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 SGLT-mediated 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 SGLT-mediated 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.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.
2It 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, showing a close relationship between carbohydrate homeostasis and NHE3 activity.
9–12Plasma glucose concentration is maintained at a constant level by a complex system, in which the kidneys perform a pivotal role by reabsorbing all the filtered glucose in the PT.
13 In addition, the kidneys and liver are the only organs that express the glucose-6-phosphatase enzyme, thus enabling them to perform gluconeogenesis.
14,15 This enzyme is only expressed in the PT,
16 highlighting the importance of this kidney segment in carbohydrate metabolism.It has been shown that the kidneys metabolize 20% of the glucose consumed in a meal.
14 The PT has a low expression of hexokinase but the highest concentration and activity of glucose-6-phosphate dehydrogenase, indicating that this segment is able to metabolize glucose.
16,17 However, it is currently believed that the PT uses noncarbohydrate compounds as energy sources.
17With relation to glucose uptake, the majority of filtered glucose is reabsorbed by the low-affinity, high-capacity sodium-glucose cotransporter isoform 2 (SGLT2). Some glucose is also reabsorbed by the high-affinity, low-capacity sodium-glucose cotransporter isoform 1 (SGLT1).
13 Recently, SGLT2 inhibitors have been approved for the treatment of hyperglycemia in diabetic patients. The use of these inhibitors has been shown to decrease blood glucose, glycated hemoglobin, postprandial glucose, insulinemia, and body weight.
18–20The role of glucose uptake in the modulation of NHE3 activity in the small intestine has been extensively studied. Experiments have shown that glucose uptake through SGLT1 promotes intracellular NHE3-dependent alkalinization.
21–26 However, functional differences between intestinal and renal NaHCO
3 NHE3-mediated reabsorption have not been established. These two systems differ physiologically, because the gastrointestinal system is exposed to fluctuations in glucose concentration between the periods of fasting and after meals.
13 The presence of large amounts of solutes within the intestinal cells after meals modulates membrane transporters, such as glucose transporter 2 (GLUT2) and NHE3,
21,27 an important process for nutrient absorption.Although the synergistic activation between SGLT1 and NHE3 has been observed in the intestine,
21 it is not known if this process also occurs in the kidneys. Considering that the kidneys also express SGLT2 and the particularities of glucose availability in this organ, the goal of the present work was to determine the effect of glucose and SGLT activity on NHE3 in the renal PT.
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