The human kidney low affinity Na+/glucose cotransporter SGLT2. Delineation of the major renal reabsorptive mechanism for D-glucose

Y. Kanai, W. S. Lee, Guofeng You, D. Brown, M. A. Hediger

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Abstract

The major reabsorptive mechanism for D-glucose in the kidney is known to involve a low affinity high capacity Na+/glucose cotransporter, which is located in the early proximal convoluted tubule segment S1, and which has a Na+ to glucose coupling ratio of 1:1. Here we provide the first molecular evidence for this renal D-glucose reabsorptive mechanism. We report the characterization of a previously cloned human kidney cDNA that codes for a protein with 59% identity to the high affinity Na+/glucose cotransporter (SGLT1). Using expression studies with Xenopus laevis oocytes we demonstrate that this protein (termed SGLT2) mediates saturable Na+-dependent and phlorizin-sensitive transport of D-glucose and α-methyl-D-glucopyranoside (αMeGlc) with K(m) values of 1.6 mM for αMeGlc and ~250 to 300 mM for Na+, consistent with low affinity Na+/glucose cotransport. In contrast to SGLT1, SGLT2 does not transport D-galactose. By comparing the initial rate of [14C]-αMeGlc uptake with the Na+-influx calculated from αMeGlc-evoked inward currents, we show that the Na+ to glucose coupling ratio of SGLT2 is 1:1. Using combined in situ hybridization and immunocytochemistry with tubule segment specific marker antibodies, we demonstrate an extremely high level of SGLT2 message in proximal tubule S1 segments. This level of expression was also evident on Northern blots and likely confers the high capacity of this glucose transport system. We conclude that SGLT2 has properties characteristic of the renal low affinity high capacity Na+/glucose cotransporter as previously reported for perfused tubule preparations and brush border membrane vesicles. Knowledge of the structural and functional properties of this major renal Na+/glucose reabsorptive mechanism will advance our understanding of the pathophysiology of renal diseases such as familial renal glycosuria and diabetic renal disorders.

Original languageEnglish (US)
Pages (from-to)397-404
Number of pages8
JournalJournal of Clinical Investigation
Volume93
Issue number1
DOIs
StatePublished - Jan 1 1994
Externally publishedYes

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Kidney
Glucose
Sodium-Glucose Transporter 2
Renal Glycosuria
Phlorhizin
Xenopus laevis
Microvilli
Galactose
Northern Blotting
Oocytes
In Situ Hybridization
Complementary DNA
Immunohistochemistry
Membranes
methylglucoside
Antibodies
Proteins

All Science Journal Classification (ASJC) codes

  • Medicine(all)

Cite this

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title = "The human kidney low affinity Na+/glucose cotransporter SGLT2. Delineation of the major renal reabsorptive mechanism for D-glucose",
abstract = "The major reabsorptive mechanism for D-glucose in the kidney is known to involve a low affinity high capacity Na+/glucose cotransporter, which is located in the early proximal convoluted tubule segment S1, and which has a Na+ to glucose coupling ratio of 1:1. Here we provide the first molecular evidence for this renal D-glucose reabsorptive mechanism. We report the characterization of a previously cloned human kidney cDNA that codes for a protein with 59{\%} identity to the high affinity Na+/glucose cotransporter (SGLT1). Using expression studies with Xenopus laevis oocytes we demonstrate that this protein (termed SGLT2) mediates saturable Na+-dependent and phlorizin-sensitive transport of D-glucose and α-methyl-D-glucopyranoside (αMeGlc) with K(m) values of 1.6 mM for αMeGlc and ~250 to 300 mM for Na+, consistent with low affinity Na+/glucose cotransport. In contrast to SGLT1, SGLT2 does not transport D-galactose. By comparing the initial rate of [14C]-αMeGlc uptake with the Na+-influx calculated from αMeGlc-evoked inward currents, we show that the Na+ to glucose coupling ratio of SGLT2 is 1:1. Using combined in situ hybridization and immunocytochemistry with tubule segment specific marker antibodies, we demonstrate an extremely high level of SGLT2 message in proximal tubule S1 segments. This level of expression was also evident on Northern blots and likely confers the high capacity of this glucose transport system. We conclude that SGLT2 has properties characteristic of the renal low affinity high capacity Na+/glucose cotransporter as previously reported for perfused tubule preparations and brush border membrane vesicles. Knowledge of the structural and functional properties of this major renal Na+/glucose reabsorptive mechanism will advance our understanding of the pathophysiology of renal diseases such as familial renal glycosuria and diabetic renal disorders.",
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The human kidney low affinity Na+/glucose cotransporter SGLT2. Delineation of the major renal reabsorptive mechanism for D-glucose. / Kanai, Y.; Lee, W. S.; You, Guofeng; Brown, D.; Hediger, M. A.

In: Journal of Clinical Investigation, Vol. 93, No. 1, 01.01.1994, p. 397-404.

Research output: Contribution to journalArticle

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