Na restriction activates epithelial Na channels in rat kidney through two mechanisms and decreases distal Na⁺ delivery

Abstract

Changes in the activity of the epithelial Na channel (ENaC) help to conserve extracellular fluid volume. In rats fed a low-salt diet, proteolytic processing of ENaC increased within 1 day, and was almost maximal after 3 days. The rapid increase in the abundance of cleaved αENaC and γENaC correlated with decreased urinary Na excretion and with increased ENaC surface expression. By contrast, ENaC activity, measured ex vivo in isolated cortical collecting ducts, increased modestly after 3 days and required 5 days to reach maximal levels. The mineralocorticoid receptor antagonist eplerenone reversed the increase in cleaved γENaC and induced natriuresis after 1 or 3 days but failed to alter either ENaC currents or Na excretion after 7 days of Na restriction. We conclude that Na depletion, through aldosterone, stimulates ENaC via independent fast and slow mechanisms. In vivo, amiloride-induced natriuresis increased after 1 day of Na depletion. By contrast, hydrochlorothiazide (HCTZ)-induced natriuresis decreased gradually over 7 days, consistent with increased ability of ENaC activity to compensate for decreased Na reabsorption in the distal convoluted tubule. Administration of amiloride and HCTZ together increased Na excretion less in Na-depleted compared to control animals, indicating decreased delivery of Na to the distal nephron when dietary Na is restricted. Measurements of creatinine and Li clearances indicated that increased Na reabsorption by the proximal tubules is responsible for the decreased delivery. Thus, Na conservation during chronic dietary salt restriction entails enhanced transport by both proximal and distal nephron segments.

Determinants of renal oxygen metabolism during low Na+ diet: effect of angiotensin II AT1 and aldosterone receptor blockade

“…The lack of effect of angiotensin II AT 1 receptor blockade onQ O 2 in the low Na + group may also be an extension of the previously stated premise. In the low Na + group, the downstream Na + reabsorption was already altered at baseline (Udwan et al 2017;Frindt et al 2018), with increasedQ O 2 and lower tubular transport efficiency, as presently observed, indicating that the angiotensin II AT 1 receptor is not the only contributor to the overall increasedQ O 2 in low Na + conditions. Importantly, the increase in renal oxygen supply maintained cortical P O 2 in the normal Na + group and increased it in the low Na + group to levels similar to the baseline normal Na + group, restoring the cortico-medullary gradient.…”

“…kidneys of animals in the low Na + group exhibited altered oxygen homeostasis with increasedQ O 2 and decreased Na + transport efficiency. This is possibly associated with a redistribution of Na + reabsorption along the tubule (Udwan et al 2017;Frindt et al 2018), and consequent increase workload in less efficient segments of the nephron where the epithelia is tighter and the energy demand is higher when compared with the proximal tubule (Cohen, 1986;Palmer & Schnermann, 2015;Layton et al 2016). Indeed, during a low Na + diet, Na + reabsorption is increased not only in the proximal tubule but also in the distal tubule/connecting tubule and collecting duct (Udwan et al 2017;Frindt et al 2018).…”

“…Indeed, the diuretic and natriuretic actions of angiotensin 1-7 are enhanced following a low Na + diet, although the blockade of the Mas receptor had no effect on basal Na + excretion (O'Neill et al 2013(O'Neill et al , 2017. Rearrangements of Na + reabsorption along the tubule during a low Na + diet are mainly attributed to proximal tubule, late distal tubule/connecting tubule and collecting duct adaptations (Udwan et al 2017;Frindt et al 2018). In these tubular segments, NHE 3 and epithelial Na + channel (ENaC) are major transporters (Palmer & Schnermann, 2015) and under strict regulation by the RAAS (Geibel et al 1990;Garty, 2000;Peti-Peterdi et al 2002;Banday & Lokhandwala, 2011).…”

“…Angiotensin II AT 1 receptor activation increases renal vascular tone, aldosterone production, Na + reabsorption mainly in the proximal tubule and reactive oxygen species (ROS) production (Onozato et al 2002;Kobori et al 2007;Banday & Lokhandwala, 2011;Patinha et al 2013). In addition, aldosterone signalling through mineralocorticoid receptors increases Na + reabsorption in the distal tubule and collecting duct and contributes to ROS formation (Garty, 2000;Miyata et al 2005;Udwan et al 2017;Frindt et al 2018). It would therefore be expected that reduced dietary Na + intake would increase kidneyQ O 2 due to elevated tubular sodium transport (T Na ) to maintain electrolyte balance, which potentially could result in intrarenal tissue hypoxia.…”

Thumb domains of the three epithelial Na+ channel subunits have distinct functions

“…ENaCs are cleaved and activated by proteases within the biosynthetic pathway and at the cell surface (4,45). ENaC proteolysis appears to have a role in activating the channel under certain physiologic conditions, including volume depletion and hyperkalemia (46,47). Studies of ENaC activation by proteases have provided clues regarding a mechanism by which the ␣ and ␥ thumb domains influence the Na ϩ self-inhibition response.…”