| Autor: |
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 |
| Jazyk: |
angličtina |
| Rok vydání: |
2022 |
| Předmět: |
|
| Zdroj: |
JCI Insight, Vol 7, Iss 3 (2022) |
| Druh dokumentu: |
article |
| ISSN: |
2379-3708 |
| DOI: |
10.1172/jci.insight.150887 |
| Popis: |
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. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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