scholarly journals Hyperaldosteronemia and Activation of the Epithelial Sodium Channel Are Not Required for Sodium Retention in Puromycin-Induced Nephrosis

2005 ◽  
Vol 16 (12) ◽  
pp. 3642-3650 ◽  
Author(s):  
Stéphane Lourdel ◽  
Johannes Loffing ◽  
Guillaume Favre ◽  
Marc Paulais ◽  
Antoine Nissant ◽  
...  
Keyword(s):  
Sodium Channel ◽  
Epithelial Sodium Channel ◽  
Sodium Retention

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.

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.

Renal NOXA1/NOX1 Signaling Regulates Epithelial Sodium Channel and Sodium Retention in Angiotensin II-induced Hypertension

2021 ◽  
Author(s):  
Aleksandr Vendrov ◽  
Mark D. Stevenson ◽  
Andrey Lozhkin ◽  
Takayuki Hayami ◽  
Nathan A Holland ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Sodium Channel ◽  
Epithelial Sodium Channel ◽  
Sodium Retention ◽  
Induced Hypertension

scholarly journals Epithelial Sodium Channel Is a Key Mediator of Growth Hormone-Induced Sodium Retention in Acromegaly

Endocrinology ◽  
2008 ◽  
Vol 149 (7) ◽  
pp. 3294-3305 ◽  
Author(s):  
Peter Kamenicky ◽  
Say Viengchareun ◽  
Anne Blanchard ◽  
Geri Meduri ◽  
Philippe Zizzari ◽  
...  
Keyword(s):  
Sodium Channel ◽  
Sodium Transport ◽  
Epithelial Sodium Channel ◽  
Janus Kinase ◽  
Sodium Reabsorption ◽  
Sodium Retention ◽  
Signal Transducer ◽  
Distal Nephron ◽  
Igf I ◽  
Gc Rats

Acromegalic patients present with volume expansion and arterial hypertension, but the renal sites and molecular mechanisms of direct antinatriuretic action of GH remain unclear. Here, we show that acromegalic GC rats, which are chronically exposed to very high levels of GH, exhibited a decrease of furosemide-induced natriuresis and an increase of amiloride-stimulated natriuresis compared with controls. Enhanced Na+,K+-ATPase activity and altered proteolytic maturation of epithelial sodium channel (ENaC) subunits in the cortical collecting ducts (CCDs) of GC rats provided additional evidence for an increased sodium reabsorption in the late distal nephron under chronic GH excess. In vitro experiments on KC3AC1 cells, a murine CCD cell model, revealed the expression of functional GH receptors and IGF-I receptors coupled to activation of Janus kinase 2/signal transducer and activator of transcription 5, ERK, and AKT signaling pathways. That GH directly controls sodium reabsorption in CCD cells is supported by: 1) stimulation of transepithelial sodium transport inhibited by GH receptor antagonist pegvisomant; 2) induction of α-ENaC mRNA expression; and 3) identification of signal transducer and activator of transcription 5 binding to a response element located in the α-ENaC promoter, indicative of the transcriptional regulation of α-ENaC by GH. Our findings provide the first evidence that GH, in concert with IGF-I, stimulates ENaC-mediated sodium transport in the late distal nephron, accounting for the pathogenesis of sodium retention in acromegaly.

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