Angiotensin II Increases Activity of the Epithelial Na+ Channel (ENaC) in Distal Nephron Additively to Aldosterone

Mamenko, Mykola; Zaika, Oleg; Ilatovskaya, Daria V.; Staruschenko, Alexander; Pochynyuk, Oleh

doi:10.1074/jbc.m111.298919

Cited by 132 publications

(138 citation statements)

References 49 publications

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“…Of interest, aldosterone did not increase the expression of the epithelial sodium channel. Thus, angiotensin II has an additive effect to aldosterone in the activation of the epithelial sodium channel, similar to what we showed for the sodium chloride cotransporter [3,4]. All in all, the net effect of the renin-angiotensin system is to make the kidneys retain sodium and water.…”

supporting

confidence: 57%

Is it true that activation of the renin–angiotensin system could induce natriuresis?

2015

Intensive Care Med

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supporting

confidence: 57%

Is it true that activation of the renin–angiotensin system could induce natriuresis?

2015

Intensive Care Med

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“…It is increasingly recognized, however, that AII also directly affects renal epithelia. AT1R is present throughout the nephron (40), and signaling increases activities of the sodium hydrogen exchanger 3 in the proximal tubule, NKCC2 in the TAL, NCC of the DCT, and ENaC in the CNT and CD (41)(42)(43)(44). AII also regulates phosphorylation and activity of MR in renal intercalated cells, allowing induction of a transcellular Cl − reabsorption pathway (14).…”

Section: Discussionmentioning

confidence: 99%

Angiotensin II signaling via protein kinase C phosphorylates Kelch-like 3, preventing WNK4 degradation

Shibata

Arroyo

Castañeda‐Bueno

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

102

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Hypertension contributes to the global burden of cardiovascular disease. Increased dietary K + reduces blood pressure; however, the mechanism has been obscure. Human genetic studies have suggested that the mechanism is an obligatory inverse relationship between renal salt reabsorption and K + secretion. Mutations in the kinases with-no-lysine 4 (WNK4) or WNK1, or in either Cullin 3 (CUL3) or Kelch-like 3 (KLHL3)-components of an E3 ubiquitin ligase complex that targets WNKs for degradation-cause constitutively increased renal salt reabsorption and impaired K + secretion, resulting in hypertension and hyperkalemia. The normal mechanisms that regulate the activity of this ubiquitin ligase and levels of WNKs have been unknown. We posited that missense mutations in KLHL3 that impair binding of WNK4 might represent a phenocopy of the normal physiologic response to volume depletion in which salt reabsorption is maximized. We show that KLHL3 is phosphorylated at serine 433 in the Kelch domain (a site frequently mutated in hypertension with hyperkalemia) by protein kinase C in cultured cells and that this phosphorylation prevents WNK4 binding and degradation. This phosphorylation can be induced by angiotensin II (AII) signaling. Consistent with these in vitro observations, AII administration to mice, even in the absence of volume depletion, induces renal KLHL3 S433 phosphorylation and increased levels of both WNK4 and the NaCl cotransporter. Thus, AII, which is selectively induced in volume depletion, provides the signal that prevents CUL3/KLHL3-mediated degradation of WNK4, directing the kidney to maximize renal salt reabsorption while inhibiting K + secretion in the setting of volume depletion.renin-angiotensin-aldosterone system | distal tubule | hypertension | posttranslational modification | PHAII H ypertension affects 1 billion people worldwide and is a major risk factor for death from stroke, myocardial infarction, and congestive heart failure. The study of Mendelian forms of hypertension has demonstrated the key role of increased renal salt reabsorption in disease pathogenesis (1-4). Observational and intervention trials (5, 6) also indicate that increased dietary K + lowers blood pressure; however, the mechanism of this effect has been unclear.Pseudohypoaldosteronism type II (PHAII; Online Mendelian Inheritance in Man no. 145260), featuring hypertension and hyperkalemia, has revealed a previously unrecognized mechanism that regulates the balance between renal salt reabsorption and K + secretion in response to aldosterone (7). Aldosterone is produced by the adrenal glomerulosa in volume depletion, in response to angiotensin II (AII), and in hyperkalemia via membrane depolarization (8). In volume depletion, aldosterone maximizes renal salt reabsorption, whereas in hyperkalemia, aldosterone promotes maximal renal K + secretion. Volume depletion increases both the NaCl cotransporter (NCC) (9) and electrogenic Na + reabsorption via the epithelial Na + channel (ENaC) (10). The lumen-negative potential produced by ENa...

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“…18,[59][60][61] Kidneys were cut into thin slices (,1 mm), with slices placed into ice-cold physiologic saline solution buffered with HEPES (pH 7.4). The CD was visually identified by its morphologic features (pale color, coarse surface, and, in some cases, bifurcations) and was mechanically isolated from kidney slices by microdissection using watchmaker forceps under a stereomicroscope.…”

Section: Tissue Isolationmentioning

confidence: 99%

TRPV4 Dysfunction Promotes Renal Cystogenesis in Autosomal Recessive Polycystic Kidney Disease

Zaika

Mamenko

Berrout

et al. 2013

Journal of the American Society of Nephrology

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Angiotensin II Increases Activity of the Epithelial Na+ Channel (ENaC) in Distal Nephron Additively to Aldosterone

Abstract: Background: Mineralocorticoid aldosterone controls ENaC-mediated Na ϩ reabsorption in the distal nephron.

Cited by 132 publications

References 49 publications

Is it true that activation of the renin–angiotensin system could induce natriuresis?

Is it true that activation of the renin–angiotensin system could induce natriuresis?

Angiotensin II signaling via protein kinase C phosphorylates Kelch-like 3, preventing WNK4 degradation

TRPV4 Dysfunction Promotes Renal Cystogenesis in Autosomal Recessive Polycystic Kidney Disease

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