SGLT2 Inhibition Is Predicted to Increase NaCl Delivery to the Medullary Thick Ascending Limb But Not to Significantly Elevate Its Oxygen Consumption

Abstract

The objective of this study was to investigate how changes in sodium reabsorption in the proximal tubule affect oxygen (O2) consumption and the metabolic efficiency of the nephron. To do so, we developed a detailed mathematical model of solute transport in a short‐loop nephron of the rat kidney. Glucose is reabsorbed via sodium‐glucose cotransporters (SGLTs) in the proximal tubule, which primarily expresses the isoforms SGLT2 in S1‐S2 and SGLT1 in S3. We used the model to investigate the effect of inhibiting SGLT2, a novel treatment for reducing proximal tubule glucose uptake in diabetes, on renal Na+ transport (TNa) and renal oxygen consumption (QO2). Inhibiting SGLT2 shifts Na+ transport to downstream nephron segments, possibly increasing their QO2. Of particular concern are the S3 segment and medullary thick ascending limb (mTAL), which are at risk for hypoxic injury. Dual SGLT2‐SGLT1 inhibition protects the S3 segment, but could further reduce mTAL oxygenation. Model simulations suggest that SGLT2 inhibition substantially increases S3 TNa and QO2. In contrast, mTAL TNa and QO2 is insensitive to SGLT inhibition and the resulting increase in Na+ load, because under physiological conditions luminal [Na+] is sufficiently high that the Na+/K+‐ATPase pump is nearly carrier‐saturated. We also used the model to determine the optimal combination of SGLT1 and SGLT2 inhibition, in terms of suppressing tubular glucose uptake and maintaining a sufficiently low S3 QO2. This research was supported in part by NIH grants DK‐89066 and DK‐56248.