DDR1 contributes to kidney inflammation and fibrosis by promoting the phosphorylation of BCR and STAT3
Corina M. Borza, … , Roy Zent, Ambra Pozzi
Corina M. Borza, … , Roy Zent, Ambra Pozzi
Published December 23, 2021
Citation Information: JCI Insight. 2022;7(3):e150887. https://doi.org/10.1172/jci.insight.150887.
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Research Article Cell biology Nephrology

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

Abstract

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.

Authors

Corina M. Borza, Gema Bolas, Fabian Bock, Xiuqi Zhang, Favour C. Akabogu, Ming-Zhi Zhang, Mark de Caestecker, Min Yang, Haichun Yang, Ethan Lee, Leslie Gewin, Agnes B. Fogo, W. Hayes McDonald, Roy Zent, Ambra Pozzi

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Figure 3

Decreased fibrosis in injured Ddr1-KO mice.

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Decreased fibrosis in injured Ddr1-KO mice. (A) Images of kidney section...
(A) Images of kidney sections from WT and Ddr1-KO mice uninjured (d–1) or 28 days after IR stained with anti–α-SMA antibody. Scale bar: 50 μm. (B) The percentage of α-SMA–positive area per microscopic field was evaluated at d28 using ImageJ. Circles represent individual kidneys (WT and Ddr1-KO n = 4), and bars are mean ± SD. (C) Picrosirius red staining of kidney sections from WT and Ddr1-KO mice uninjured (d–1) or 28 days after IRI. Scale bar: 50 μm. (D) The percentage of Picrosirius red–positive area was evaluated using ImageJ. Circles represent individual kidneys (d–1 WT and Ddr1-KO n = 4, d28 WT and Ddr1-KO n = 5), and bars are mean ± SD. (E) Kidney lysates from uninjured WT (d–1) and WT and Ddr1-KO 28 days after IR were analyzed for the level of collagen I by Western blot analysis. (F) Collagen I and β-tubulin bands were quantified by densitometry analysis, and collagen I is expressed as collagen I/β-tubulin ratio. Circles represent individual kidneys (d–1 WT n = 4, d28 WT and Ddr1-KO n = 5), and bars are mean ± SD. Statistical analysis: 2-tailed t test for B and 1-way ANOVA followed by Tukey’s multiple-comparison test for D and F.