Urinary serine proteases and activation of ENaC in kidney—implications for physiological renal salt handling and hypertensive disorders with albuminuria

Svenningsen, Per; Andersen, Henning Haahr; Nielsen, Lise Hald; Jensen, Boye L.

doi:10.1007/s00424-014-1661-5

Cited by 55 publications

(52 citation statements)

References 133 publications

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“…However, after glomerular injury, larger amounts of plasminogen can be filtered and activated in the tubulus lumen. Urokinasetype plasminogen activator lining the tubular epithelium is thought to be the principal enzyme responsible for the generation of active urinary plasmin (2). However, serine protease inhibitors, such as antiplasmin (27) or uristatin (28), have been found to enter the tubular lumen during proteinuria, adding to the complexity of the situation.…”

Section: Discussionmentioning

confidence: 99%

“…The pathogenesis of edema formation is still a matter of debate, and both underfill and overfill mechanisms have been put forward (1). Recent evidence points to the crucial role of proteinuria in promoting sodium retention through activation of the epithelial sodium channel (ENaC) (2), which is known to be an important player in sodium homeostasis and BP control (3). Studies with protein-rich urine from both nephrotic rats and patients have shown a stimulation of ENaC currents in vitro that was attributed to occurrence of the serine protease plasmin in the urine (4,5).…”

Section: Introductionmentioning

confidence: 99%

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Association of Plasminuria with Overhydration in Patients with CKD

Schork

Woern

Kalbacher

et al. 2016

CJASN

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Background and objectives Hypervolemia is a common feature of patients with CKD and associated with hypertension. Recent work has shown stimulation of sodium retention by urinary plasmin during nephrotic syndrome. However, it is unclear whether plasminuria plays a role in patients with stable CKD and non-nephrotic proteinuria.Design, setting, participants, & measurements In this cross-sectional study, we analyzed the fluid status of 171 patients with CKD consecutively presenting to our outpatient clinic from 2012 to 2013 using bioimpedance spectroscopy (Body Composition Monitor [BCM]; Fresenius Medical Care, Germany) and its associations to the urinary excretion of plasminogen and plasmin from a spot urine sample. Two-electrode voltage clamp measurements were performed in Xenopus laevis oocytes expressing human epithelial sodium channel to investigate whether plasmin in concentrations found in urine can activate the channel.Results Overhydration .5% and overhydration .10% of the extracellular volume were found in 29% and 17% of the patients, respectively, and overhydration was associated with edema, hypertension, higher stages of CKD, and proteinuria. Proteinuria was the strongest independent predictor for overhydration (+0.58 L/1.73 m 2 per 10-fold increase; P,0.001). Urinary excretion of plasmin(ogen) quantified by ELISA correlated strongly with proteinuria (r=0.87) and overhydration (r=0.47). Using a chromogenic substrate, active plasmin was found in 44% of patients and correlated with proteinuria and overhydration. Estimated urinary plasmin concentrations were in a range sufficient to activate epithelial sodium channel currents in vitro. In multivariable analysis, urinary excretion of plasmin(ogen) was associated with overhydration similar to proteinuria.Conclusions Hypervolemia in patients with CKD is strongly associated with proteinuria, even in the nonnephrotic range. Protein-rich urine contains high amounts of plasminogen and active plasmin, rendering plasminuria as a possible link between proteinuria and hypervolemia.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Association of Plasminuria with Overhydration in Patients with CKD

Schork

Woern

Kalbacher

et al. 2016

CJASN

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“…Among the three subunits of ENaC, α and γ subunits are activated by cleavage of the inhibitory domain in the extracellular loop, which is mediated by cell-surface or soluble extracellular serine proteases such as prostasin, plasmin and kallikrein (Vallet et al 1997, Narikiyo et al 2002, Svenningsen et al 2015. For example, prostasin promotes the cleavage of the ENaCγ protein inhibitory domain (Narikiyo et al 2002).…”

Section: Mr Signaling In Principal Cells Of the Collecting Ductmentioning

confidence: 99%

30 YEARS OF THE MINERALOCORTICOID RECEPTOR: Mineralocorticoid receptor and NaCl transport mechanisms in the renal distal nephron

