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.

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.

Role of renal nerves in renal sodium retention of nephrotic syndrome

1989 ◽  
Vol 256 (5) ◽  
pp. F823-F829 ◽  
Author(s):  
P. J. Herman ◽  
L. L. Sawin ◽  
G. F. DiBona
Keyword(s):  
Nephrotic Syndrome ◽  
Renal Denervation ◽  
Sodium Content ◽  
Vehicle Control ◽  
Dietary Sodium ◽  
Sodium Balance ◽  
Renal Nerves ◽  
Sodium Retention ◽  
Edema Formation

To define the role of the renal nerves in the renal sodium retention of the nephrotic syndrome, experiments were conducted in rats given adriamycin to produce nephrotic syndrome. All rats developed proteinuria and hypoalbuminemia and exhibited edema formation. Adriamycin-injected nephrotic rats were subjected to bilateral renal denervation (ADRIADNX) or sham renal denervation (ADRIASHAM). Rats injected with adriamycin vehicle were subjected to bilateral renal denervation (DNX) or sham renal denervation (SHAM). Metabolic balance studies were carried out in all rats beginning on the 8th day after bilateral or sham renal denervation. Dietary sodium content was 210 meq/kg Na on days 8-12 and days 24-26 and was 10 meq/kg Na on days 13-23. Nephrotic rats demonstrated significantly greater overall (19 days) cumulative sodium balance than vehicle control rats, ADRIASHAM 8.47 +/- 0.81 vs. SHAM 5.74 +/- 0.34 meq Na, P less than 0.01. Bilateral renal denervation did not significantly affect overall cumulative sodium balance in the vehicle control rats, DNX 6.15 +/- 0.71 vs. SHAM 5.74 +/- 0.34 meq Na. However, bilateral renal denervation significantly decreased overall cumulative sodium balance in the nephrotic rats, ADRIADNX 6.59 +/- 0.56 vs. ADRIASHAM 8.47 +/- 0.81 meq Na, P less than 0.01. Results indicated that the increased renal sodium retention characteristic of nephrotic syndrome is dependent, in large part, on increased efferent renal sympathetic nerve activity.

Phosphodiesterase activity as a mediator of renal resistance to ANP in pathological salt retention

1996 ◽  
Vol 271 (1) ◽  
pp. F3-F6 ◽  
Author(s):  
E. Y. Lee ◽  
M. H. Humphreys
Keyword(s):  
Nephrotic Syndrome ◽  
Natriuretic Peptide ◽  
Collecting Duct ◽  
Biologically Active ◽  
Sodium Retention ◽  
Phosphodiesterase Activity ◽  
Edema Formation ◽  
Novel Approach ◽  
Medullary Collecting Duct ◽  
Clinical Conditions

Resistance to the natriuretic action of atrial natriuretic peptide (ANP) is a hallmark of states of pathological sodium retention including congestive heart failure, cirrhosis of the liver, and nephrotic syndrome. A variety of mechanisms including reduced delivery of filtrate to ANP-sensitive sites in the inner medullary collecting duct and diminished receptor density in this tubular segment have been offered to account for this resistance. Recent studies in experimental nephrotic syndrome and in liver disease produced by ligation of the common bile duct in rats suggest that increased activity of cyclic guanosine 3',5'-monophosphate (cGMP) phosphodiesterase may be an important mediator of renal resistance to ANP. Such increased enzyme activity rapidly catabolizes the second messenger cGMP, normally formed when ANP interacts with its biologically active natriuretic peptide A receptors, thereby leading to blunted ANP responsiveness. This increased phosphodiesterase activity offers a novel approach to the management of clinical conditions associated with sodium retention and edema formation.

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.

scholarly journals Inferior Vena Cava Collapsibility Index: A Precise Non-invasive Tool for Evaluation of Edema in Children with Nephrotic Syndrome.

2021 ◽  
Author(s):  
Hanan El-Halaby ◽  
Ashraf Bakr ◽  
Mohamed El-Assmy ◽  
Hussein Abdelaziz Abdalla ◽  
Marwa Salem ◽  
...  
Keyword(s):  
Nephrotic Syndrome ◽  
Inferior Vena Cava ◽  
Inferior Vena ◽  
Vena Cava ◽  
Fractional Excretion ◽  
Volume Status ◽  
Non Invasive ◽  
Collapsibility Index ◽  
Fractional Excretion Of Sodium ◽  
Status Assessment

Abstract Evaluating the volume status in children with Idiopathic nephrotic syndrome (INS) is mandatory to guide treatment and avoid unnecessary possibly hazardous albumin use. This study aimed to evaluate and compare the available tools used for volume status assessment and differentiating type of edema in children with INS. Sixty children with active INS were included and subdivided into hypovolemic and non-hypovolemic groups based on fractional excretion of sodium (FeNa%) and clinical assessment. All patients were studied for Inferior vena cava collapsibility index (IVCCI), plasma atrial natriuretic peptide (ANP) concentration and Body composition monitor (BCM). Forty-four patients (77.3%) had non-hypovolemic and 16 (26.7%) had hypovolemic states. Plasma ANP levels didn’t differ between hypovolemic and non-hypovolemic subgroups. IVCCI was higher in hypovolemic group (p<0.001) with sensitivity 87.5% and specificity 81.8% for hypovolemia detection while BCM-over hydration (BCM-OH) values were higher in non-hypovolemic group (p=0.04) with sensitivity= 68.2% and specificity =75% for detection of hypervolemia. FeNa% showed negative significant correlation with IVCCI (r= -0.578, p <0.001) and positive significant correlation with BCM-OH (r= 0.33, p=0.018), while FeNa% showed non-significant correlation to plasma ANP concentration (p=0.25). Conclusion: Non-hypovolemic edema is more frequent in edematous INS children than hypovolemic states. IVCCI is a reliable non-invasive bedside tool for evaluating volume status in INS children and is superior to BCM while plasma ANP levels can’t discriminate type of edema in INS.

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
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