Modified cycloartanes with improved inhibitory effect on SGLT-mediated glucose uptake in human renal proximal tubular cells

Sodium/glucose co-transporters (SGLTs) play an important role in renal glucose reabsorption. Inhibition of SGLT2 by derivatives of O-glucoside phlorizin dihydrochalcones has been approved for treatment of type 2 diabetes. The present study searches for the inhibitory effect of schisandronic acid (4), a cycloartane isolated from leaves and twigs of Gardenia collinsae Craib, and its derivatives 1-3 on SGLTs in human renal proximal tubular cells. SGLT-mediated glucose uptake in human renal proximal tubular cells was performed by measuring accumulation of H-3-deoxyglucose ( H-3-2DG) in human renal proximal tubular cell lines, kidney 2 (HK-2), and RPTEC/TERT1 cells. Schisandronic acid slightly inhibited 3H-2DG accumulation in HK-2 cells. Compounds 1 and 2 exhibited significant inhibition of transport activity of SGLT in HK-2 cells. The half inhibitory concentration (IC50) showed that compound 2 was found to be the most potent with IC50 of 32.18 mu M. In addition, the inhibitory effect of compound 2 was not a result of cytotoxicity. Reduction of IC50 of compound 2 on H-3-2DG uptake (16.81 mu M) was found in RPTEC/TERT1 cells that mainly express SGLT2. This study represents the first reported evidence of cycloartane derivatives inhibiting SGLT-mediated glucose uptake in human renal proximal tubular cells.