Aldosterone Paradox: Differential Regulation of Ion Transport in Distal Nephron

Arroyo, Juan Pablo; Ronzaud, Caroline; Lagnaz, Dagmara; Staub, Olivier; Gamba, Gerardo

doi:10.1152/physiol.00049.2010

Cited by 122 publications

(118 citation statements)

References 97 publications

Supporting

Mentioning

113

Contrasting

Unclassified

Order By: Relevance

“…In line with this, recent studies have shown that angiotensin II directly inhibits ROMK, further contributing to potassium conservation during hypovolemia [49,129,140]. The effects of angiotensin II on NCC and ROMK therefore help to understand the aldosterone paradox, the question how aldosterone increases sodium reabsorption during hypovolemia, but potassium secretion during hyperkalemia [3,122]. Further insight into the aldosterone paradox comes from the effects of potassium on NCC.…”

Section: Structure-function Relationshipmentioning

confidence: 85%

See 1 more Smart Citation

The sodium chloride cotransporter SLC12A3: new roles in sodium, potassium, and blood pressure regulation

Moes

Lubbe

Zietse

et al. 2013

Pflugers Arch - Eur J Physiol

View full text Add to dashboard Cite

SLC12A3 encodes the thiazide-sensitive sodium chloride cotransporter (NCC), which is primarily expressed in the kidney, but also in intestine and bone. In the kidney, NCC is located in the apical plasma membrane of epithelial cells in the distal convoluted tubule. Although NCC reabsorbs only 5 to 10 % of filtered sodium, it is important for the fine-tuning of renal sodium excretion in response to various hormonal and non-hormonal stimuli. Several new roles for NCC in the regulation of sodium, potassium, and blood pressure have been unraveled recently. For example, the recent discoveries that NCC is activated by angiotensin II but inhibited by dietary potassium shed light on how the kidney handles sodium during hypovolemia (high angiotensin II) and hyperkalemia. The additive effect of angiotensin II and aldosterone maximizes sodium reabsorption during hypovolemia, whereas the inhibitory effect of potassium on NCC increases delivery of sodium to the potassium-secreting portion of the nephron. In addition, great steps have been made in unraveling the molecular machinery that controls NCC. This complex network consists of kinases and ubiquitinases, including WNKs, SGK1, SPAK, Nedd4-2, Cullin-3, and Kelch-like 3. The pathophysiological significance of this network is illustrated by the fact that modification of each individual protein in the network changes NCC activity and results in salt-dependent hypotension or hypertension. This review aims to summarize these new insights in an integrated manner while identifying unanswered questions.

show abstract

Section: Structure-function Relationshipmentioning

confidence: 85%

“…It has been suggested that NCC is expressed in various other tissues but this has not been confirmed [29]. In the kidney, NCC is located in the early part of the DCT (also called DCT1) (Figure 1), but gradually decreases along the later part of the DCT (DCT2), where it co-localizes with the epithelial sodium channel (ENaC) [3].…”

Section: Typical Hallmarks Of Nccmentioning

confidence: 99%

The sodium chloride cotransporter SLC12A3: new roles in sodium, potassium, and blood pressure regulation

Moes

Lubbe

Zietse

et al. 2013

Pflugers Arch - Eur J Physiol

View full text Add to dashboard Cite

show abstract

“…1 After induction of ENaC deletion along the nephron, NCC is significantly less phosphorylated. This finding is unexpected, because the Scnn1a…”

Section: Aldosterone-independent Regulation Of Ncc In Scnn1amentioning

confidence: 99%

“…This mechanism is commonly referred as the aldosterone paradox, but how aldosterone exerts these apparently opposite effects is not yet completely understood. 1 Na + reabsorption in the distal nephron occurs through two different means: the electroneutral thiazide-sensitive Na + /Cl 2 cotransporter (NCC) expressed mainly in the DCT1, with lower expression in the DCT2, and the amiloridesensitive epithelial sodium channel (ENaC) expressed in the aldosterone-sensitive distal nephron (ASDN), namely the DCT2, CNT, and CD. Na + and K + are the most important cations for the transmembrane potential across the plasma membrane, and electrogenic Na + reabsorption through ENaC increases the driving force for K + transport and thus, K + excretion.…”

mentioning

confidence: 99%

Severe Salt–Losing Syndrome and Hyperkalemia Induced by Adult Nephron–Specific Knockout of the Epithelial Sodium Channel α-Subunit

