratory of Dr. Stanton has discovered that precise intracellular signals do regulate this pathway closely; these signals control activation of the pathway and the exact location inside the cell where the pathway provides NADPH. Research from the lab has demonstrated that defects in these signals can lead to improper regulation of the pentose phosphate pathway, making cells much more vulnerable to the toxic effects of oxidants.

Specifically, Dr. Stanton’s research shows that diabetes causes a major decrease in the activity of the enzyme glucose 6-phosphatedehydrogenase (G6PD), which is part of the pentose phosphate pathway and the enzyme that regulates the pathway. G6PD is the critical source of NADPH. Decreased G6PD activity leads to decreased NADPH. This lack of sufficient NADPH is likely a significant cause of the increased oxidative stress seen in diabetes that causes kidney disease, vascular disease and other complications.

NADPH is also required by a critical enzyme called nitric oxide synthase that produces nitric oxide. Nitric oxide acts as a vasodilator and leads to a lowering of blood pressure. Thus, lack of NADPH also likely plays an important role in the development of hypertension in patients with diabetes. Lastly, NADPH also is required by a number of other cellular reactions including the white blood cell enzyme NADPH oxidase, which is required for proper bacterial killing. Thus lack of NADPH leads to impaired antioxidant function, making cells susceptible to damage; decreased nitric oxide, leading to hypertension; and decreased white blood cell function, increasing susceptibility to infections.

Dr. Stanton’s laboratory focuses on understanding the causes of impaired G6PD enzyme activity to see whether prevention of this impairment helps prevent diabetic kidney disease and diabetic vascular disease. Dr. Stanton also looks for specific drugs that restore G6PD activity and increase levels of NADPH. Such drugs might play a major role in preventing the development and worsening of diabetic complications.

Diabetic kidney disease is now the major cause of kidney failure worldwide. In addition to determining the causes of diabetic kidney disease, Dr. Stanton is expanding his research by collaborating with colleagues from the Joslin Clinic Nephrology Section and the Section on Genetics and Epidemiology as well as with Joseph Loscalzo, Chairman of the Department of Medicine at  Brigham and Women’s Hospital, using basic science and clinical approaches to determine how to diagnose diabetic kidney disease as early as possible and prevent worsening of kidney disease.

Selected References

Xu Y, Osborne B, Stanton RC. Diabetes causes inhibition of glucose-6-phosphate dehydrogenase via activation of PKA, which contributes to oxidative stress in rat kidney cortex. Am J Physiol Renal Physiol 289:F1040-1047, 2005.

Leopold JA, Walker J, Scribner AA, Voetsch B, Zhang YY, Loscalzo AJ, Stanton RC, Loscalzo J. Glucose-6-phospate dehydrogenase modulates vascular endothelial growth factor-mediated angiogenesis. J Biol Chem 278:32100-32106, 2003.

Leopold JA, Zhang YY, Scribner AA, Stanton RC, Loscalzo J. Glucose-6-phospate dehydrogenase overexpression decreases endothelial cell oxidant stress and increases bioavailable nitric oxide. Arterioscler Thromb Vasc Biol 23:411-417, 2003.

Guo L, Zhang Z, Green K, Stanton RC. Suppression of interleukin-1ß-induced nitric oxide production in RINm5f cells by inhibition of glucose-6-phosphate dehydrogenase. Biochemistry 41:14726-14733, 2002.

Zhang Z, Yu J, Stanton RC. A method for determination of pyridine nucleotides using a single extract. Anal Biochem 285:163-167, 2000.

Zhang Z, Apse K, Pang J, Stanton RC. High glucose inhibits glucose-6-phosphate dehydrogenase via cAMP in aortic endothelial cells. J Biol Chem 275:40042-40047, 2000.

Page last updated: July 26, 2014