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

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

doi:10.1016/j.isci.2025.112176

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

iScience. 2025 Mar 7;28(4):112176. doi: 10.1016/j.isci.2025.112176. eCollection 2025 Apr 18.

Authors

Tomohiro Nakata¹, Yuhei Kirita¹, Minato Umehara¹, Masashi Nakamura¹, Shinji Sawai¹, Atsushi Minamida¹, Hiroko Yamauchi-Sawada¹, Yasuto Sunahara¹, Yayoi Matoba¹, Natsuko Okuno-Ozeki¹, Itaru Nakamura¹, Kunihiro Nakai¹, Aya Yagi-Tomita¹, Noriyuki Yamashita¹, Keiichi Tamagaki¹, Benjamin D Humphreys², Satoaki Matoba³, Tetsuro Kusaba¹

Affiliations

¹ Department of Nephrolog, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
² Division of Nephrology, Washington University School of Medicine in St. Louis, St. Louis, MO, USA.
³ Department of Cardiovascular Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.

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.

Keywords: biochemical mechanism; biology of human development; integrative aspects of cell biology; molecular interaction.