Injured tubular epithelia-derived CCN1 promotes the mobilization of fibroblasts toward injury sites after kidney injury

IF 4.1 2区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES iScience Pub Date : 2025-03-07 DOI:10.1016/j.isci.2025.112176

Tomohiro Nakata , Yuhei Kirita , Minato Umehara , Masashi Nakamura , Shinji Sawai , Atsushi Minamida , Hiroko Yamauchi-Sawada , Yasuto Sunahara , Yayoi Matoba , Natsuko Okuno-Ozeki , Itaru Nakamura , Kunihiro Nakai , Aya Yagi-Tomita , Noriyuki Yamashita , Keiichi Tamagaki , Benjamin D. Humphreys , Satoaki Matoba , Tetsuro Kusaba

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Abstract

Humoral factors that prompt fibroblasts to migrate to an injury site at an appropriate time point are deemed indispensable for repair after kidney injury. We herein demonstrated the pivotal roles of injured tubule-derived cellular communication network factor 1 (CCN1) in the mobilization of fibroblasts to the injury site after kidney injury. Based on analyses of ligand-receptor interactions in vitro and tubular epithelial-specific transcriptomics in vivo, we identified the up-regulation of CCN1 during the early phases of kidney injury. CCN1 promotes fibroblast chemotaxis through focal adhesion kinase-extracellular signal-regulated kinase (ERK) signaling. In vivo analyses utilizing tubular-specific CCN1 knockout (KO) mice demonstrated the sparse accumulation of fibroblasts around injured sites after injury, resulting in ameliorated tissue fibrosis in CCN1-KO mice. These results reveal an epithelial-fibroblast CCN1 signaling axis that mobilizes fibroblasts to injured tubule early after acute injury but that promotes interstitial fibrosis at late time points.

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受损小管上皮来源的CCN1促进成纤维细胞向肾损伤部位的动员

促使成纤维细胞在适当的时间点迁移到损伤部位的体液因子被认为是肾损伤后修复不可或缺的。我们在此证明了受损小管源性细胞通信网络因子1 （CCN1）在肾损伤后成纤维细胞向损伤部位动员中的关键作用。通过对体外配体-受体相互作用和体内小管上皮特异性转录组学的分析，我们确定了CCN1在肾损伤早期的上调。CCN1通过局灶黏附激酶-细胞外信号调节激酶（ERK）信号传导促进成纤维细胞趋化。利用小管特异性CCN1敲除（KO）小鼠进行的体内分析显示，损伤后，成纤维细胞在损伤部位周围稀疏积累，导致CCN1-KO小鼠的组织纤维化改善。这些结果揭示了上皮-成纤维细胞CCN1信号轴在急性损伤后早期将成纤维细胞动员到受损小管，但在晚时间点促进间质纤维化。

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

iScience Multidisciplinary-Multidisciplinary

CiteScore

7.20

自引率

1.70%

发文量

1972

审稿时长

6 weeks

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