Abstract

Recent studies have suggested that postprandial increases in insulin directly contribute to reduced urinary sodium (Na+) excretion by altering renal Na+ transport. While there are a number of renal transporters that respond to insulin stimulation, which of these transporters are involved in this Na+ sparing mechanism under normal physiological conditions is not fully established. The epithelial sodium channel (ENaC) is the rate limiting step for sodium reabsorption in the distal nephron and its regulation by insulin is well established; however, the regulatory effect of acute hyperinsulinemia (as would result from a meal) on ENaC under normal conditions is still being debated. The main objective of this study was to test the contribution of ENaC as well as other Na+ transporters to the increase in renal Na+ reabsorption following a meal. To test this, we used fasted Sprague Dawley rats that had been given a high carbohydrate supplement to simulate a meal and analyzed changes to ENaC activity as well as expression of other renal transporters involved in sodium homeostasis. Postprandial changes in circulating renin‐angiotensin‐aldosterone system (RAAS) hormones known to enhance ENaC activity were also tested. We found that 4 hours post carbohydrate stimulus, ENaC open probability increased relative to controls in split‐open isolated collecting duct tubules (0.34 ±0.06 vs. 0.70 ± 0.07, n≥5, p<0.01), while the number of channels at the surface and total ENaC α‐ and β‐subunit levels remained unchanged. We also examined expression levels of the Na+‐Cl− cotransporter (NCC), Na+‐K+‐2Cl− cotransporter (NKCC2), and Na+‐K+‐ATPase (NKA). While there were no significant differences in expression of NCC or NKCC2 in either group, NKA expression in the postprandial group was significantly increased (1.0 ± 0.08 vs. 1.62 ± 0.10, n=5, p<0.001). Additionally, using mass spectrometry‐based analysis, we interrogated different metabolites of RAAS signaling between the stimulated and fasted rats and found no significant changes in aldosterone or angiotensin metabolite levels. These results suggest that acute hyperinsulinemia following a meal increases ENaC activity independent of the RAAS signaling cascade. Our study demonstrates that ENaC and NKA regulation via insulin is a likely contributor to an evolutionary mechanism for preserving sodium and volume loss after a meal, and that this regulation is distinct from classical ENaC regulation by RAAS.Support or Funding InformationT32 HL134643; R35 HL135749, HL56259This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Highlights

  • Many diabetic studies in the past have focused on physiological changes that occur during fasting; the importance of postprandial metabolic effects, the role of systemic insulin signaling, is becoming increasingly realized

  • We investigated if there were any changes to the renin angiotensin aldosterone (RAAS) system to determine whether the insulin signaling was working independently on ENaC or part of a more complex, intertwined regulatory control system

  • Rats that were prevented from raising circulating insulin levels above baseline had significant urinary sodium and volume losses over 24 hours of ad libitum eating and after a glucose bolus[21]

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Summary

Introduction

Many diabetic studies in the past have focused on physiological changes that occur during fasting; the importance of postprandial metabolic effects, the role of systemic insulin signaling, is becoming increasingly realized. Multiple studies have demonstrated the ability of insulin to increase sodium transport via ENaC, and while pathologically high levels of circulating insulin are hypothesized to help contribute to the development of hypertension, the role of naturally fluctuating levels of insulin on ENaC under normal physiological conditions have yet to be investigated, in the postprandial time frame. We investigated the hypothesis that ENaC activity would increase during the postprandial period, likely in response to temporary hyperinsulinemia, and that this increase in ENaC activity could be essential to prevent postprandial sodium loss To test this hypothesis, we recorded ENaC from isolated split-open cortical collecting ducts and measured its activity. We investigated if there were any changes to the renin angiotensin aldosterone (RAAS) system to determine whether the insulin signaling was working independently on ENaC or part of a more complex, intertwined regulatory control system

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