Acute and chronic effects of SGLT2 blockade on glomerular and tubular function in the early diabetic rat

Abstract

Thomson SC, Rieg T, Miracle C, Mansoury H, Whaley J, Vallon V, Singh P. Acute and chronic effects of SGLT2 blockade on glomerular and tubular function in the early diabetic rat. Am J Physiol Regul Integr Comp Physiol 302: R75-R83, 2012. First published September 21, 2011 doi:10.1152/ajpregu.00357.2011.-Tubuloglomerular feedback (TGF) stabilizes nephron function from minute to minute and adapts to different steady-state inputs to maintain this capability. Such adaptation inherently renders TGF less efficient at buffering long-term disturbances, but the magnitude of loss is unknown. We undertook the present study to measure the compromise between TGF and TGF adaptation in transition from acute to chronic decline in proximal reabsorption (Jprox). As a tool, we blocked proximal tubule sodium-glucose cotransport with the SGLT2 blocker dapagliflozin in hyperglycemic rats with early streptozotocin diabetes, a condition in which a large fraction of proximal fluid reabsorption owes to SGLT2. Dapagliflozin acutely reduced proximal reabsorption leading to a 70% increase in early distal chloride, a saturated TGF response, and a major reduction in single nephron glomerular filtration rate (SNGFR). Acute and chronic effects on Jprox were indistinguishable. Adaptations to 10 -12 days of dapagiflozin included increased reabsorption by Henle's loop, which caused a partial relaxation in the increased tone exerted by TGF that could be explained without desensitization of TGF. In summary, TGF contributes to long-term fluid and salt balance by mediating a persistent decline in SNGFR as the kidney adapts to a sustained decrease in Jprox.dapagliflozin; hyperfiltration AN ONGOING DISTURBANCE IN salt transport anywhere along the nephron will eventually be compensated by a combination of changes in glomerular filtration of salt, salt transport elsewhere along the nephron, and salt intake to fulfill the requirement for long-term balance. The kidney cannot obviate this requirement, but exerts some control over how it is achieved. Tubuloglomerular feedback (TGF) is one mechanism that the kidney can employ to influence how the response to an outside disturbance is compensated. TGF senses the amount of fluid and salt reaching the macula densa and evokes counterbalancing changes in single nephron glomerular filtration rate (SNGFR), thereby reducing the impact that an outside disturbance in proximal reabsorption would otherwise have on distal delivery. The usual way to measure the effectiveness of TGF is by in vivo micropuncture, which is most adapted to studying the TGF responses to events that occur on a time scale of several minutes (17). TGF responses over periods of 1-2 h have been partially characterized using carbonic anhydrase inhibitors to perturb proximal reabsorption (3). But little is known about the influence of TGF over the compensatory response to an outside disturbance lasting several days, which is the critical time frame over which the kidney regulates salt balance and blood pressure (5).The present studies were performed to...

Interaction Between the Sodium‐Glucose–Linked Transporter 2 Inhibitor Dapagliflozin and the Loop Diuretic Bumetanide in Normal Human Subjects

“…However, this was dissipated during regular administration, despite a maintained reduction in proximal tubule fluid reabsorption of ≈24%5 because of an adaptive increase in NaCl reabsorption by the loop of Henle via the Na + /K + /2Cl luminal transporter. This adaptation could underlie the increased Na + excretion with bumetanide observed in this study in subjects adapted to a week of dapagliflozin.…”

“…It is approved for the treatment of type 2 diabetes mellitus (T2DM), where it promotes glycosuria 1, 5. T2DM increases the incidence of congestive heart failure (CHF) 6, 7.…”

“…Thus, there is little potential for pharmacokinetic interaction,11 but this has yet to be tested 5, 12…”

The effect of sodium glucose cotransporter 2 inhibition with empagliflozin on microalbuminuria and macroalbuminuria in patients with type 2 diabetes

“…The albuminuria-lowering effect of SGLT2 inhibition may be due to several mechanisms. First, SGLT2 inhibition achieved through either pharmacological blockade or genetic knockout models reduces renal hyperfiltration, which is considered to be a surrogate marker for intraglomerular pressure in humans [11,12,19,26]. Such a mechanism would be expected to reduce albuminuria independent of changes in systemic BP, similar to the effects of RAAS blockade, but through afferent vasoconstrictive effects rather than efferent vasodilatory effects.…”

SGLT2 Inhibitors and the Diabetic Kidney

“…Accordingly, in SGLT2 knockout mice, the induction of diabetes was associated with less hyperfiltration compared with wildtype diabetic mice (34). Micropuncture studies in rats with streptozotocininduced diabetes treated with SGLT2 inhibitors demonstrated reductions in proximal sodium reabsorption and in single nephron GFR (35).…”