Effect of SGLT Inhibition on Medullary Oxygen Consumption: A Multi‐Nephron Model of the Rat Kidney

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 kidney. To do so, we developed a detailed mathematical model of solute transport in a multi‐nephron representation of the rat kidney. The model represents one superficial nephron and five juxtamedullary nephrons with loops of Henle reaching to differing depths of the inner medulla. The six representative nephrons merge at the entrance of the cortical collecting duct. Glucose is reabsorbed via sodium‐glucose cotransporters (SGLTs) in the proximal tubules, which express SGLT2 in S1–S2 and the 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 and renal oxygen consumption (QO2). Inhibiting SGLT2 shifts Na+ transport to downstream nephron segments, increasing their QO2. In particular, the S3 segment and medullary thick ascending limb (mTAL) are at risk for hypoxic injury. Dual SGLT1‐SGLT2 inhibition protects the S3 segment, but could further lower mTAL oxygenation. We considered the importance of the GFR‐lowering effect of SGLT2 inhibitors. Additionally, we used the model to determine the optimal combination of SGLT1 and SGLT2 inhibition, in terms of reducing tubular glucose uptake while maintaining sufficiently low S3 and mTAL QO2.Support or Funding InformationThis research was supported in part by NIH grant DK‐89066.