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

Abstract

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 [Formula: see text] 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 [Formula: see text] by 5-12% in the cortex and medulla. Diabetes increases overall TNa and [Formula: see text] by ∼50 and 100%, mainly because it enhances glomerular filtration rate (GFR) and transport load. In diabetes, acute and chronic SGLT2 inhibition lowers [Formula: see text] in the cortex by ∼30%, due to GFR reduction that lowers proximal tubule active TNa, but raises [Formula: see text] in the medulla by ∼7%. In the medulla specifically, chronic SGLT2 inhibition is predicted to increase [Formula: see text] 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 [Formula: see text] by 33% in S3 segments, and raises [Formula: see text] by <1% in mTAL, OMCD, and IMCD. In summary, the model predicts that SGLT2 blockade in diabetes lowers cortical [Formula: see text] and raises medullary [Formula: see text], particularly in S3 segments.

Cell Volume Regulation in the Proximal Tubule of Rat Kidney

“…However, it must be noted that changes in transport along the upper portion of the proximal tubule might be partially compensated by variations in transport along the downstream portion of the segment. Thus, the overall impact of CVR on whole-nephron transport and urinary excretion would be more accurately assessed using computational models of the entire proximal tubule (e.g., [11]) and of the whole nephron (e.g., [12,13]).…”

Can a Shift in Fuel Energetics Explain the Beneficial Cardiorenal Outcomes in the EMPA-REG OUTCOME Study? A Unifying Hypothesis

“…In a rat single nephron modeling study (44), chronic SGLT2 inhibition lowered renal cortical QO2 by ;30% in diabetic conditions primarily due to GFR reduction, which lowered proximal tubule active Na + reabsorption. In the medulla, chronic SGLT2 inhibition was predicted to increase QO2 by 26% in the S3 segment (in part by increasing SGLT1-mediated glucose uptake), by 2% in medullary thick ascending limb, and by 9% and 21% in outer and inner medullary collecting ducts, respectively.…”

“…According to the tubular hypothesis, GFR increase in the diabetic kidney is due to primary proximal tubular hyperreabsorption caused by increased SGLT activity and tubular growth (43). Consequently, SGLT2 inhibition can lower QO2 in the diabetic kidney by lowering GFR (and the tubular Na + load) and by direct inhibition of SGLT2-mediated Na reabsorption in the early proximal tubule (44). Thus, it is possible that in humans QO2 is significantly increased in patients with diabetes and that treatment with SGLT2 inhibitors decreases renal QO2 and leads to less hypoxic stress on the diabetic kidney.…”

A Multicellular Vascular Model of the Renal Myogenic Response

“…As the triggering signals of the two mechanisms are largely independent but interrelated through blood flow which influences both local pressure and filtration rate, highly non-trivial interactions among the two mechanisms are developed [4,7,26,77]. A potential extension of the present afferent arteriole model would be to include a model of nephron transport (e.g., [78][79][80][81][82]) and tubuloglomerular feedback (e.g., [7,[83][84][85]). That would result in an integrative model of renal hemodynamics regulation that can be used for studying the interactions between the myogenic and tubuloglomerular feedback mechanisms in the context of renal autoregulation and for investigating changes in renal hemodynamics in pathophysiological conditions, especially under circumstances (e.g., hypertension and diabetes mellitus) involving complex multilevel responses [5].…”