Physiological regulation of epithelial sodium channel by proteolysis

Svenningsen, Per; Friis, Ulla Glenert; Bistrup, Claus; Buhl, Kristian Bergholt; Jensen, Boye L.; Skøtt, Ole

doi:10.1097/mnh.0b013e328348bcc7

Cited by 27 publications

(28 citation statements)

References 64 publications

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“…33 While direct ENaC channel activity was not assessed in this study, we did assess cleavage and abundance of the alpha and gamma subunits. Cleavage is well established to activate channels in vitro and in vivo, 25, 26 evident as greater amiloride sensitive natriuresis. 27 …”

Section: Discussionmentioning

confidence: 99%

Potassium Supplementation Prevents Sodium Chloride Cotransporter Stimulation During Angiotensin II Hypertension

et al. 2016

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Ang II hypertension increases distal tubule Na-Cl cotransporter (NCC) abundance and phosphorylation (NCCp), as well as epithelial Na+ channel (ENaC) abundance and activating cleavage. Acutely raising plasma [K+] by infusion or ingestion provokes a rapid decrease in NCCp that drives a compensatory kaliuresis. The first aim tested whether acutely raising plasma [K+] with a single 3 hr 2% potassium meal would lower NCCp in Sprague Dawley rats after 14 days of AngII (400 ng/kg/min). The potassium-rich meal neither decreased NCCp nor increased K+ excretion. AngII infused rats exhibited lower plasma [K+] versus controls (3.6 ± 0.2 vs. 4.5 ± 0.1 mmol/L, p < 0.05) suggesting that Ang II mediated ENaC activation provokes K+ depletion. The second aim tested whether doubling dietary potassium intake from 1% (A1K) to 2% (A2K) would prevent K+ depletion during AngII infusion and, thus, prevent NCC accumulation. A2K fed rats exhibited normal plasma [K+] and 2-fold higher K+ excretion and plasma [aldosterone] versus A1K. In A1K rats, NCC, NCCpS71, and NCCpT53 abundance increased 1.5- to 3-fold versus controls (p< 0.05). The rise in NCC and NCCp abundance was prevented in the A2K rats, yet blood pressure did not significantly decrease. ENaC subunit abundance and cleavage increased 1.5- to 3-fold in both A1K and A2K; ROMK abundance was unaffected by Ang II or dietary K+. In summary, the accumulation and phosphorylation of NCC seen during chronic AngII infusion hypertension is likely secondary to potassium deficiency driven by ENaC stimulation.

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Section: Discussionmentioning

confidence: 99%

Potassium Supplementation Prevents Sodium Chloride Cotransporter Stimulation During Angiotensin II Hypertension

et al. 2016

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“…Aldosterone can increase renal ENaC activity by increasing a-subunit expression and increasing cell surface localization. The aENaC and gENaC subunits can also be activated via protease-dependent removal of inhibitory peptides, and the cleaved forms increase 16,20 Other potential explanations for the increased abundance of this gENaC [112][113][114][115][116][117][118][119][120][121][122] peptide include increased absolute gENaC production and urinary excretion, or more efficient trypsin digestion after gENaC is proteolytically cleaved in vivo. Although this gENaC [112][113][114][115][116][117][118][119][120][121][122] biomarker may be useful in humans, this peptide region is variable across species, so an analogous peptide sequence would be needed in rodents.…”

Section: Discussionmentioning

confidence: 99%

Activation of the Endogenous Renin-Angiotensin-Aldosterone System or Aldosterone Administration Increases Urinary Exosomal Sodium Channel Excretion

Wang²,

Rose

et al. 2016

Journal of the American Society of Nephrology

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Urinary exosomes secreted by multiple cell types in the kidney may participate in intercellular signaling and provide an enriched source of kidney-specific proteins for biomarker discovery. Factors that alter the exosomal protein content remain unknown. To determine whether endogenous and exogenous hormones modify urinary exosomal protein content, we analyzed samples from 14 mildly hypertensive patients in a crossover study during a high-sodium (HS, 160 mmol/d) diet and low-sodium (LS, 20 mmol/d) diet to activate the endogenous renin-angiotensin-aldosterone system. We further analyzed selected exosomal protein content in a separate cohort of healthy persons receiving intravenous aldosterone (0.7 mg/kg per hour for 10 hours) versus vehicle infusion. The LS diet increased plasma renin activity and aldosterone concentration, whereas aldosterone infusion increased only aldosterone concentration. Protein analysis of paired urine exosome samples by liquid chromatography-tandem mass spectrometry-based multidimensional protein identification technology detected 2775 unique proteins, of which 316 exhibited significantly altered abundance during LS diet. Sodium chloride cotransporter (NCC) and a-and g-epithelial sodium channel (ENaC) subunits from the discovery set were verified using targeted multiple reaction monitoring mass spectrometry quantified with isotope-labeled peptide standards. Dietary sodium restriction or acute aldosterone infusion similarly increased urine exosomal gENaC [112][113][114][115][116][117][118][119][120][121][122] peptide concentrations nearly 20-fold, which correlated with plasma aldosterone concentration and urinary Na/K ratio. Urine exosomal NCC and aENaC concentrations were relatively unchanged during these interventions. We conclude that urinary exosome content is altered by renin-angiotensin-aldosterone system activation. Urinary measurement of exosomal gENaC [112][113][114][115][116][117][118][119][120][121][122] concentration may provide a useful biomarker of ENaC activation in future clinical studies.

