Physiology of Kidney Glucose Transport and Mechanisms of Kidney Protection by SGLT2 Inhibitors

The Na⁺-coupled glucose transporter SGLT2 is expressed in the early proximal tubule of the kidney, where it reabsorbs most of the filtered glucose. Drugs that inhibit SGLT2 (SGLT2i) can protect the kidneys in patients with and without type 2 diabetes mellitus. In a nutshell, SGLT2i shift the reabsorption of large amounts of glucose from the early proximal tubule to downstream tubular segments that take up glucose via SGLT1. Non-reabsorbed glucose is lost into the urine associated with an osmotic diuresis. Why should this protect the kidney? This review first outlines the physiology of kidney glucose transport. Then it outlines how primary effects of SGLT2i on the early proximal tubule can explain clinical phenotypes that, according to mediation analyses, are predictors of kidney (and heart) protection by SGLT2i, including an increase in hematocrit and lowering of plasma volume, serum urate levels, and albuminuria. Tubule-glomerular communication forms the physiological basis for SGLT2i to acutely lower glomerular filtration rate (GFR) and glomerular capillary pressure. This lowers albuminuria and kidney cortex oxygen demand, which both preserve tubular integrity and GFR in the long run. In the early proximal tubule, SGLT2 is functionally co-regulated with other apical sodium and metabolite transporters. This explains why SGLT2i initially excrete more sodium than expected and are uricosuric, lowering plasma volume and serum urate levels. SGLT2i lower early proximal tubule glucotoxicity and by shifting transport downstream better distribute tubular transport burden and energy needs. Moreover, the transport shift tricks the kidney by simulating "systemic hypoxia" at the oxygen sensors in outer medullary interstitial cells. The resulting release of erythropoietin, together with the osmotic diuresis, enhances hematocrit and thereby oxygen delivery to kidneys and other organs. This is complemented by an SGLT2i-induced insulin-sparing and fasting-like metabolic and anti-inflammatory phenotype and by off-target effects including less microbiotic formation of uremic toxins.