Extracellular glutathione peroxidase (Gpx3) is produced primarily by the proximal convoluted tubule (PCT) cells of the kidney. Gpx3 catabolizes H2O2 and other hydroperoxides outside cells using GSH as its reducing substrate. Thus, Gpx3 functions as an extracellular antioxidant. We have developed immunocytochemistry methods to detect Gpx3 and have used them to show that Gpx3 binds specifically to the basement membranes of kidney tubules, small intestine, colon, and other absorptive epithelia. It does not bind to basement membranes in most tissues. We have also acquired mice with the Gpx3 gene deleted. Using these mice, we have found that extracellular glutathione metabolism is sharply affected by Gpx3 deletion with plasma glutathione concentration being almost tripled. This finding supports GSH as being the reducing substrate of Gpx3. We have also shown that Gpx3 is not involved in the regulated transport of selenium. We hypothesize that Gpx3 protects basement membranes and their associated epithelial cells in kidney and intestine from damage by oxidative stresses. We propose to characterize the relationship of Gpx3 with basement membranes and to assess its effect on oxidative stresses in intestine, kidney, and liver. We also propose to characterize the effect of the kidney on the presence and function of Gpx3 in other tissues. These studies are designed to provide insight into Gpx3 function and to assess how kidney disease might deprive other tissues of Gpx3 and thereby render them susceptible to injury from oxidative stress.

Public Health Relevance

Extracellular glutathione peroxidase (Gpx3) is an antioxidant enzyme. Our preliminary data show that Gpx3 binds to basement membranes in the intestine and in other tissues. We produced mice with Gpx3 deleted and will assess Gpx3 protection against oxidative stress in those mice to shed light on some diseases.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
Project #
Application #
Study Section
Integrative Nutrition and Metabolic Processes Study Section (INMP)
Program Officer
Ketchum, Christian J
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Vanderbilt University Medical Center
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Hill, Kristina E; Motley, Amy K; Winfrey, Virginia P et al. (2014) Selenoprotein P is the major selenium transport protein in mouse milk. PLoS One 9:e103486
Kurokawa, Suguru; Eriksson, Sofi; Rose, Kristie L et al. (2014) Sepp1(UF) forms are N-terminal selenoprotein P truncations that have peroxidase activity when coupled with thioredoxin reductase-1. Free Radic Biol Med 69:67-76
Burk, Raymond F; Olson, Gary E; Hill, Kristina E et al. (2013) Maternal-fetal transfer of selenium in the mouse. FASEB J 27:3249-56
Barrett, Caitlyn W; Ning, Wei; Chen, Xi et al. (2013) Tumor suppressor function of the plasma glutathione peroxidase gpx3 in colitis-associated carcinoma. Cancer Res 73:1245-55
Barrett, Caitlyn W; Singh, Kshipra; Motley, Amy K et al. (2013) Dietary selenium deficiency exacerbates DSS-induced epithelial injury and AOM/DSS-induced tumorigenesis. PLoS One 8:e67845
Burk, Raymond F; Olson, Gary E; Winfrey, Virginia P et al. (2011) Glutathione peroxidase-3 produced by the kidney binds to a population of basement membranes in the gastrointestinal tract and in other tissues. Am J Physiol Gastrointest Liver Physiol 301:G32-8