Dietary Sodium Intake Regulates the Ubiquitin-Protein Ligase Nedd4-2 in the Renal Collecting System

Loffing‐Cueni, Dominique; Flores, Sandra Y.; Sauter, Daniel; Daidié, Dorothée; Siegrist, Nicole; Staub, Olivier; Loffing, Johannes

doi:10.1681/asn.2005060659

Cited by 62 publications

(49 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Immunofluorescence analysis showed that Cre recombinase is expressed in every tubular cell along the renal tubules of doxycycline-treated KO, but not in the blood vessels ( Figure 1A). Consistent with previous report (26), Nedd4L mRNA could be detected in the proximal tubule (PT), DCT, CNT, and CD in microdissected tubules of control mice, but not in KO ( Figure 1B). Western blot on total kidney lysates revealed a decrease of the 130-kDa NEDD4-2 protein in doxycycline-treated KO mice ( Figure 1C).…”

Section: Resultssupporting

confidence: 92%

Renal tubular NEDD4-2 deficiency causes NCC-mediated salt-dependent hypertension

Ronzaud¹,

Loffing‐Cueni²,

Hausel³

et al. 2013

J. Clin. Invest.

Self Cite

103

160

View full text Add to dashboard Cite

The E3 ubiquitin ligase NEDD4-2 (encoded by the Nedd4L gene) regulates the amiloride-sensitive epithelial Na + channel (ENaC/SCNN1) to mediate Na + homeostasis. Mutations in the human β/γENaC subunits that block NEDD4-2 binding or constitutive ablation of exons 6-8 of Nedd4L in mice both result in salt-sensitive hypertension and elevated ENaC activity (Liddle syndrome). To determine the role of renal tubular NEDD4-2 in adult mice, we generated tetracycline-inducible, nephron-specific Nedd4L KO mice. Under standard and highNa + diets, conditional KO mice displayed decreased plasma aldosterone but normal Na + /K + balance. Under a high-Na + diet, KO mice exhibited hypercalciuria and increased blood pressure, which were reversed by thiazide treatment. Protein expression of βENaC, γENaC, the renal outer medullary K + channel (ROMK), and total and phosphorylated thiazide-sensitive Na + Cl -cotransporter (NCC) levels were increased in KO kidneys. Unexpectedly, Scnn1a mRNA, which encodes the αENaC subunit, was reduced and proteolytic cleavage of αENaC decreased. Taken together, these results demonstrate that loss of NEDD4-2 in adult renal tubules causes a new form of mild, salt-sensitive hypertension without hyperkalemia that is characterized by upregulation of NCC, elevation of β/γENaC, but not αENaC, and a normal Na + /K + balance maintained by downregulation of ENaC activity and upregulation of ROMK.

show abstract

Section: Resultssupporting

confidence: 92%

Renal tubular NEDD4-2 deficiency causes NCC-mediated salt-dependent hypertension

Ronzaud¹,

Loffing‐Cueni²,

Hausel³

et al. 2013

J. Clin. Invest.

Self Cite

103

160

View full text Add to dashboard Cite

show abstract

“…study 22 indicate that chronic activation of MR leads to decreased collecting duct expression of Nedd4-2. A key finding of our study is that the kidney is able to circumvent a genetic obligation for avid sodium reabsorption.…”

Section: ␤Hsd2mentioning

confidence: 80%

A Switch in the Mechanism of Hypertension in the Syndrome of Apparent Mineralocorticoid Excess

