DDR1 contributes to kidney inflammation and fibrosis by promoting the phosphorylation of BCR and STAT3

JCI Insight. 2022 Feb 8;7(3):e150887. doi: 10.1172/jci.insight.150887.


Discoidin domain receptor 1 (DDR1), a receptor tyrosine kinase activated by collagen, contributes to chronic kidney disease. However, its role in acute kidney injury and subsequent development of kidney fibrosis is not clear. Thus, we performed a model of severe ischemia/reperfusion-induced acute kidney injury that progressed to kidney fibrosis in WT and Ddr1-null mice. We showed that Ddr1-null mice had reduced acute tubular injury, inflammation, and tubulointerstitial fibrosis with overall decreased renal monocyte chemoattractant protein (MCP-1) levels and STAT3 activation. We identified breakpoint cluster region (BCR) protein as a phosphorylated target of DDR1 that controls MCP-1 production in renal proximal tubule epithelial cells. DDR1-induced BCR phosphorylation or BCR downregulation increased MCP-1 secretion, suggesting that BCR negatively regulates the levels of MCP-1. Mechanistically, phosphorylation or downregulation of BCR increased β-catenin activity and in turn MCP-1 production. Finally, we showed that DDR1-mediated STAT3 activation was required to stimulate the secretion of TGF-β. Thus, DDR1 contributes to acute and chronic kidney injury by regulating BCR and STAT3 phosphorylation and in turn the production of MCP-1 and TGF-β. These findings identify DDR1 an attractive therapeutic target for ameliorating both proinflammatory and profibrotic signaling in kidney disease.

Keywords: Cell Biology; Fibrosis; Nephrology.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Acute Kidney Injury
  • Animals
  • Cell Line
  • Cells, Cultured
  • Discoidin Domain Receptor 1 / biosynthesis
  • Discoidin Domain Receptor 1 / genetics*
  • Female
  • Fibrosis / complications
  • Fibrosis / genetics
  • Fibrosis / pathology
  • Gene Expression Regulation*
  • Inflammation / complications*
  • Inflammation / genetics
  • Inflammation / pathology
  • Kidney Tubules, Proximal / metabolism*
  • Kidney Tubules, Proximal / pathology
  • Male
  • Mice
  • Mice, Knockout
  • Phosphorylation
  • Proto-Oncogene Proteins c-bcr / biosynthesis
  • Proto-Oncogene Proteins c-bcr / genetics*
  • RNA / genetics*
  • STAT3 Transcription Factor / biosynthesis
  • STAT3 Transcription Factor / genetics*
  • Signal Transduction


  • STAT3 Transcription Factor
  • Stat3 protein, mouse
  • RNA
  • Ddr1 protein, mouse
  • Discoidin Domain Receptor 1
  • Bcr protein, mouse
  • Proto-Oncogene Proteins c-bcr