Canagliflozin Inhibits Electrogenic Na+ Transport in Mouse Cortical Collecting Duct Cells
Abstract
Sodium-glucose cotransporter 2 inhibitors (SGLT2i) exhibit cardiorenal protective effects that likely involve mechanisms aside from SGLT2 inhibition. Still, many details surrounding these clinically important pleiotropic effects remain unclear. We previously showed that several SGLT2-independent proximal tubular transport functions are inhibited by canagliflozin, but not empagliflozin. Here, we demonstrate a canagliflozin-specific reduction in Sgk1 abundance in both opossum kidney proximal tubule and mouse cortical collecting duct (mCCDcl1) cells, pointing to a possible underlying mechanism. Given the role of Sgk1 in the distal nephron, we hypothesized that canagliflozin would also inhibit epithelial Na+ channel (ENaC)-dependent Na+ transport. Canagliflozin inhibited ENaC-dependent Na+ transport (amiloride-sensitive short circuit current; ISC) in mCCDcl1 cells while empagliflozin had no effect. Selective membrane permeabilization revealed canagliflozin-induced inhibition of both apical conductance through ENaC and basolateral transport via the Na+/K+ ATPase. These effects were mimicked by the selective Sgk1 inhibitor, GSK650394. Surface labeling studies demonstrated reduced membrane localization of ENaC, but not Na+/K+ ATPase subunits, consistent with a mechanism involving Sgk1. Canagliflozin reduced ISC in the presence and absence of rotenone, suggesting inhibition occurs independently of effects on mitochondrial complex I, another known target of canagliflozin. ENaC…
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