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Abstract: TH-OR10

Injured Tubular Epithelia-Derived CCN1 Promotes the Mobilization of Fibroblasts Toward the Injury Sites at the Acute Phase After Kidney Injury

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms


  • Nakata, Tomohiro, Department of Nephrology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
  • Kirita, Yuhei, Kyoto Prefectural University of Medicine, Kyoto, Japan
  • Tamagaki, Keiichi, Kyoto Prefectural University of Medicine, Kyoto, Japan
  • Kusaba, Tetsuro, Kyoto Prefectural University of Medicine, Kyoto, Japan

Renal fibrosis is associated with the progression of renal injury. Conversely, the function of fibroblasts is indispensable for the reconstruction of normal tissue structure following injury in various organs. Consequently, the humoral factors that prompt fibroblasts to migrate to the injury site at an appropriate time point are deemed indispensable. However, the precise mechanisms through which these factors influence fibroblasts and promote migration to the tissue-injured site remain unclear.


To expound on the paracrine effects on fibroblasts (NRK49F), we subjected them to treatment with conditioned medium (CM) derived from either normal or injured tubular epithelial cells (NRK52E). Based on the transcriptomics data, we identified Cellular Communication Network Factor 1 (CCN1) signaling as a candidate
and analyzed its impact on kidney injury.


The CM from injured NRK52E expedited NRK49F chemotaxis and proliferation. Based on ligand-receptor analysis of RNA-seq between NRK49F and NRK52E in vitro, as well as proximal tubular-specific transcriptomics utilizing proximal tubular-specific tdTomato-reporter mice, we identified the upregulation of CCN1 signaling during the early phases of various kidney injury models. The enhanced fibroblast chemotaxis induced by CM from injured NRK52E was nullified by CM from injured NRK52E with CRISPR-mediated CCN1 knockout. CCN1 activated FAK-ERK signaling, thereby expediting the migration and proliferation of fibroblasts, which were attenuated by ERK and FAK inhibitors. Lastly, in vivo analyses utilizing proximal tubular-specific CCN1 knockout (SLC34a1GCE/CCN1-floxed) mice demonstrated the accumulation of fibroblasts surrounding injured tubular epithelial cells was scarcely observed during the acute phase following cisplatin-induced kidney injury in tubular CCN1 knockout mice. Furthermore, tubular injury was exacerbated in CCN1 knockout mice, suggesting that mobilized fibroblasts by tubule-derived CCN1 may impede the expansion of tubular injury.


During the acute phase after injury, the interaction between tubular epithelia and fibroblasts hinges upon the pivotal role played by damaged tubule-derived CCN1 in mobilizing fibroblasts toward the injury sites, thereby potentially inhibiting the progression of tubular injury expansion.