{"doi":"10.1111/apha.13640","title":"Zymogen‐locked mutant prostasin (Prss8) leads to incomplete proteolytic activation of the epithelial sodium channel (ENaC) and severely compromises triamterene tolerance in mice","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.","journal":"Acta Physiologica","year":2021,"id":173221,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":24,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9494,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":710388,"name":"Alexandr V. Ilyaskin","orcid":"0000-0002-2153-7849","position":1,"is_corresponding":false},{"id":484036,"name":"Matthias Wörn","orcid":null,"position":2,"is_corresponding":false},{"id":483262,"name":"Bernhard N. Bohnert","orcid":"0000-0003-0169-3948","position":3,"is_corresponding":false},{"id":483261,"name":"Mengyun Xiao","orcid":"0000-0002-4489-8794","position":4,"is_corresponding":false},{"id":483268,"name":"Christoph Daniel","orcid":"0000-0002-6803-4755","position":5,"is_corresponding":false},{"id":483269,"name":"Kerstin Amann","orcid":"0000-0001-6116-8315","position":6,"is_corresponding":false},{"id":483270,"name":"Andreas L. Birkenfeld","orcid":"0000-0003-1407-9023","position":7,"is_corresponding":false},{"id":376299,"name":"Roman Szabo","orcid":"0000-0002-7661-8718","position":8,"is_corresponding":false},{"id":371359,"name":"Thomas Bugge","orcid":"0000-0001-7046-4060","position":9,"is_corresponding":false},{"id":509957,"name":"Christoph Korbmacher","orcid":"0000-0003-2127-4185","position":10,"is_corresponding":false},{"id":483271,"name":"Ferruh Artunç","orcid":"0000-0002-3777-9316","position":11,"is_corresponding":false},{"id":483267,"name":"Daniel Essigke","orcid":"0000-0002-1473-377X","position":0,"is_corresponding":true}],"reference_count":50,"raw_metadata":null,"created_at":"2026-07-18T23:46:45.768135Z","pmid":"33650216","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}