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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

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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 8

DDR1 activation promotes TGF-β production by activating STAT3.

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DDR1 activation promotes TGF-β production by activating STAT3.
(A) Cell ...
(A) Cell lysates of RPTECs expressing or not STAT3C-Flag were analyzed by Western blot for STAT3 using anti-STAT3 or anti-Flag antibody. (B) TGF-β was measured by ELISA in conditioned medium of RPTECs treated ± collagen I (CI). Circles represent a single experiment performed in triplicate. Values are mean ± SD of at least 4 experiments and represent fold-changes versus vehicle-treated cells assigned as 1. Statistical analysis: 1-way ANOVA followed by Tukey’s multiple-comparison test. (C) TGF-β was measured by ELISA in conditioned medium of HK2 cells treated ± CI ± the STAT3 inhibitor S31-201 (10 μM). Values represent mean ± SD of at least 4 experiments and are expressed as fold-changes versus vehicle-treated cells assigned as 1. Statistical analysis: 1-way ANOVA followed by Dunnett’s multiple-comparison test versus CI-treated group.

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