SGLT2-independent effects of canagliflozin on NHE3 and mitochondrial complex I activity inhibit proximal tubule fluid transport and albumin uptake
Wafaa N. Albalawy, Elynna B. Youm, Katherine E. Shipman, Keelan J. Trull, Catherine J. Baty, Kimberly R. Long, Youssef Rbaibi, Xue‐Ping Wang, Olayemi G. Fagunloye, Katharine A. White, Michael J. Jurczak, Ossama B. Kashlan, Ora A. Weisz
Abstract
Reduced NHE3-mediated Na + transport has been suggested to underlie the cardiorenal protection provided by SGLT2 inhibitors. We found that canagliflozin, but not empagliflozin, reduced NHE3-dependent fluid transport and endocytic uptake in cultured proximal tubule cells. These effects were independent of SGLT2 activity and resulted from inhibition of mitochondrial complex I and NHE3. Studies in mice are consistent with greater effects of canagliflozin versus empagliflozin on fluid transport. Our data suggest that these selective effects of canagliflozin contribute to reduced Na + -dependent transport in proximal tubule cells.