Inhibition of the inflammasome ameliorates orthologous polycystic kidney disease

• 成果类型: Article
• 署名作者: Liu, Junwei; Rogg, Manuel; Moos, Katharina; Sasanpour, Shaya; Strassl, Vera; Jain, Manaswita; Magassa, Sato; Neubauer, Bjorn; Braeg, Simone; Saller, Benedikt S.; Weisser, Lisa; Bienaime, Frank; Gorka, Oliver; Boerries, Melanie; Viau, Amandine; Gross, Olaf; Schell, Christoph; Kuehn, E. Wolfgang
• 署名单位: University of Freiburg; University of Freiburg; University of Freiburg; University of Freiburg; University of Freiburg; University of Freiburg; Universite Paris Cite; Assistance Publique Hopitaux Paris (APHP); Hopital Universitaire Necker-Enfants Malades - APHP; Institut National de la Sante et de la Recherche Medicale (Inserm); Universite Paris Cite; University of Freiburg; Helmholtz Association; German Cancer Research Center (DKFZ); Helmholtz Association; German Cancer Research Center (DKFZ); University of Freiburg; Universite Paris Cite; Institut National de la Sante et de la Recherche Medicale (Inserm); University of Freiburg; University of Freiburg; University of Freiburg; University of Freiburg
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2511204122
• 发表日期: 2025-11-18
• 页码: e2511204122
• 关键词: ADPKD; inflammasome; PKD1 mouse model; nlrp3 inflammasome; TOLVAPTAN; biomarkers; protein-1; il-1-beta; mutations; excretion; fibrosis; MODEL

摘要

Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic kidney disease. Limited treatment options lead to renal failure in the vast majority of affected individuals. Novel therapeutic approaches are needed. Recent evidence has identified inflammation as an important driver of ADPKD. We analyzed transcriptional profiles in an orthologous Pkd1 mouse model and found a strong upregulation of the inflammasome pathway. To investigate the role of inflammasomes on cyst formation and kidney function, we modulated inflammasome activity through genetic targeting of the essential inflammasome component Pycard/Asc or treatment with the inflammasome inhibitor MCC950. Genetic deletion of Pycard/Asc in Pkd1 mutant mice significantly reduced cyst formation, and kidney function was improved. Reductions were seen in inflammation, fibrosis, and urinary excretion of IL-18. Analogous results were obtained through tubule-specific inactivation of Pycard/Asc or treatment of Pkd1 mutant mice with the inflammasome inhibitor MCC950. These findings demonstrate that inflammasomes act as drivers of disease severity in an orthologous mouse model of ADPKD. We pinpoint a separate, epithelial pool of inflammasomes in the diseased kidney and identify inflammasome inhibition as a promising strategy for the treatment ofADPKD.