XB-ART-54628Acta Physiol (Oxf). February 28, 2018;
Plasma kallikrein activates the epithelial sodium channel (ENaC) in vitro but is not essential for volume retention in nephrotic mice.
AIM: Recent work has demonstrated that activation of the epithelial sodium channel (ENaC) by aberrantly filtered serine proteases causes sodium retention in nephrotic syndrome. The aim of this study was to elucidate a potential role of plasma kallikrein (PKLK) as a candidate serine protease in this context. METHODS: We analyzed PKLK in the urine of patients with chronic kidney disease (CKD, n=171) and investigated its ability to activate human ENaC expressed in Xenopus laevis oocytes. Moreover, we studied sodium retention in PKLK deficient mice (klkb1 -/- ) with experimental nephrotic syndrome induced by doxorubicin injection. RESULTS: In CKD patients, we found that PKLK is excreted in the urine up to a concentration of 2 μg mL -1 which was correlated with albuminuria (r=0.71) and overhydration as assessed by bioimpedance spectroscopy (r=0.44). PKLK increased ENaC-mediated whole-cell currents, which was associated with the appearance of a 67 kDa γ-ENaC cleavage product at the cell surface consistent with proteolytic activation. Mutating a putative prostasin cleavage site in γ-ENaC prevented channel stimulation by PKLK. In a mouse model for nephrotic syndrome active PKLK was present in nephrotic urine of klkb1 +/+ but not of klkb1 -/- mice. However,klkb1 -/- mice were not protected from ENaC activation and sodium retention compared to nephrotic klkb1 +/+ mice. CONCLUSION: PKLK is detected in the urine of proteinuric patients and mice and activates ENaC in vitro involving the putative prostasin cleavage site. However, PKLK is not essential for volume retention in nephrotic mice. This article is protected by copyright. All rights reserved.
PubMed ID: 29489063
Article link: Acta Physiol (Oxf).