Functional Role of Glucose Metabolism, Osmotic Stress, and Sodium-Glucose Cotransporter Isoform-Mediated Transport on Na+/H+ Exchanger Isoform 3 Activity in the Renal Proximal Tubule

Author(s)

Pessoa, Thaissa Dantas ^[1] ; Gastalho Campos, Luciene Cristina ^[2] ; Carraro-Lacroix, Luciene ^[3] ; Girardi, Adriana C. C. ^[2] ; Malnic, Gerhard ^[1]

Affiliation

^[1] Univ Sao Paulo, Inst Biomed Sci, Dept Physiol & Biophys, Sao Paulo - Brazil

^[2] Univ Sao Paulo, Sch Med, Heart Inst InCor, Sao Paulo - Brazil

^[3] Univ Fed Parana, Dept Biol Sci, BR-80060000 Curitiba, Parana - Brazil

• Document type: Journal article
• Source: JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY; v. 25, n. 9, p. 2028-2039, SEP 2014.
• Web of Science Citations: 49

Abstract

Na+-glucose cotransporter 1 (SGLT1)-mediated glucose uptake leads to activation of Na+ -H+ exchanger 3 (NHE3) in the intestine by a process that is not dependent on glucose metabolism. This coactivation may be important for postprandial nutrient uptake. However, it remains to be determined whether SGLT-mediated glucose uptake regulates NHE3-mediated NaHCO3 reabsorption in the renal proximal tubule. Considering that this nephron segment also expresses SGLT2 and that the kidneys and intestine show significant variations in daily glucose availability, the goal of this study was to determine the effect of SGLT-mediated glucose uptake on NHE3 activity in the renal proximal tubule. Stationary in vivo microperfusion experiments showed that luminal perfusion with 5 mM glucose stimulates NHE3-mediated bicarbonate reabsorption. This stimulatory effect was mediated by glycolytic metabolism but not through ATP production. Conversely, luminal perfusion with 40 mM glucose inhibited NHE3 because of cell swelling. Notably, pharmacologic inhibition of SGLT activity by Phlorizin produced a marked inhibition of NHE3, even in the absence of glucose. Furthermore, innmunofluorescence experiments showed that NHE3 colocalizes with SGLT2 but not SGLT1 in the rat renal proximal tubule. Collectively, these findings show that glucose exerts a bimodal effect on NHE3. The physiologic metabolism of glucose stimulates NHE3 transport activity, whereas, supraphysiologic glucose concentrations inhibit this exchanger. Additionally, Phlorizin-sensitive SGLT transporters and NHE3 interact functionally in the proximal tubule. (AU)

• FAPESP's process: 12/10146-0 - Molecular mechanisms of regulation of the proximal tubular function in hypertension
• Grantee: Adriana Castello Costa Girardi
• Support Opportunities: Regular Research Grants
• FAPESP's process: 08/58287-5 - Molecular and functional study of ion transporters in membranes
• Grantee: Gerhard Malnic
• Support Opportunities: Research Projects - Thematic Grants