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

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 for 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-ERK signaling. In vivo analyses utilizing tubular-specific CCN1 knockout mice demonstrated the sparse accumulation of fibroblasts around injured sites after injury, resulting that tissue fibrosis was ameliorated 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 timepoints.在恰当时间点引导成纤维细胞迁移至损伤部位的体液因子，被认为是肾损伤后修复过程中不可或缺的关键因素。本研究证实，损伤肾小管衍生的细胞通讯网络因子1（Cellular Communication Network Factor 1，CCN1）在肾损伤后成纤维细胞向损伤部位的募集过程中发挥关键作用。基于体外配体-受体相互作用分析与体内肾小管上皮特异性转录组学研究，我们发现肾损伤早期阶段CCN1表达上调。CCN1通过黏着斑激酶-ERK信号通路促进成纤维细胞趋化。利用肾小管特异性CCN1敲除小鼠开展的体内分析显示，损伤后损伤部位周围成纤维细胞的聚集稀疏，使得CCN1敲除（CCN1-KO）小鼠的组织纤维化程度得到缓解。上述研究结果揭示了一条上皮细胞-成纤维细胞CCN1信号轴：该信号轴在急性损伤早期可将成纤维细胞募集至受损肾小管，而在后期则促进间质纤维化。