A variant of ASIC2 mediates sodium retention in nephrotic syndrome

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.

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Collecting Duct Na+/K+-ATPase Activity Is Correlated with Urinary Sodium Excretion in Rat Nephrotic Syndromes

Journal of the American Society of Nephrology ◽

10.1681/asn.v114604 ◽

2000 ◽

Vol 11 (4) ◽

pp. 604-615 ◽

Cited By ~ 6

Author(s):

GEORGES DESCHÊNES ◽

ALAIN DOUCET

Keyword(s):

Nephrotic Syndrome ◽

Atpase Activity ◽

Sodium Excretion ◽

Collecting Duct ◽

Urinary Sodium ◽

Sodium Balance ◽

Brattleboro Rats ◽

Sodium Retention ◽

Puromycin Aminonucleoside ◽

Stimulation Of

Abstract. In puromycin aminonucleoside (PAN)-treated nephrotic rats, sodium retention is associated with increased Na+/K+-ATPase activity in the cortical collecting ducts (CCD). This study was undertaken to determine whether stimulation of Na+/K+-ATPase in the CCD is a feature of other experimental nephrotic syndromes, whether it might be responsible for renal sodium retention, and whether it is mediated by increased plasma vasopressin levels or activation of calcineurin. For this purpose, the time courses of urinary excretion of sodium and protein, sodium balance, ascites, and Na+/K+-ATPase activities in microdissected CCD were studied in rats with PAN or adriamycin nephrosis or HgCl2nephropathy. The role of vasopressin and calcineurin in PAN nephrosis were evaluated by measuring these parameters in Brattleboro rats and in rats treated with cyclosporin or tacrolimus. Despite different patterns of changes in urinary sodium and protein excretion in the three nephrotic syndrome models, there was a linear relationship between CCD Na+/K+-ATPase activities and sodium excretion in all three cases. The results also indicated that there was no correlation between proteinuria and sodium retention, but ascites was present only when proteinuria was associated with marked reduction of sodium excretion. Finally, the lack of vasopressin in Brattleboro rats or the inhibition of calcineurin by administration of either cyclosporin or tacrolimus did not prevent development of the nephrotic syndrome in PAN-treated rats or stimulation of CCD Na+/K+-ATPase. It is concluded that stimulation of Na+/K+-ATPase in the CCD of nephrotic rats might be responsible for sodium retention and that this phenomenon is independent of proteinuria and vasopressin and calcineurin activities.

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Atrial natriuretic peptide, sodium retention, and proteinuria in nephrotic syndrome

Nephrology Dialysis Transplantation ◽

10.1093/ndt/11.6.1034 ◽

1996 ◽

Vol 11 (6) ◽

pp. 1034-1042 ◽

Cited By ~ 7

Author(s):

J. Plum ◽

Y. Mirzaian ◽

B. Grabensee

Keyword(s):

Nephrotic Syndrome ◽

Atrial Natriuretic Peptide ◽

Natriuretic Peptide ◽

Sodium Retention ◽

Atrial Natriuretic

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Increased apical targeting of renal ENaC subunits and decreased expression of 11βHSD2 in HgCl2-induced nephrotic syndrome in rats

AJP Renal Physiology ◽

10.1152/ajprenal.00084.2005 ◽

2006 ◽

Vol 290 (3) ◽

pp. F674-F687 ◽

Cited By ~ 28

Author(s):

Soo Wan Kim ◽

Sophie de Seigneux ◽

Martin C. Sassen ◽

JongUn Lee ◽

Jin Kim ◽

...

