Better insight into the regulation of the two primary Na absorptive pathways in the mammalian small intestine, Na:H exchange (NHE3) and Na-glucose co-transport (SGLT1), is necessary to develop more efficacious treatments for a variety of common medical conditions (e.g. diarrheal diseases, hypertension, diabetes, obesity). NHE3 mediates coupled NaCl absorption via the dual operation of Na:H and Cl:HCO3 exchange while SGLT1 is important to assimilate Na and glucose on the brush border membrane (BBM) of absorptive villus cells . The regulation of both by nitric oxide (NO), one of the most biologically active molecules, was unclear. We reported that in vivo and in vitro inhibition of constitutive NO (cNO) resulted in the inhibition SGLT1 but the stimulation of NHE3. In contrast, stimulation of cNO resulted in the stimulation of SGLT1 and inhibition of NHE3. Thus, our data indicate that BBM NHE3 and SGLT1 may be compensatorily regulated by NO to maintain cellular Na homeostasis. This then led to our novel overall hypothesis that the major Na absorptive pathways, NHE3 and SGLT1, regulate one another to maintain cellular Na homeostasis in epithelial cells likely via NO. The overall aim that will address this hypothesis will be to determine how permanent silencing of SGLT1 or NHE3 stimulates the other transporter and define the cellular and molecular mechanisms likely mediated by cNO. The results of this study will provide significant and new mechanistic insight into whether and how SGLT1 and NHE3 directly regulate one another. These resulting novel insights may form the basis for developing novel strategies to promote electrolyte and nutrient absorption where deficient and inhibit the same in disease states where it would be advantageous to do so.

Public Health Relevance

Sodium and glucose absorption by the intestine is essential for health and critically involved in many diseases including diarrhea, diabetes and hypertension. This study will seek to determine how the major pathways that absorb sodium and glucose regulate each other via nitric oxide. The new information will facilitate development of new treatments to promote sodium and glucose absorption where needed and reduce the same in diseases where it would be helpful to do so.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Clinical, Integrative and Molecular Gastroenterology Study Section (CIMG)
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Perrin, Peter J
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Marshall University
Internal Medicine/Medicine
Schools of Medicine
United States
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Kekuda, Ramesh; Manoharan, Palanikumar; Baseler, Walter et al. (2013) Monocarboxylate 4 mediated butyrate transport in a rat intestinal epithelial cell line. Dig Dis Sci 58:660-7