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Zymogen-locked mutant prostasin (Prss8) leads to incomplete proteolytic activation of the epithelial sodium channel (ENaC) and severely compromises triamterene tolerance in mice
- Source :
- Acta Physiol. 232:e13640 (2021), Acta Physiol (Oxf)
- Publication Year :
- 2021
-
Abstract
- Aim The serine protease prostasin (Prss8) is expressed in the distal tubule and stimulates proteolytic activation of the epithelial sodium channel (ENaC) in co-expression experiments in vitro. The aim of this study was to explore the role of prostasin in proteolytic ENaC activation in the kidney in vivo. Methods We used genetically modified knockin mice carrying a Prss8 mutation abolishing proteolytic activity (Prss8-S238A) or a mutation leading to a zymogen-locked state (Prss8-R44Q). Mice were challenged with low sodium diet and diuretics. Regulation of ENaC activity by Prss8-S238A and Prss8-R44Q was studied in vitro using the Xenopus laevis oocyte expression system. Results Co-expression of murine ENaC with Prss8-wt or Prss8-S238A in oocytes caused maximal proteolytic ENaC activation, whereas ENaC was activated only partially in oocytes co-expressing Prss8-R44Q. This was paralleled by a reduced proteolytic activity at the cell surface of Prss8-R44Q expressing oocytes. Sodium conservation under low sodium diet was preserved in Prss8-S238A and Prss8-R44Q mice but with higher plasma aldosterone concentrations in Prss8-R44Q mice. Treatment with the ENaC inhibitor triamterene over four days was tolerated in Prss8-wt and Prss8-S238A mice, whereas Prss8-R44Q mice developed salt wasting and severe weight loss associated with hyperkalemia and acidosis consistent with impaired ENaC function and renal failure. Conclusion Unlike proteolytically inactive Prss8-S238A, zymogen-locked Prss8-R44Q produces incomplete proteolytic ENaC activation in vitro and causes a severe renal phenotype in mice treated with the ENaC inhibitor triamterene. This indicates that Prss8 plays a role in proteolytic ENaC activation and renal function independent of its proteolytic activity.
- Subjects :
- 0301 basic medicine
Epithelial sodium channel
medicine.medical_specialty
Physiology
Sodium
food.diet
chemistry.chemical_element
030204 cardiovascular system & hematology
Low sodium diet
Article
03 medical and health sciences
chemistry.chemical_compound
Mice
Xenopus laevis
0302 clinical medicine
food
Zymogen
Internal medicine
medicine
Animals
Epithelial Sodium Channels
Enac
Prostasin
Prss8
Prss8-r44q
Prss8-s238a
Epithelial Sodium Channel
Triamterene
Kidney
Enzyme Precursors
Aldosterone
urogenital system
PRSS8
Serine Endopeptidases
respiratory system
030104 developmental biology
medicine.anatomical_structure
Endocrinology
chemistry
Oocytes
medicine.drug
Subjects
Details
- ISSN :
- 17481716
- Volume :
- 232
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- Acta physiologica (Oxford, England)
- Accession number :
- edsair.doi.dedup.....39dc782ab0453a3ed5733647de3f1fed