Abstract
Under diabetic conditions, sodium–glucose cotransporter 2 (SGLT2) for glucose uptake in proximal tubules (PTs) increases, whereas NAD+-dependent protein deacetylase silent mating type information regulation 2 homolog 1 (Sirtuin-1; SIRT1) for PT survival decreases. Therefore, we hypothesized that increased glucose influx by SGLT2 reduces SIRT1 expression. To test this hypothesis, db/db mice with diabetes and high-glucose (HG)-cultured porcine PT LLC-PK1 cells in a two-chamber system were treated with the SGLT2 inhibitor canagliflozin. We also examined SIRT1 and SGLT2 expression in human kidney biopsies. In db/db mice, SGLT2 expression increased with concomitant decreases in SIRT1, but was inhibited by canagliflozin. For determination of the polarity of SGLT2 and SIRT1 expression, LLC-PK1 cells were seeded into Transwell chambers (pore size, 0.4 µm; Becton Dickinson, Oxford, UK). HG medium was added to either or to both of the upper and lower chambers, which corresponded to the apical and basolateral sides of the cells, respectively. In this system, the lower chamber with HG showed increased SGLT2 and decreased SIRT1 expression. Canagliflozin reversed HG-induced SIRT1 downregulation. Gene silencing and inhibitors for glucose transporter 2 (GLUT2) blocked HG-induced SGLT2 expression upregulation. Gene silencing for the hepatic nuclear factor-1α (HNF-1α), whose nuclear translocation was enhanced by HG, blocked HG-induced SGLT2 expression upregulation. Similarly, gene silencing for importin-α1, a chaperone protein bound to GLUT2, blocked HG-induced HNF-1α nuclear translocation and SGLT2 expression upregulation. In human kidney, SIRT1 immunostaining was negatively correlated with SGLT2 immunostaining. Thus, under diabetic conditions, SIRT1 expression in PTs was downregulated by an increase in SGLT2 expression, which was stimulated by basolateral HG through activation of the GLUT2/importin-α1/HNF-1α pathway.
Highlights
Sodium–glucose co-transporters (SGLT) mediate glucose reabsorption and cellular glucose entry
sodium–glucose cotransporter 2 (SGLT2) plays a dominant role in glucose transport in proximal tubules (PTs), SGLT1 plays a significant role under the condition of SGLT2 inhibition or diabetic milieu
We demonstrated increased SGLT2 expression and decreased SIRT1 expression in db/db mice
Summary
Sodium–glucose co-transporters (SGLT) mediate glucose reabsorption and cellular glucose entry. SGLT2 plays a dominant role in glucose transport in PTs, SGLT1 plays a significant role under the condition of SGLT2 inhibition or diabetic milieu. SGLT2 inhibitors were recently made available for clinical use as glucose-lowering reagents. Accumulating evidence suggests their protective effects on diabetic PT cells. We surmised that activation of SGLT2 reduces SIRT1 expression by inducing excessive glucose entry into PTs under diabetic conditions. To elucidate a more detailed mechanism for the relationship between SGLT2 and SIRT1, we used obese-type db/db mice with diabetes treated with the SGLT2 inhibitor canagliflozin (Cana) and investigated SIRT1 and SGLT2 expressions. SGLT2 inhibition may reverse reductions in SIRT1 in PT in DN, thereby providing a tissue-protective effect in DN
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