Shibata

2017

Journal of Endocrinology

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A key role of aldosterone and mineralocorticoid receptor is to regulate fluid volume and K + homeostasis in the body by acting on the renal distal nephron. Global responses of the kidney to elevated aldosterone levels are determined by the coordinate action of different constituent tubule cells, including principal cells, intercalated cells and distal convoluted tubule cells. Recent studies on genetic mutations causing aldosterone overproduction have identified the molecules involved in aldosterone biosynthesis in the adrenal gland, and there is also increasing evidence for mechanisms and signaling pathways regulating the balance between renal NaCl reabsorption and K + secretion, the two major effects of aldosterone. In particular, recent studies have demonstrated that mineralocorticoid receptor in intercalated cells is selectively regulated by phosphorylation, which prevents ligand binding and activation. Moreover, the ubiquitin ligase complex composed of Kelch-like 3 and Cullin 3 acts downstream of angiotensin II and plasma K + alterations, regulating Na-Cl cotransporter independently of aldosterone in distal convoluted tubule cells. These and other effects are integrated to produce appropriate kidney responses in a high-aldosterone state, and are implicated in fluid and electrolyte disorders in humans. This review summarizes the current knowledge on mechanisms modulating mineralocorticoid receptor and its downstream effectors in the distal nephron.

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“…Each subunit has two membrane-spanning domains and an extracellular loop [27,[30][31][32]. The extracellular domains of α and γ subunits of ENaC are targets for proteases [27,32].…”

Section: Introductionmentioning

confidence: 99%

Analysis of Aprotinin, a Protease Inhibitor, Action on the Trafficking of Epithelial Na+ Channels (ENaC) in Renal Epithelial Cells Using a Mathematical Model

Sasamoto¹,

Marunaka²,

Niisato

et al. 2017

Cell Physiol Biochem

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Background/Aim: Epithelial Na⁺ channels (ENaC) play a crucial role in control of blood pressure by regulating renal Na⁺ reabsorption. Intracellular trafficking of ENaC is one of the key regulators of ENaC function, but a quantitative description of intracellular recycling of endogenously expressed ENaC is unavailable. We attempt here to provide a model for intracellular recycling after applying a protease inhibitor under hypotonic conditions. Methods: We simulated the ENaC-mediated Na⁺ transport in renal epithelial A6 cells measured as short-circuit currents using a four-state mathematical ENaC trafficking model. Results: We developed a four-state mathematical model of ENaC trafficking in the cytosol of renal epithelial cells that consists of: an insertion state of ENaC that can be trafficked to the apical membrane state (insertion rate); an apical membrane state of ENaC conducting Na⁺ across the apical membrane; a recycling state containing ENaC that are retrieved from the apical membrane state (endocytotic rate) and then to the insertion state (recycling rate) communicating with the apical membrane state or to a degradation state (degradation rate). We studied the effect of aprotinin (a protease inhibitor) blocking protease-induced cleavage of the extracellular loop of γ ENaC subunit on the rates of intracellular ENaC trafficking using the above-defined four-state mathematical model of ENaC trafficking and the recycling number relative to ENaC staying in the apical membrane. We found that aprotinin significantly reduced the insertion rate of ENaC to the apical membrane by 40%, the recycling rate of ENaC by 81%, the cumulative time of an individual ENaC staying in the apical membrane by 32%, the cumulative life-time after the first endocytosis of ENaC by 25%, and the cumulative Na⁺ absorption by 31%. The most interesting result of the present study is that cleavage of ENaC affects the intracellular ENaC trafficking rate and determines the residency time of ENaC, indicating that more active cleaved ENaCs stay longer at the apical membrane contributing to transcellular Na⁺ transport via an increase in recycling of ENaC to the apical membrane. Conclusion: The extracellular protease-induced cleavage of the extracellular loop of γ ENaC subunit increases transcellular epithelial Na⁺ transport by elevating the recycling rate of ENaC due to an increase in the recycling rate of ENaCs associated with increases in the insertion rate of ENaC.

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Urinary serine proteases and activation of ENaC in kidney—implications for physiological renal salt handling and hypertensive disorders with albuminuria

Cited by 55 publications

References 133 publications

Association of Plasminuria with Overhydration in Patients with CKD

Association of Plasminuria with Overhydration in Patients with CKD

30 YEARS OF THE MINERALOCORTICOID RECEPTOR: Mineralocorticoid receptor and NaCl transport mechanisms in the renal distal nephron

Analysis of Aprotinin, a Protease Inhibitor, Action on the Trafficking of Epithelial Na+ Channels (ENaC) in Renal Epithelial Cells Using a Mathematical Model

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