{"title":"Low Potassium Triggers Tubular Epithelial NLR Family Pyrin Domain-Containing 3/Apoptosis-Associated Speck-Like Protein-Containing CARD-Driven Kidney Inflammation Independently of Inflammasomes.","authors":"Satoko Komori, Takanori Komada, Takayoshi Matsumura, Tadayoshi Karasawa, Yutaka Miura, Chintogtokh Baatarjav, Yoshitaka Gunji, Hidetoshi Aizawa, Yoshiko Mizushina, Noriyoshi Fukushima, Toru Sugihara, Satoshi Ando, Tetsuya Fujimura, Daisuke Nagata, Masafumi Takahashi","doi":"10.1016/j.ajpath.2025.08.010","DOIUrl":null,"url":null,"abstract":"<p><p>Pathologic potassium (K<sup>+</sup>) deficiency causes kidney inflammation and injury, known as hypokalemic nephropathy (HN), the underlying pathogenesis of which is obscure. NLR family pyrin domain-containing 3 (NLRP3) inflammasomes are platforms that sense the reduction of intracellular K<sup>+</sup>, engaging inflammation and tissue injury. The present study investigated whether or not systemic K<sup>+</sup> deficiency induces NLRP3 inflammasome activation in HN. Clinically diagnosed HN in humans manifested up-regulation of NLRP3 and apoptosis-associated speck-like protein-containing CARD (ASC) in the kidney epithelia. A K<sup>+</sup> depletion model in mice demonstrated that kidney-resident NLRP3 and ASC play key roles in triggering early inflammation in HN kidneys. Unexpectedly, the K<sup>+</sup> depletion-induced kidney inflammation was not dependent on inflammasome activation. A single-cell RNA-sequencing analysis revealed ASC up-regulation, NF-κB activation, and an increased level of tumor necrosis factor-like weak inducer of apoptosis receptor FN14 in the HN kidneys, primarily in the distal nephron/collecting duct epithelial cells. Although kidney epithelial cells did not drive NLRP3 inflammasomes, NLRP3 and ASC alternatively enhanced with-no-lysine kinase-dependent NF-κB signaling in response to tumor necrosis factor-like weak inducer of apoptosis under a low-K<sup>+</sup> milieu. These findings indicate a unique proinflammatory cascade mediated by NLRP3 and ASC beyond the framework of inflammasomes, which broadens the understanding of electrolyte-associated immunity in the kidney.</p>","PeriodicalId":7623,"journal":{"name":"American Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":3.6000,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"American Journal of Pathology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.ajpath.2025.08.010","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"PATHOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Pathologic potassium (K+) deficiency causes kidney inflammation and injury, known as hypokalemic nephropathy (HN), the underlying pathogenesis of which is obscure. NLR family pyrin domain-containing 3 (NLRP3) inflammasomes are platforms that sense the reduction of intracellular K+, engaging inflammation and tissue injury. The present study investigated whether or not systemic K+ deficiency induces NLRP3 inflammasome activation in HN. Clinically diagnosed HN in humans manifested up-regulation of NLRP3 and apoptosis-associated speck-like protein-containing CARD (ASC) in the kidney epithelia. A K+ depletion model in mice demonstrated that kidney-resident NLRP3 and ASC play key roles in triggering early inflammation in HN kidneys. Unexpectedly, the K+ depletion-induced kidney inflammation was not dependent on inflammasome activation. A single-cell RNA-sequencing analysis revealed ASC up-regulation, NF-κB activation, and an increased level of tumor necrosis factor-like weak inducer of apoptosis receptor FN14 in the HN kidneys, primarily in the distal nephron/collecting duct epithelial cells. Although kidney epithelial cells did not drive NLRP3 inflammasomes, NLRP3 and ASC alternatively enhanced with-no-lysine kinase-dependent NF-κB signaling in response to tumor necrosis factor-like weak inducer of apoptosis under a low-K+ milieu. These findings indicate a unique proinflammatory cascade mediated by NLRP3 and ASC beyond the framework of inflammasomes, which broadens the understanding of electrolyte-associated immunity in the kidney.
期刊介绍:
The American Journal of Pathology, official journal of the American Society for Investigative Pathology, published by Elsevier, Inc., seeks high-quality original research reports, reviews, and commentaries related to the molecular and cellular basis of disease. The editors will consider basic, translational, and clinical investigations that directly address mechanisms of pathogenesis or provide a foundation for future mechanistic inquiries. Examples of such foundational investigations include data mining, identification of biomarkers, molecular pathology, and discovery research. Foundational studies that incorporate deep learning and artificial intelligence are also welcome. High priority is given to studies of human disease and relevant experimental models using molecular, cellular, and organismal approaches.