Bailey

Paterson

Hadoke

et al. 2008

Journal of the American Society of Nephrology

View full text Add to dashboard Cite

The syndrome of apparent mineralocorticoid excess arises from nonfunctional mutations in 11␤-hydroxysteroid dehydrogenase type 2 (11␤HSD2), an enzyme that inactivates cortisol and confers aldosterone specificity on the mineralocorticoid receptor. Loss of 11␤HSD2 permits glucocorticoids to activate the mineralocorticoid receptor, and the hypertension in the syndrome is presumed to arise from volume expansion secondary to renal sodium retention. An 11␤HSD2 null mouse was generated on an inbred C57BL/6J genetic background, allowing survival to adulthood. 11␤HSD2 Ϫ/Ϫ mice had BP approximately 20 mmHg higher on average compared with wild-type mice but were volume contracted, not volume expanded as expected. Initially, impaired sodium excretion associated with increased activity of the epithelial sodium channel was observed. By 80 days of age, however, channel activity was abolished and 11␤HSD2 Ϫ/Ϫ mice lost salt. Despite the natriuresis, hypertension remained but was not attributable to intrinsic vascular dysfunction. Instead, urinary catecholamine levels in 11␤HSD2 Ϫ/Ϫ mice were double those in wild-type mice, and ␣1-adrenergic receptor blockade rescued the hypertensive phenotype, suggesting that vasoconstriction contributes to the sustained hypertension in this model. In summary, it is proposed that renal sodium retention remains a key event in apparent mineralocorticoid excess but that the accompanying hypertension changes from a renal to a vascular etiology over time. In 90% of hypertensive patients, the causal pathophysiology cannot be defined and, in 25%, BP fails to fall to target values with existing therapies. Improved understanding of pathogenesis is key to addressing this problem. Fundamental principles of BP homeostasis have been established through investigation of the rare Mendelian hypertensive disorders. These disorders result almost exclusively from mutations in genes encoding proteins influencing directly or indirectly sodium balance, 1 suggesting that altered renal salt homeostasis is a key factor in the misregulation of BP 2 The fine-tuning of sodium balance is achieved in the distal nephron, determined principally by the actions of aldosterone at the mineralocorticoid receptor (MR). In vitro, MR can be activated with equal potency by both mineralocorticoids and glucocorticoids. 3 In vivo, ligand access is determined by the enzyme 11␤-hydroxysteroid dehydrogenase type 2 (11␤HSD2), which catalyzes the rapid conversion of the active glucocorticoid cortisol (corticosterone in mice) to inert cortisone (11-dehydrocorticosterone), thereby

show abstract

“…This steroid hormone produces salt-sensitive hypertension partly by stimulating renal Na ϩ and Cl Ϫ transporters such as ENaC and pendrin (12,22,24,36). Aldosterone increases ENaC surface expression largely through a mechanism that involves the ubiquitin ligase NEDD4-2 (20,33). After binding to NEDD4-2, transporters such as ENaC are ubiquitinated and then endocytosed and degraded (10,20,27).…”

Section: Discussionmentioning

confidence: 99%

Pendrin gene ablation alters ENaC subcellular distribution and open probability

Pech

Wall

Nanami

et al. 2015

American Journal of Physiology-Renal Physiology

View full text Add to dashboard Cite

The present study explored whether the intercalated cell Cl−/HCO3− exchanger pendrin modulates epithelial Na+ channel (ENaC) function by changing channel open probability and/or channel density. To do so, we measured ENaC subunit subcellular distribution by immunohistochemistry, single channel recordings in split open cortical collecting ducts (CCDs), as well as transepithelial voltage and Na+ absorption in CCDs from aldosterone-treated wild-type and pendrin-null mice. Because pendrin gene ablation reduced 70-kDa more than 85-kDa γ-ENaC band density, we asked if pendrin gene ablation interferes with ENaC cleavage. We observed that ENaC-cleaving protease application (trypsin) increased the lumen-negative transepithelial voltage in pendrin-null mice but not in wild-type mice, which raised the possibility that pendrin gene ablation blunts ENaC cleavage, thereby reducing open probability. In mice harboring wild-type ENaC, pendrin gene ablation reduced ENaC-mediated Na+ absorption by reducing channel open probability as well as by reducing channel density through changes in subunit total protein abundance and subcellular distribution. Further experiments used mice with blunted ENaC endocytosis and degradation (Liddle's syndrome) to explore the significance of pendrin-dependent changes in ENaC open probability. In mouse models of Liddle's syndrome, pendrin gene ablation did not change ENaC subunit total protein abundance, subcellular distribution, or channel density, but markedly reduced channel open probability. We conclude that in mice harboring wild-type ENaC, pendrin modulates ENaC function through changes in subunit abundance, subcellular distribution, and channel open probability. In a mouse model of Liddle's syndrome, however, pendrin gene ablation reduces channel activity mainly through changes in open probability.

show abstract

Dietary Sodium Intake Regulates the Ubiquitin-Protein Ligase Nedd4-2 in the Renal Collecting System

Cited by 62 publications

References 51 publications

Renal tubular NEDD4-2 deficiency causes NCC-mediated salt-dependent hypertension

Renal tubular NEDD4-2 deficiency causes NCC-mediated salt-dependent hypertension

A Switch in the Mechanism of Hypertension in the Syndrome of Apparent Mineralocorticoid Excess

Pendrin gene ablation alters ENaC subcellular distribution and open probability

Contact Info

Product

Resources

About