Predicted consequences of diabetes and SGLT inhibition on transport and oxygen consumption along a rat nephron

Diabetes increases the reabsorption of Na+ (TNa) and glucose via the sodium-glucose cotransporter SGLT2 in the early proximal tubule (S1-S2 segments) of the renal cortex. SGLT2 inhibitors enhance glucose excretion and lower hyperglycemia in diabetes. We aimed to investigate how diabetes and SGLT2 inhibition affect TNa and sodium transport-dependent oxygen consumption Q(O2)(active) along the whole nephron. To do so, we developed a mathematical model of water and solute transport from the Bowman space to the papillary tip of a superficial nephron of the rat kidney. Model simulations indicate that, in the nondiabetic kidney, acute and chronic SGLT2 inhibition enhances active TNa in all nephron segments, thereby raising Q(O2)(active) by 5-12% in the cortex and medulla. Diabetes increases overall TNa and Q(O2)(active) by similar to 50 and 100%, mainly because it enhances glomerular filtration rate (GFR) and transport load. In diabetes, acute and chronic SGLT2 inhibition lowers Q(O2)(active) in the cortex by similar to 30%, due to GFR reduction that lowers proximal tubule active TNa, but raises Q(O2)(active) in the medulla by similar to 7%. In the medulla specifically, chronic SGLT2 inhibition is predicted to increase Q(O2)(active) by 26% in late proximal tubules (S3 segments), by 2% in medullary thick ascending limbs (mTAL), and by 9 and 21% in outer and inner medullary collecting ducts (OMCD and IMCD), respectively. Additional blockade of SGLT1 in S3 segments enhances glucose excretion, reduces Q(O2)(active) by 33% in S3 segments, and raises Q(O2)(active) by < 1% in mTAL, OMCD, and IMCD. In summary, the model predicts that SGLT2 blockade in diabetes lowers cortical Q(O2)(active) and raises medullary Q(O2)(active), particularly in S3 segments.