TY - JOUR AU - Borza, Corina M. AU - Bolas, Gema AU - Bock, Fabian AU - Zhang, Xiuqi AU - Akabogu, Favour C. AU - Zhang, Ming-Zhi AU - de Caestecker, Mark AU - Yang, Min AU - Yang, Haichun AU - Lee, Ethan AU - Gewin, Leslie AU - Fogo, Agnes B. AU - McDonald, W. Hayes AU - Zent, Roy AU - Pozzi, Ambra T1 - DDR1 contributes to kidney inflammation and fibrosis by promoting the phosphorylation of BCR and STAT3 PY - 2022/02/08/ AB - 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. JF - JCI Insight JA - JCI Insight SN - 2379-3708 DO - 10.1172/jci.insight.150887 VL - 7 IS - 3 UR - https://doi.org/10.1172/jci.insight.150887 PB - The American Society for Clinical Investigation ER -