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

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Abstract

Serine proteases, both soluble and cell-attached, can activate the epithelial sodium channel (ENaC) proteolytically through release of a putative 43-mer inhibitory tract from the ectodomain of the γ-subunit. ENaC controls renal Na+ excretion and loss-of-function mutations lead to low blood pressure, while gain-of-function mutations lead to impaired Na+ excretion, hypertension, and hypokalemia. We review an emerging pathophysiological concept that aberrant glomerular filtration of plasma proteases, e.g., plasmin, prostasin, and kallikrein, contributes to proteolytic activation of ENaC, both in acute conditions with proteinuria, like nephrotic syndrome and preeclampsia, and in chronic diseases, such as diabetes with microalbuminuria. A vast literature on renin-angiotensin-aldosterone system and volume homeostasis from the last four decades show a number of common characteristics for conditions with albuminuria compatible with impaired renal Na+ excretion: hypertension and volume retention is secondary to proteinuria in, e.g., preeclampsia and nephrotic syndrome; plasma concentrations of renin, angiotensin II, and aldosterone are frequently suppressed in proteinuric conditions, e.g., preeclampsia and diabetic nephropathy; blood pressure is salt-sensitive in conditions with microalbuminuria/proteinuria; and extracellular volume is expanded, plasma atrial natriuretic peptide (ANP) concentration is increased, and diuretics, like amiloride and spironolactone, are effective blood pressure-reducing add-ons. Active plasmin in urine has been demonstrated in diabetes, preeclampsia, and nephrosis. Urine from these patients activates, plasmin-dependently, amiloride-sensitive inward current in vitro. The concept predicts that patients with albuminuria may benefit particularly from reduced salt intake with RAS blockers; that distally acting diuretics, in particular amiloride, are warranted in low-renin/albuminuric conditions; and that urine serine proteases and their activators may be pharmacological targets.

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Acknowledgments

Research in the authors’ lab has been supported by the following sources: The Strategic Research Council (Danish Innovation Foundation), The Danish Research Council for Independent Research - Health Sciences, The Danish Heart Foundation, The Danish Kidney Association, Helen and Ejnar Bjørnow’s Foundation, Odense University Hospital, the Lundbeck Foundation, and The Region of Southern Denmark.

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  1. Department of Cardiovascular and Renal Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark

    Per Svenningsen, Henrik Andersen & Boye L. Jensen

  2. Department of Endocrinology, Odense University Hospital, Odense, Denmark

    Henrik Andersen

  3. Department of Clinical Medicine - Obstetrics and Gynaecology, Aarhus University, Aarhus, Denmark

    Lise H. Nielsen

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  1. Per Svenningsen
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Svenningsen, P., Andersen, H., Nielsen, L.H. et al. Urinary serine proteases and activation of ENaC in kidney—implications for physiological renal salt handling and hypertensive disorders with albuminuria. Pflugers Arch - Eur J Physiol 467, 531–542 (2015). https://doi.org/10.1007/s00424-014-1661-5

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