scholarly journals Proteolytic Activation of the Epithelial Sodium Channel in Nephrotic Syndrome by Proteasuria: Concept and Therapeutic Potential

2020 ◽  
Vol 29 (1) ◽  
pp. 59-65 ◽  
Author(s):  
Ferruh Artunc ◽  
Keyword(s):  
Nephrotic Syndrome ◽  
Sodium Channel ◽  
Therapeutic Potential ◽  
Epithelial Sodium Channel ◽  
Proteolytic Activation

Experimental nephrotic syndrome leads to proteolytic activation of the epithelial sodium channel (ENaC) in the mouse kidney

2021 ◽  
Author(s):  
Bernhard N. Bohnert ◽  
Daniel Essigke ◽  
Andrea Janessa ◽  
Jonas C Schneider ◽  
Matthias Wörn ◽  
...  
Keyword(s):  
Nephrotic Syndrome ◽  
Sodium Channel ◽  
Serine Protease ◽  
Cleavage Site ◽  
Mineralocorticoid Receptor ◽  
Epithelial Sodium Channel ◽  
Sodium Retention ◽  
Cleavage Sites ◽  
Proteolytic Activation ◽  
Epithelial Sodium Channel Enac

Proteolytic activation of the renal epithelial sodium channel ENaC involves cleavage events in its α- and γ-subunits and is thought to mediate sodium retention in nephrotic syndrome (NS). However, detection of proteolytically processed ENaC in kidney tissue from nephrotic mice has been elusive so far. We used a refined Western blot technique to reliably discriminate full-length α- and γ-ENaC and their cleavage products after proteolysis at their proximal and distal cleavage sites (designated from the N-terminus), respectively. Proteolytic ENaC activation was investigated in kidneys from mice with experimental NS induced by doxorubicin or inducible podocin deficiency with or without treatment with the serine protease inhibitor aprotinin. Nephrotic mice developed sodium retention and increased expression of fragments of α- and γ-ENaC cleaved at both the proximal and more prominently at the distal cleavage site, respectively. Treatment with aprotinin but not with the mineralocorticoid receptor antagonist canrenoate prevented sodium retention and upregulation of the cleavage products in nephrotic mice. Increased expression of cleavage products of α- and γ-ENaC was similarly found in healthy mice treated with a low salt diet, sensitive to mineralocorticoid receptor blockade. In human nephrectomy specimens, γ-ENaC was found in the full-length form and predominantly cleaved at its distal cleavage site. In conclusion, murine experimental NS leads to aprotinin-sensitive proteolytic activation of ENaC at both proximal and more prominently distal cleavage sites of its α- and γ-subunit, most likely by urinary serine protease activity or proteasuria.

Proteolytic activation of the epithelial sodium channel, ENaC in preeclampsia examined with urinary exosomes

Placenta ◽  
2014 ◽  
Vol 35 (9) ◽  
pp. A79-A80
Author(s):  
Maria R. Nielsen ◽  
Mie R. Hansen ◽  
Britta Frederiksen-Møller ◽  
Per Svenningsen ◽  
Rikke M. Zachar ◽  
...  
Keyword(s):  
Sodium Channel ◽  
Epithelial Sodium Channel ◽  
Proteolytic Activation ◽  
Urinary Exosomes ◽  
Epithelial Sodium Channel Enac

scholarly journals Truncated Variant of ASIC2b Confers Epithelial Sodium Channel Properties to ASIC2: Role in Nephrotic Syndrome

2015 ◽  
Vol 29 (S1) ◽  
Author(s):  
Alain Doucet ◽  
Ali Sassi ◽  
Gaelle Brideau ◽  
Lydie Cheval ◽  
Bruno Vogt ◽  
...  
Keyword(s):  
Nephrotic Syndrome ◽  
Sodium Channel ◽  
Epithelial Sodium Channel ◽  
Channel Properties

scholarly journals Proteolytic activation of the epithelial sodium channel (ENaC) by factor VII activating protease (FSAP) and its relevance for sodium retention in nephrotic mice

2021 ◽  
Author(s):  
Ferruh Artunc ◽  
Bernhard N. Bohnert ◽  
Jonas C. Schneider ◽  
Tobias Staudner ◽  
Florian Sure ◽  
...  
Keyword(s):  
Nephrotic Syndrome ◽  
Sodium Channel ◽  
Serine Protease ◽  
Cleavage Site ◽  
Factor Vii ◽  
Sodium Retention ◽  
Protease Domain ◽  
Proteolytic Activation ◽  
Serine Protease Domain ◽  
Epithelial Sodium Channel Enac

