Low Potassium Triggers Tubular Epithelial NLR Family Pyrin Domain-Containing 3/Apoptosis-Associated Speck-Like Protein-Containing CARD-Driven Kidney Inflammation Independently of Inflammasomes.

IF 3.6 2区 医学 Q1 PATHOLOGY
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
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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.

低钾触发小管上皮NLRP3/ asc驱动的肾脏炎症,独立于炎症小体。
病理性钾(K+)缺乏引起肾脏炎症和损伤,称为低钾血症肾病(HN),其潜在的发病机制尚不清楚。NLRP3炎性小体是感知细胞内K+减少的平台,参与炎症和组织损伤。本研究探讨了全身性K+缺乏是否会诱导HN的NLRP3炎性体激活。临床诊断为HN的人表现为肾上皮NLRP3和ASC的上调。小鼠K+耗竭模型表明,肾常驻NLRP3和ASC在引发HN肾脏早期炎症中起关键作用。出乎意料的是,K+消耗引起的肾脏炎症并不依赖于炎性体的激活。单细胞RNA测序分析显示,HN肾中ASC上调,NF-κB活化,肿瘤坏死因子样细胞凋亡弱诱导剂(TWEAK)受体FN14水平升高,主要发生在远端肾元/集管上皮细胞中。虽然肾上皮细胞不驱动NLRP3炎性小体,但在低k +环境下,NLRP3和ASC可选择性地通过无赖氨酸(WNK)激酶依赖性NF-κB信号传导增强。这些发现表明,NLRP3和ASC介导的独特的促炎级联反应超出了炎性小体的框架,这拓宽了对肾脏电解质相关免疫的理解。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
11.40
自引率
0.00%
发文量
178
审稿时长
30 days
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.
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