Aufgrund von Vorbereitungen auf eine neue Version von KOPS, können kommenden Montag und Dienstag keine Publikationen eingereicht werden. (Due to preparations for a new version of KOPS, no publications can be submitted next Monday and Tuesday.)

Canagliflozin impairs citric acid cycle in renal proximal tubule cells

Cite This

Files in this item

Files Size Format View

There are no files associated with this item.

SECKER, Philipp F., Johannes DELP, Sascha BENEKE, Marcel LEIST, 2017. Canagliflozin impairs citric acid cycle in renal proximal tubule cells. In: Naunyn-Schmiedeberg's Archives of Pharmacology. Springer. 390(Suppl 1), pp. S6. ISSN 0028-1298. eISSN 1432-1912. Available under: doi: 10.1007/s00210-017-1354-7

@article{Secker2017Canag-52685, title={Canagliflozin impairs citric acid cycle in renal proximal tubule cells}, year={2017}, doi={10.1007/s00210-017-1354-7}, number={Suppl 1}, volume={390}, issn={0028-1298}, journal={Naunyn-Schmiedeberg's Archives of Pharmacology}, author={Secker, Philipp F. and Delp, Johannes and Beneke, Sascha and Leist, Marcel}, note={Meeting Abstract} }

Leist, Marcel Secker, Philipp F. Canagliflozin impairs citric acid cycle in renal proximal tubule cells 2021-02-03T07:46:15Z 2017 Beneke, Sascha Leist, Marcel Beneke, Sascha Delp, Johannes Secker, Philipp F. terms-of-use Introduction: Canagliflozin is a pharmaceutical indicated for treatment of type 2 diabetes mellitus. Currently approved gliflozins specifically inhibit sodium/glucose transporter 2 (SGLT2). The protein is mainly expressed in renal proximal tubule epithelial cells and its inhibition increases urinary glucose excretion. Pre-clinical toxicological findings differ strikingly among the three approved and marketed gliflozins suggesting distinct off-target profiles. We therefore investigated and compared gliflozins for their off-target toxicities in human proximal tubule epithelial cells in vitro.<br />Objectives: Human proximal tubule epithelial cells (RPTEC/TERT1) were exposed to the SGLT2 inhibitors canagliflozin, dapagliflozin and empagliflozin and the impact on the cellular energy metabolism was studied.<br />Material and Methods: Lactate and glucose were quantified in cell culture supernatant. Seahorse XF24 was used to assess mitochondrial respiration in intact and permeabilized cells. Cellular amino acids were quantified using HPLC. Cytotoxicity was assessed by MTT reduction and LDH leakage.<br />Results: Canagliflozin (50 μM) but not the other two gliflozins markedly increased cellular glucose consumption and lactate secretion rates, indicative of impaired mitochondrial function. Measurements of cellular oxygen consumption revealed that canagliflozin acutely reduced mitochondrial respiration. This finding suggests a direct interference with components of the electron transport chain (ETC). Analysis of respiration in permeabilized cells ruled out inhibition of complexes II to V, but was consistent with complex I as potential target. A quantification of cellular amino acids revealed that canagliflozin but not other SGLT2 or ETC inhibitors caused a pronounced accumulation of glutamine, glutamate and alanine. These data suggest that canagliflozin disrupts the entry of glutamine into the citric acid cycle (anaplerosis), possibly by inhibiting the 2-oxoglutarate dehydrogenase complex (OGDC). Consistent with the latter, cells relying on glutaminolysis for energy generation were much more sensitive to canagliflozin-induced toxicity. Consequently, canagliflozin appears to affect mitochondrial metabolism, whereas this was not observed for the other two gliflozins tested. Delp, Johannes 2021-02-03T07:46:15Z eng

This item appears in the following Collection(s)

Search KOPS


My Account