Keyword(s):

Nephrotic Syndrome ◽

Sodium Excretion ◽

Collecting Duct ◽

Urinary Sodium Excretion ◽

Brown Norway ◽

Apical Plasma Membrane ◽

Control Group ◽

Sodium Retention ◽

Outer Medulla ◽

Outer Stripe

Nephrotic syndrome is often accompanied by sodium retention and generalized edema. We hypothesize that dysregulation of the epithelial sodium channel (ENaC) and/or of sodium (co)transporters may be responsible for the increased sodium retention associated with HgCl2-induced nephropathy. In addition, we examined the hypothesis that the expression of type 2 11β-hydroxysteroid dehydrogenase (11βHSD2) is reduced, contributing to the enhanced mineralocorticoid activity. Membranous nephropathy was induced in Brown Norway rats by repeated injections of HgCl2 (1 mg/kg sc), whereas the control group received only vehicle. After 13 days of treatment, the abundance of ENaC subunits, sodium (co)transporters, and 11βHSD2 in the kidney was examined by immunoblotting and immunohistochemistry. HgCl2 treatment induced marked proteinuria, hypoalbuminemia, decreased urinary sodium excretion, and ascites. The protein abundance of α-ENaC was increased in the cortex/outer stripe of outer medulla (OSOM) and inner stripe of the outer medulla (ISOM). The protein abundances of β-ENaC and γ-ENaC were decreased in the cortex/OSOM while increased in the ISOM. Immunoperoxidase microscopy demonstrated increased targeting of ENaC subunits to the apical plasma membrane in the distal convoluted tubule, connecting tubule, and cortical and medullary collecting duct segments. Moreover, 11βHSD2 abundance was decreased in cortex/OSOM and ISOM. The protein abundances of type 3 Na/H exchanger (NHE3), Na-K-2Cl cotransporter (NKCC2), and thiazide-sensitive Na-Cl cotransporter (NCC) were decreased. Moreover, the abundance of the α-1 subunit of the Na-K-ATPase was decreased in the cortex/OSOM and ISOM but remained unchanged in the inner medulla. These results suggest that increased apical targeting of ENaC subunits combined with diminished abundance of 11βHSD2 may contribute to sodium retention associated with HgCl2-induced nephrotic syndrome. The decreased abundance of NHE3, NKCC2, NCC, and Na-K-ATPase may play a compensatory role in promoting sodium excretion.

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Plasminogen deficiency does not prevent sodium retention in a genetic mouse model of experimental nephrotic syndrome

Acta Physiologica ◽

10.1111/apha.13512 ◽

2020 ◽

Vol 231 (1) ◽

Author(s):

Mengyun Xiao ◽

Bernhard N. Bohnert ◽

Hande Aypek ◽

Oliver Kretz ◽

Florian Grahammer ◽

...

Keyword(s):

Nephrotic Syndrome ◽

Mouse Model ◽

Sodium Retention ◽

Genetic Mouse Model ◽

Plasminogen Deficiency

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EVIDENCE THAT SOME MECHANISM OTHER THAN THE RENIN SYSTEM CAUSES SODIUM RETENTION IN NEPHROTIC SYNDROME

The Lancet ◽

10.1016/s0140-6736(82)90102-7 ◽

1982 ◽

Vol 320 (8310) ◽

pp. 1237-1240 ◽

Cited By ~ 48

Author(s):

EdwinaA. Brown ◽

GiuseppeA. Sagnella ◽

BarbaraE. Jones ◽

NirmalaD. Markandu ◽

Marilyn Squires ◽

...

Keyword(s):

Nephrotic Syndrome ◽

Sodium Retention

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Role of renal nerves in renal sodium retention of nephrotic syndrome

AJP Renal Physiology ◽

10.1152/ajprenal.1989.256.5.f823 ◽

1989 ◽

Vol 256 (5) ◽

pp. F823-F829 ◽

Cited By ~ 5

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.

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Sodium Retention in Nephrotic Syndrome Is Due to an Intrarenal Defect: Evidence from Steroid-Induced Remission

Nephron ◽

10.1159/000183392 ◽

1985 ◽

Vol 39 (4) ◽

pp. 290-295 ◽

Cited By ~ 30

Author(s):

Edwina A. Brown ◽

Nirmala Markandu ◽

Giuseppe A. Sagnella ◽

Barbara E. Jones ◽

Graham A. MacGregor

Keyword(s):

Nephrotic Syndrome ◽

Sodium Retention

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

AJP Renal Physiology ◽

10.1152/ajprenal.1996.271.1.f3 ◽

1996 ◽

Vol 271 (1) ◽

pp. F3-F6 ◽

Cited By ~ 2

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.

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