Perrier

Boscardin

Malsure

et al. 2015

JASN

View full text Add to dashboard Cite

Systemic pseudohypoaldosteronism type 1 (PHA-1) is a severe salt-losing syndrome caused by loss-of-function mutations of the amiloride-sensitive epithelial sodium channel (ENaC) and characterized by neonatal lifethreatening hypovolemia and hyperkalemia. The very high plasma aldosterone levels detected under hypovolemic or hyperkalemic challenge can lead to increased or decreased sodium reabsorption, respectively, through the Na + /Cl 2 cotransporter (NCC). However, the role of ENaC deficiency remains incompletely defined, because constitutive inactivation of individual ENaC subunits is neonatally lethal in mice. We generated adult inducible nephron-specific aENaC-knockout mice (Scnn1a) that exhibit hyperkalemia and body weight loss when kept on a regular-salt diet, thus mimicking PHA-1. Compared with control mice fed a regular-salt diet, knockout mice fed a regular-salt diet exhibited downregulated expression and phosphorylation of NCC protein, despite high plasma aldosterone levels. In knockout mice fed a high-sodium and reduced-potassium diet (rescue diet), although plasma aldosterone levels remained significantly increased, NCC expression returned to control levels, and body weight, plasma and urinary electrolyte concentrations, and excretion normalized. Finally, shift to a regular diet after the rescue diet reinstated the symptoms of severe PHA-1 syndrome and significantly reduced NCC phosphorylation. In conclusion, lack of ENaC-mediated sodium transport along the nephron cannot be compensated for by other sodium channels and/or transporters, only by a high-sodium and reduced-potassium diet. We further conclude that hyperkalemia becomes the determining factor in regulating NCC activity, regardless of sodium loss, in the ENaC-mediated salt-losing PHA-1 phenotype.

show abstract

“…Both NCC SV and NCC 3 are present as glycosylated oligomeric structures in uEVs [74,75]. Hence, uEVs were used to assessed the role of NCC SV in vivo .…”

Section: The Role Of Nccsv In (Patho)physiologymentioning

confidence: 99%

Role of the alternative splice variant of NCC in blood pressure control

2018

View full text Add to dashboard Cite

The renal thiazide-sensitive sodium-chloride cotransporter (NCC), located in the distal convoluted tubule (DCT) of the kidney, plays an important role in blood pressure regulation by fine-tuning sodium excretion. The human SLC12A3 gene, encoding NCC, gives rise to three isoforms, of which only the third isoform (NCC3) has been extensively investigated so far. However, recent studies unraveled the importance of the isoforms 1 and 2, collectively referred to as NCC splice variant (NCCSV), in several (patho)physiological conditions. In the human kidney, NCCSV localizes to the apical membrane of the DCT and could constitute a functional route for renal sodium-chloride reabsorption. Analysis of urinary extracellular vesicles (uEVs), a non-invasive method for measuring renal responses, demonstrated that NCCSV abundance changes in response to acute water loading and correlates with patients’ thiazide responsiveness. Furthermore, a novel phosphorylation site at serine 811 (S811), exclusively present in NCCSV, was shown to play an instrumental role in NCCSV as well as NCC3 function. This review aims to summarize these new insights of NCCSV function in humans that broadens the understanding on NCC regulation in blood pressure control.

show abstract

Aldosterone Paradox: Differential Regulation of Ion Transport in Distal Nephron

Cited by 122 publications

References 97 publications

The sodium chloride cotransporter SLC12A3: new roles in sodium, potassium, and blood pressure regulation

The sodium chloride cotransporter SLC12A3: new roles in sodium, potassium, and blood pressure regulation

Severe Salt–Losing Syndrome and Hyperkalemia Induced by Adult Nephron–Specific Knockout of the Epithelial Sodium Channel α-Subunit

Role of the alternative splice variant of NCC in blood pressure control

Contact Info

Product

Resources

About