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“…Studies with protein-rich urine from both nephrotic rats and patients have shown a stimulation of ENaC currents in vitro that was attributed to occurrence of the serine protease plasmin in the urine (4,5). It is an emerging concept that serine proteases contribute to ENaC regulation by cleaving specific sites in the extracellular domains of the a-and g-subunits (6)(7)(8)(9)(10), resulting in the release of inhibitory peptides and activation of the channel (11)(12)(13). Proteolytic activation of ENaC by serine proteases as shown in native renal tissue (14) is enhanced by low-salt diet or aldosterone infusion (15) and might involve membrane-anchored prostasin (16) and/or tissue (urinary) kallikreins (17).…”

Section: Introductionmentioning

confidence: 99%

“…Proteolytic activation of ENaC by serine proteases as shown in native renal tissue (14) is enhanced by low-salt diet or aldosterone infusion (15) and might involve membrane-anchored prostasin (16) and/or tissue (urinary) kallikreins (17). Under pathophysiologic conditions of proteinuria, ENaC is thought to be aberrantly activated by plasmin that arises from filtered plasminogen and conversion by the tubular urokinase-type plasminogen activator (4,6).…”

Section: Introductionmentioning

confidence: 99%

Association of Plasminuria with Overhydration in Patients with CKD

Schork

Woern

Kalbacher

et al. 2016

CJASN

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Background and objectives Hypervolemia is a common feature of patients with CKD and associated with hypertension. Recent work has shown stimulation of sodium retention by urinary plasmin during nephrotic syndrome. However, it is unclear whether plasminuria plays a role in patients with stable CKD and non-nephrotic proteinuria.Design, setting, participants, & measurements In this cross-sectional study, we analyzed the fluid status of 171 patients with CKD consecutively presenting to our outpatient clinic from 2012 to 2013 using bioimpedance spectroscopy (Body Composition Monitor [BCM]; Fresenius Medical Care, Germany) and its associations to the urinary excretion of plasminogen and plasmin from a spot urine sample. Two-electrode voltage clamp measurements were performed in Xenopus laevis oocytes expressing human epithelial sodium channel to investigate whether plasmin in concentrations found in urine can activate the channel.Results Overhydration .5% and overhydration .10% of the extracellular volume were found in 29% and 17% of the patients, respectively, and overhydration was associated with edema, hypertension, higher stages of CKD, and proteinuria. Proteinuria was the strongest independent predictor for overhydration (+0.58 L/1.73 m 2 per 10-fold increase; P,0.001). Urinary excretion of plasmin(ogen) quantified by ELISA correlated strongly with proteinuria (r=0.87) and overhydration (r=0.47). Using a chromogenic substrate, active plasmin was found in 44% of patients and correlated with proteinuria and overhydration. Estimated urinary plasmin concentrations were in a range sufficient to activate epithelial sodium channel currents in vitro. In multivariable analysis, urinary excretion of plasmin(ogen) was associated with overhydration similar to proteinuria.Conclusions Hypervolemia in patients with CKD is strongly associated with proteinuria, even in the nonnephrotic range. Protein-rich urine contains high amounts of plasminogen and active plasmin, rendering plasminuria as a possible link between proteinuria and hypervolemia.

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Physiological regulation of epithelial sodium channel by proteolysis

Abstract: The discovery of serine protease-mediated activation of renal ENaC in physiological and pathophysiological conditions opens the way for new understanding of the pathogenesis of proteinuric sodium retention, which may involve plasmin and present several potential new drug targets.

Cited by 27 publications

References 64 publications

Potassium Supplementation Prevents Sodium Chloride Cotransporter Stimulation During Angiotensin II Hypertension

Potassium Supplementation Prevents Sodium Chloride Cotransporter Stimulation During Angiotensin II Hypertension

Activation of the Endogenous Renin-Angiotensin-Aldosterone System or Aldosterone Administration Increases Urinary Exosomal Sodium Channel Excretion

Association of Plasminuria with Overhydration in Patients with CKD

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