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. Overall design: To examine the paracrine effects of injured tubular epithelial cells on fibroblasts, we initially performed in vitro experiments using rat epithelial cells (NRK52E), fibroblasts (NRK49F), and conditioned medium (CM) from these cell lines (CME and CMF). We examined differences in the transcriptome between NRK52E treated with 40 µM of cisplatin or vehicle for 24 hours by RNA-seq. We also compared the transcriptome between NRK49F treated with Cis 40-CME and untreated CME for 24 hours.