SGLT2 Inhibitor Effects on Proximal Tubule Cell Function

Sodium glucose transporter inhibitors (SGLTis) have been shown to improve cardiac and kidney health outcomes in patients with type 2 diabetes mellitus as well as in nondiabetic individuals. Both renal and extrarenal targets of SGLTis have been implicated in these protective effects, and it is unclear whether SGLTi protection against kidney disease occurs via the same mechanisms under diabetic vs nondiabetic conditions. To begin to address these questions, we examined the effects of SGLTis on proximal tubule (PT) transport and endocytosis in a well-differentiated opossum kidney (OK) cell model that recapitulates essential morphological, metabolic, and functional characteristics of the PT in vivo. Treatment with canagliflozin, empagliflozin, or tofogliflozin reduced endocytic uptake of albumin by these cells in a dose-dependent manner. Similarly, treatment with SGLTis inhibited fluid transport across OK cell monolayers. SGLTis have been shown to impair NHE3 transport, and as predicted, inhibition of NHE3 had similar effects on endocytic uptake and fluid transport. We recently discovered that knockout (KO) of megalin in OK cells results in a dramatic reduction in SGLT2 transcription with no change in NHE3 expression. Megalin KO cells had considerably lower rates of fluid transport that were not further affected by SGLT2i treatment. Current studies are directed towards understanding the interplay between megalin, SGLTs, and NHE3 expression and activity at the plasma membrane and in endosomal compartments in the modulation of PT endocytic function and transport.