title: SGLT2 mediates glucose reabsorption in the early proximal tubule.
abstract: Mutations in the gene encoding for the Na(+)-glucose co-transporter SGLT2 (SLC5A2) associate with familial renal glucosuria, but the role of SGLT2 in the kidney is incompletely understood. Here, we determined the localization of SGLT2 in the mouse kidney and generated and characterized SGLT2-deficient mice. In wild-type (WT) mice, immunohistochemistry localized SGLT2 to the brush border membrane of the early proximal tubule. Sglt2(-/-) mice had glucosuria, polyuria, and increased food and fluid intake without differences in plasma glucose concentrations, GFR, or urinary excretion of other proximal tubular substrates (including amino acids) compared with WT mice. SGLT2 deficiency did not associate with volume depletion, suggested by similar body weight, BP, and hematocrit; however, plasma renin concentrations were modestly higher and plasma aldosterone levels were lower in Sglt2(-/-) mice. Whole-kidney clearance studies showed that fractional glucose reabsorption was significantly lower in Sglt2(-/-) mice compared with WT mice and varied in Sglt2(-/-) mice between 10 and 60%, inversely with the amount of filtered glucose. Free-flow micropuncture revealed that for early proximal collections, 78 ± 6% of the filtered glucose was reabsorbed in WT mice compared with no reabsorption in Sglt2(-/-) mice. For late proximal collections, fractional glucose reabsorption was 93 ± 1% in WT and 21 ± 6% in Sglt2(-/-) mice, respectively. These results demonstrate that SGLT2 mediates glucose reabsorption in the early proximal tubule and most of the glucose reabsorption by the kidney, overall. This mouse model mimics and explains the glucosuric phenotype of individuals carrying SLC5A2 mutations.
authors.affiliation: Department of Medicine, University of California San Diego, VA San Diego Healthcare System, 3350 La Jolla Village Drive (9151), San Diego, CA 92161, USA. vvallon@ucsd.edu
authors.forename: Volker
authors.initials: V
authors.lastname: Vallon
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Platt
authors.forename: Robyn
authors.initials: R
authors.lastname: Cunard
authors.forename: Jana
authors.initials: J
authors.lastname: Schroth
authors.forename: Jean
authors.initials: J
authors.lastname: Whaley
authors.forename: Scott C
authors.initials: SC
authors.lastname: Thomson
authors.forename: Hermann
authors.initials: H
authors.lastname: Koepsell
authors.forename: Timo
authors.initials: T
authors.lastname: Rieg
mesh_terms: D000042:Absorption / Q000502:physiology; D000450:Aldosterone / Q000097:blood; D000818:Animals; D004195:Disease Models, Animal; D005947:Glucose / Q000378:metabolism*; D007687:Kidney Tubules, Proximal / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008871:Microvilli / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D012083:Renin / Q000097:blood; D051297:Sodium-Glucose Transporter 2 / Q000235:genetics / Q000378:metabolism*
chemical_list: D012333:RNA, Messenger; C490299:Slc5a2 protein, mouse; D051297:Sodium-Glucose Transporter 2; D000450:Aldosterone; D012083:Renin; D005947:Glucose