AbstractProteolytic activation of the epithelial sodium channel (ENaC) by aberrantly filtered serine proteases is thought to contribute to renal sodium retention in nephrotic syndrome. However, the identity of the responsible proteases remains elusive. This study evaluated factor VII activating protease (FSAP) as a candidate in this context. We analyzed FSAP in the urine of patients with nephrotic syndrome and nephrotic mice and investigated its ability to activate human ENaC expressed in Xenopus laevis oocytes. Moreover, we studied sodium retention in FSAP-deficient mice (Habp2−/−) with experimental nephrotic syndrome induced by doxorubicin. In urine samples from nephrotic humans, high concentrations of FSAP were detected both as zymogen and in its active state. Recombinant serine protease domain of FSAP stimulated ENaC-mediated whole-cell currents in a time- and concentration-dependent manner. Mutating the putative prostasin cleavage site in γ-ENaC (γRKRK178AAAA) prevented channel stimulation by the serine protease domain of FSAP. In a mouse model for nephrotic syndrome, active FSAP was present in nephrotic urine of Habp2+/+ but not of Habp2−/− mice. However, Habp2−/− mice were not protected from sodium retention compared to nephrotic Habp2+/+ mice. Western blot analysis revealed that in nephrotic Habp2−/− mice, proteolytic cleavage of α- and γ-ENaC was similar to that in nephrotic Habp2+/+ animals. In conclusion, active FSAP is excreted in the urine of nephrotic patients and mice and activates ENaC in vitro involving the putative prostasin cleavage site of γ-ENaC. However, endogenous FSAP is not essential for sodium retention in nephrotic mice.

Pathogenesis of oedema in nephrotic syndrome: Role of epithelial sodium channel

Nephrology ◽  
2007 ◽  
Vol 12 (s3) ◽  
pp. S8-S10 ◽  
Author(s):  
SOO WAN KIM ◽  
JØRGEN FRØKIÆR ◽  
SØREN NIELSEN
Keyword(s):  
Nephrotic Syndrome ◽  
Sodium Channel ◽  
Epithelial Sodium Channel

Association of Urinary Plasminogen-Plasmin with Edema and Epithelial Sodium Channel Activation in Patients with Nephrotic Syndrome

2019 ◽  
Vol 50 (2) ◽  
pp. 92-104 ◽  
Author(s):  
Jun-Liang Chen ◽  
Li Wang ◽  
Xing-Mei Yao ◽  
Ying-Jun Zang ◽  
Yi Wang ◽  
...  
Keyword(s):  
Nephrotic Syndrome ◽  
Sodium Channel ◽  
Influencing Factor ◽  
Fractional Excretion ◽  
Epithelial Sodium Channel ◽  
Pathophysiological Mechanism ◽  
Sodium Retention ◽  
Edema Formation ◽  
Fractional Excretion Of Sodium ◽  
Serial Samples

Background: Previous animal experiments and small human studies suggest that urinary plasmin can activate the epithelial sodium channel (ENaC) and contribute to sodium retention in nephrotic syndrome (NS), but this however is not well studied in clinical settings, and its relevance to edema formation is not well characterized in humans. We have investigated the association between urinary plasmin and clinical phenotypes in a large group of patients with NS from multiple etiologies, aiming to assess the role of urinary plasmin in sodium handling and edema formation. Methods: Two hundred and three NS patients with urine and blood samples were divided into mild and severe symptom groups based on their edema severity. Twenty six of them had serial samples collected during the course of immunosuppressive therapy. The plasminogen-plasmin level and other key parameters were assayed, and their association with clinical manifestations were analyzed. Results: One hundred and one of the 203 patients had renal biopsies performed, the results of which had included all the common types of primary NS and various types of secondary NS. Quantitative comparison and multivariate logistic regression analysis identified urinary plasminogen-plasmin to creatinine ratio (uPLG-PL/C), serum albumin, D-Dimer, and cardiac dysfunction history, but not albuminuria or 24-h urine protein, as independent risk factors for edema (p < 0.01). In patients who were treated and had serial samples, a decrease in uPLG-PL/C was identified as an independent influencing factor of edema remission (p < 0.01). Finally, the urinary fractional excretion of sodium (FENa) in patients was inversely correlated with the fractional excretion of potassium (FEK; p< 0.001), and FEK/FENa ratio was positively correlated with uPLG-PL/C (p < 0.001), suggesting a close association between uPLG-PL and ENaC activation. Conclusions: Our study identifies uPLG-PL abundance as an independent influencing factor of edema in adult NS patients, and supports the conclusion that plasmin-dependent ENaC activation is an important pathophysiological mechanism of sodium retention and edema formation in humans with NS.

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