SGLT2 Mediates Glucose Reabsorption in the Early Proximal Tubule

Abstract

Mutations in the gene encoding for the Na ϩ -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 Ϫ/Ϫ 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 Sglt2mice. Whole-kidney clearance studies showed that fractional glucose reabsorption was significantly lower in Sglt2 Ϫ/Ϫ mice compared with WT mice and varied in Sglt2 Ϫ/Ϫ mice between 10 and 60%, inversely with the amount of filtered glucose. Free-flow micropuncture revealed that for early proximal collections, 78 Ϯ 6% of the filtered glucose was reabsorbed in WT mice compared with no reabsorption in Sglt2 Ϫ/Ϫ mice. For late proximal collections, fractional glucose reabsorption was 93 Ϯ 1% in WT and 21 Ϯ 6% in Sglt2 Ϫ/Ϫ 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. 22: 104 -112, 201122: 104 -112, . doi: 10.1681 Glucose is the main source of energy in eukaryotic organisms. The homeostasis of glucose is maintained by intestinal glucose absorption and the coordinated regulation of hepatic and renal glucose production, as well as tissue consumption of glucose. As a consequence of renal glomerular filtration, approximately 180 g/d glucose enter the tubular system of the kidneys in a healthy individual with normoglycemia, which is equivalent to approximately one third of the total energy consumed by the human body. Glucose in urine, however, is absent or at very low concentrations in healthy adults (range 0.03 to 0.30 g/d) as a result of near complete reabsorption along the nephron segments, primarily in the proximal tubule. The genes encoding transporter proteins participating in renal J Am Soc Nephrol

Use of SGLT-2 inhibitors in the treatment of type 2 diabetes mellitus

“…Due to reabsorption, glucose in the urine is either absent or present at very low concentrations (0.03 to 0.30 g/dL). 7,8 The sodium and glucose linked transporter (SGLT) is a sodium/glucose cotransporter membrane protein. Type 2 (SGLT-2) is present in S1 of the proximal convoluted tubule and is the main glucose transporter, whereas type 1 is found in S3 of the proximal convoluted tubule and the small intestine.…”

Risks and Benefits of Sweet Pee

“…20 Free-flow micropuncture studies show more than 70% of filtered glucose is reabsorbed in early proximal tubules of wild-type mice, but no significant glucose reabsorption is observed in early proximal tubules of sglt2 Ϫ/Ϫ mice. 20 Glucose reabsorption in later segments of the proximal tubule result in the overall reabsorption of approximately 33% of filtered glucose in the sglt2 Ϫ/Ϫ mice. 20 Interestingly, the expression of SGLT1 is not increased but rather decreased in sglt2 Ϫ/Ϫ mice, which limits the compensatory increase of SGLT1-mediated glucose transport.…”

“…Moreover, Na ϩ -coupled glucose transport is affected by dietary Na ϩ , 16 hyperglycemia, 16 intracellular Na ϩ activity, 17 transplantation, 18 and exposure to cadmium. 19 Vallon et al 20 in this issue of JASN generated an SGLT2 (Slc5a2) null mouse (sglt2…”

“…Both mice display marked glucosuria. 20,21 According to immunohistochemistry, SGLT2 is localized in the brush border of early proximal tubules. 20 Free-flow micropuncture studies show more than 70% of filtered glucose is reabsorbed in early proximal tubules of wild-type mice, but no significant glucose reabsorption is observed in early proximal tubules of sglt2 Ϫ/Ϫ mice.…”

“…20,21 According to immunohistochemistry, SGLT2 is localized in the brush border of early proximal tubules. 20 Free-flow micropuncture studies show more than 70% of filtered glucose is reabsorbed in early proximal tubules of wild-type mice, but no significant glucose reabsorption is observed in early proximal tubules of sglt2 Ϫ/Ϫ mice. 20 Glucose reabsorption in later segments of the proximal tubule result in the overall reabsorption of approximately 33% of filtered glucose in the sglt2 Ϫ/Ϫ mice.…”