Functional Role of Glucose Metabolism, Osmotic Stress, and Sodium-Glucose Cotransporter Isoform-Mediated Transport on Na+/H+ Exchanger Isoform 3 Activity in the Renal Proximal Tubule

Abstract

Na + -glucose cotransporter 1 (SGLT1)-mediated glucose uptake leads to activation of Na + -H + exchanger 3 (NHE3) in the intestine by a process that is not dependent on glucose metabolism. This coactivation may be important for postprandial nutrient uptake. However, it remains to be determined whether SGLTmediated glucose uptake regulates NHE3-mediated NaHCO 3 reabsorption in the renal proximal tubule. Considering that this nephron segment also expresses SGLT2 and that the kidneys and intestine show significant variations in daily glucose availability, the goal of this study was to determine the effect of SGLTmediated glucose uptake on NHE3 activity in the renal proximal tubule. Stationary in vivo microperfusion experiments showed that luminal perfusion with 5 mM glucose stimulates NHE3-mediated bicarbonate reabsorption. This stimulatory effect was mediated by glycolytic metabolism but not through ATP production. Conversely, luminal perfusion with 40 mM glucose inhibited NHE3 because of cell swelling. Notably, pharmacologic inhibition of SGLT activity by Phlorizin produced a marked inhibition of NHE3, even in the absence of glucose. Furthermore, immunofluorescence experiments showed that NHE3 colocalizes with SGLT2 but not SGLT1 in the rat renal proximal tubule. Collectively, these findings show that glucose exerts a bimodal effect on NHE3. The physiologic metabolism of glucose stimulates NHE3 transport activity, whereas, supraphysiologic glucose concentrations inhibit this exchanger. Additionally, Phlorizin-sensitive SGLT transporters and NHE3 interact functionally in the proximal tubule. 25: 202825: -203925: , 201425: . doi: 10.1681 The kidney proximal tubule (PT) is the site where the reabsorption of approximately 70% of filtered sodium bicarbonate occurs. It is mainly performed by the Na + /H + exchanger isoform 3 (NHE3). 1 The physiologic importance of NHE3 became evident after the development of NHE3 knockout mice, which presented mild metabolic acidosis and volume depletion with reduced BP, underscoring the role of NHE3 in volume homeostasis. 2 It has been shown that NHE3 physically and functionally interacts with dipeptidyl-peptidase IV, an enzyme that degrades and inactivates the incretin hormone glucagon like peptide-1. 3 The inhibition of dipeptidyl-peptidase IV and the action of glucagon like peptide-1 were shown to inhibit NHE3 and promote natriuresis. 3-8 Additionally, various conditions and substances related to glucose metabolism, including diabetes, insulin, ATP, and glucose, modulate NHE3 in different tissues, J Am Soc Nephrol

The Potential Role of SGLT2 Inhibitors in the Treatment of Type 1 Diabetes Mellitus

“…Na + /H + -exchanger 3 (NHE3) is an early proximal tubule transporter that is co-expressed with SGLT2. Inhibition of SGLT2 may also inhibit NHE3 as recently proposed [2, 40]. This interaction between SGLT2 and NHE3 could be relevant to the blood pressurelowering effect of SGLT2.…”

MAP17 Is a Necessary Activator of Renal Na+/Glucose Cotransporter SGLT2

“…41 A recent paper reported that activating the Na/ glucose cotransporter (presumably SGLT2, which is colocalized with NHE3) by adding 5 mM glucose in the lumen of rat proximal tubules can upregulate the Na/HCO 3 transport mediated by NHE3. 42 More interestingly, in the total absence of luminal glucose, addition of luminal Pz produced a clear inhibition of NHE3 activity. This unexpected observation could be explained if SGLT2/MAP17 and NHE3 are part of a "signaling platform" held together by the scaffolding protein PDZK1.…”

Effects of diuretics on sodium-dependent glucose cotransporter 2 inhibitor-induced changes in blood pressure in obese rats suffering from the metabolic syndrome

“…These data suggest that a compensatory increase in NHE3 activity is elicited by luseogliflozin-induced increases in sodium and water load at the proximal tubules. Conversely, recent studies have shown that NHE3 colocalizes with SGLT2 and that the nonselective SGLT2-inhibitor phlorizin can inhibit NHE3 function [37]. The reason for these discrepant data is not clear, but could be explained by differences in the animal model (SHRcp vs. normal Wistar rats), experimental setup (chronic vs. acute administration) or specificity for the SGLT2 inhibitor (luseogliflozin vs. phlorizin).…”