SGLT2 mediates glucose reabsorption in the early proximal tubule

To elucidate the role of the Na‐glucose transporter SGLT2, we performed in vivo clearance and micropuncture studies under inactin/ketamine anesthesia in gene‐targeted mice lacking Sglt2 (−/−; generated by replacing a 2419 bp region containing exons 1–5 of Slc5a2 by homologous recombination). Blood pressure, glomerular filtration rate and blood glucose levels were not different between Sglt2−/− and wild‐type (WT) mice (101±4 vs. 107±7 mmHg; 6.5±0.7 vs. 6.8±0.6 μl/min/g bw; 8.0±0.8 vs. 7.6±0.6 mM; n=6; NS). Fractional renal reabsorption of glucose was lower in Sglt2−/− mice compared to WT (35±8 vs. 99.7±0.1%; P<0.0001) and varied inversely with the amount of filtered glucose in Sglt2−/− mice (between 60 and 10%). Free‐flow collections of tubular fluid were performed along accessible proximal tubules at the kidney surface to establish a profile for fractional reabsorption of glucose versus fluid (FR‐fluid, FR‐glucose). We found that for early proximal collections (FR‐fluid <40%) 79±7% of the filtered glucose were reabsorbed in WT mice whereas mean net reabsorption of glucose was zero (−0.1±8.0%) in Sglt2−/− mice (P<0.0001). For late proximal collections (FR‐fluid >=40%) FR‐glucose was 93±1% in WT and 22±7% in Sglt2−/− mice (P<0.0001). In conclusion, the results demonstrate that SGLT2 mediates glucose reabsorption in the early proximal tubule and is a major determinant of glucose reabsorption in the kidney.