Nephrotic syndrome is associated with increased plasma K+concentration, intestinal K+losses, and attenuated urinary K+excretion: a study in rats and humans

Ydegaard, Rikke; Svenningsen, Per; Bistrup, Claus; Andersen, Rebecca; Stubbe, Jane; Buhl, Kristian Bergholt; Marcussen, Niels; Hinrichs, Gitte Rye; Iraqi, Hiba; Zamani, Reza; Dimke, Henrik; Jensen, Boye L.

doi:10.1152/ajprenal.00179.2019

Cited by 4 publications

(6 citation statements)

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“…In the nephrotic state, plasma potassium concentrations were significantly increased compared to the baseline in both genotypes. This has been analogously shown in nephrotic rats 25 . In nephrotic nphs2 Δipod *plg −/− mice, mild hypernatremia was present (Table 2).…”

Section: Resultssupporting

confidence: 81%

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

et al. 2020

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Aim Sodium retention is the hallmark of nephrotic syndrome (NS) and mediated by the proteolytic activation of the epithelial sodium channel (ENaC) by aberrantly filtered serine proteases. Plasmin is highly abundant in nephrotic urine and has been proposed to be the principal serine protease responsible for ENaC activation in NS. However, a proof of the essential role of plasmin in experimental NS is lacking. Methods We used a genetic mouse model of NS based on an inducible podocin knockout (Bl6‐Nphs2tm3.1Antc*Tg(Nphs1‐rtTA*3G)8Jhm*Tg(tetO‐cre)1Jaw or nphs2Δipod). These mice were crossed with plasminogen deficient mice (Bl6‐Plgtm1Jld or plg−/−) to generate double knockout mice (nphs2Δipod*plg−/−). NS was induced after oral doxycycline treatment for 14 days and mice were followed for subsequent 14 days. Results Uninduced nphs2Δipod*plg−/− mice had normal kidney function and sodium handling. After induction, proteinuria increased similarly in both nphs2Δipod*plg+/+ and nphs2Δipod*plg−/− mice. Western blot revealed the urinary excretion of plasminogen and plasmin in nphs2Δipod*plg+/+ mice which were absent in nphs2Δipod*plg−/− mice. After the onset of proteinuria, amiloride‐sensitive natriuresis was increased compared to the uninduced state in both genotypes. Subsequently, urinary sodium excretion dropped in both genotypes leading to an increase in body weight and development of ascites. Treatment with the serine protease inhibitor aprotinin prevented sodium retention in both genotypes. Conclusions This study shows that mice lacking urinary plasminogen are not protected from ENaC‐mediated sodium retention in experimental NS. This points to an essential role of other urinary serine proteases in the absence of plasminogen.

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Section: Resultssupporting

confidence: 81%

“…This has been analogously shown in nephrotic rats. 25 In nephrotic nphs2 Δipod *plg −/− mice, mild hypernatremia was present ( Table 2).…”

Section: Nephrotic Nphs2 δIpod *Plg +/+ and Nphs2 δIpod *Plg −/− MImentioning

confidence: 99%

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

et al. 2020

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“…In the nephrotic state, plasma potassium concentrations were significantly increased compared to baseline in Prss8-wt and Prss8-R44Q mice. This has been analogously shown in nephrotic rats [ 38 ] and mice [ 15 ].…”

Section: Resultssupporting

confidence: 79%

Sodium retention in nephrotic syndrome is independent of the activation of the membrane-anchored serine protease prostasin (CAP1/PRSS8) and its enzymatic activity

Essigke

Bohnert

Janessa³

et al. 2022

Pflugers Arch - Eur J Physiol

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Experimental nephrotic syndrome leads to activation of the epithelial sodium channel (ENaC) by proteolysis and promotes renal sodium retention. The membrane-anchored serine protease prostasin (CAP1/PRSS8) is expressed in the distal nephron and participates in proteolytic ENaC regulation by serving as a scaffold for other serine proteases. However, it is unknown whether prostasin is also involved in ENaC-mediated sodium retention of experimental nephrotic syndrome. In this study, we used genetically modified knock-in mice with Prss8 mutations abolishing its proteolytic activity (Prss8-S238A) or prostasin activation (Prss8-R44Q) to investigate the development of sodium retention in doxorubicin-induced nephrotic syndrome. Healthy Prss8-S238A and Prss8-R44Q mice had normal ENaC activity as reflected by the natriuretic response to the ENaC blocker triamterene. After doxorubicin injection, all genotypes developed similar proteinuria. In all genotypes, urinary prostasin excretion increased while renal expression was not altered. In nephrotic mice of all genotypes, triamterene response was similarly increased, consistent with ENaC activation. As a consequence, urinary sodium excretion dropped in all genotypes and mice similarly gained body weight by + 25 ± 3% in Prss8-wt, + 20 ± 2% in Prss8-S238A and + 28 ± 3% in Prss8-R44Q mice (p = 0.16). In Western blots, expression of fully cleaved α- and γ-ENaC was similarly increased in nephrotic mice of all genotypes. In conclusion, proteolytic ENaC activation and sodium retention in experimental nephrotic syndrome are independent of the activation of prostasin and its enzymatic activity and are consistent with the action of aberrantly filtered serine proteases or proteasuria.

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“…In the same line, nephrotic patients have elevated plasma potassium levels independent of GFR decline before corticosteroid initiation [109].…”

Section: Secondary Dysfunction Of the Ion And Water Transport System ...mentioning

confidence: 97%

Mechanistic insights into the primary and secondary alterations of renal ion and water transport in the distal nephron

Tabibzadeh

Crambert

2022

J Intern Med

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Nephrotic syndrome is associated with increased plasma K⁺concentration, intestinal K⁺losses, and attenuated urinary K⁺excretion: a study in rats and humans

Cited by 4 publications

References 54 publications

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

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

Sodium retention in nephrotic syndrome is independent of the activation of the membrane-anchored serine protease prostasin (CAP1/PRSS8) and its enzymatic activity

Mechanistic insights into the primary and secondary alterations of renal ion and water transport in the distal nephron

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