title: 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.
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, immunofluorescence 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.
authors.affiliation: Department of Physiology and Biophysics, Institute of Biomedical Sciences, and.
authors.forename: Thaissa Dantas
authors.initials: TD
authors.lastname: Pessoa
authors.affiliation: Heart Institute (InCor) Medical School, University of São Paulo, São Paulo, Brazil; and.
authors.forename: Luciene Cristina Gastalho
authors.initials: LC
authors.lastname: Campos
authors.affiliation: Department of Biological Sciences, Federal University of Paraná, Curitiba, Paraná, Brazil.
authors.forename: Luciene
authors.initials: L
authors.lastname: Carraro-Lacroix
authors.affiliation: Heart Institute (InCor) Medical School, University of São Paulo, São Paulo, Brazil; and.
authors.forename: Adriana C C
authors.initials: AC
authors.lastname: Girardi
authors.affiliation: Department of Physiology and Biophysics, Institute of Biomedical Sciences, and gemalnic@usp.br.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Malnic
mesh_terms: D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000818:Animals; D001639:Bicarbonates / Q000378:metabolism / Q000652:urine; D005690:Galactose / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D007150:Immunohistochemistry; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008757:Methylglucosides / Q000378:metabolism; D008954:Models, Biological; D009997:Osmotic Pressure; D010695:Phlorhizin / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D051269:Sodium-Glucose Transporter 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051297:Sodium-Glucose Transporter 2 / Q000378:metabolism*; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers / Q000378:metabolism*
chemical_list: D001639:Bicarbonates; D008757:Methylglucosides; C495676:Slc5a1 protein, rat; C490300:Slc5a2 protein, rat; C000613387:Slc9a3 protein, rat; D051269:Sodium-Glucose Transporter 1; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers; C027020:methylglucoside; D000255:Adenosine Triphosphate; D010695:Phlorhizin; D005947:Glucose; D005690:Galactose