Abstract: SA-PO1054

Cathepsin B Mediated ENaC Activation in Nephrotic Syndrome

Session Information

  • Na+, K+, Cl-
    November 04, 2017 | Location: Hall H, Morial Convention Center
    Abstract Time: 10:00 AM - 10:00 AM

Category: Fluid, Electrolytes, and Acid-Base

  • 703 Na+, K+, Cl- Basic

Authors

  • Larionov, Alexey, University of Fribourg, Fribourg, Switzerland
  • Alli, Abdel A., University of FL, Gainesville, Florida, United States
  • Mollet, Geraldine, Inserm U1163, Paris, France
  • Theilig, Franziska, University of Fribourg, Fribourg, Switzerland
Background

Patients with nephrotic syndrome (NS) often present symptoms of volume retention, such as edema formation or hypertension. The primary dysregulation was localized to the renal cortical collecting duct and involves an inappropriate activation of the epithelial sodium channel, ENaC. Plasma proteases passing the leaky glomerular filter were made responsible; however clinical observations demonstrate volume retention before the onset of proteinuria.

Methods

To elucidate its relationship and the underlying mechanisms, inducible podocyte-specificCre; Nphs2fl/fl developing FSGS with NS was used.

Results

Analysis of renal functional parameters from NS mice revealed sodium retention between day 4 – 7, hypertension and proteinuria starting at day 10 and 12 after FSGS induction. Morphological and biochemical analysis of NS mice kidneys demonstrated at 5 and 9 days increased full-length α- and γENaC expression and proteolytical cleavage of αENaC, and at 17 days increased full-length ENaC and cleaved subunit expression. Aldosterone and vasopressin levels remained unaltered. Urine analysis from NS mice revealed proteolytic activity starting at day 2 after FSGS induction which increased over the time. Urine from day 2 – 9 of NS mice was separated by HPLC and proteases of proteolytic fractions were identified by mass spectrometry. From the identified proteases cathepsin B cleaved αENaC and cathepsin D and legumain cleaved γENaC and all of them resulted in increased ENaC activity.

Conclusion

We identified cathepsin B induced proteolytical activation of αENaC as a new mechanism of volume retention in NS early in FSGS development. Cathepsin D and legumain are new γENaC cleaving proteases; their role needs to be further clarified.

Funding

  • Government Support - Non-U.S.