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.
Highlights
Severe acute kidney injury (AKI) has been linked to progression to chronic kidney disease (CKD) [1]
To determine how discoidin domain receptor 1 (DDR1) participates in AKI, we examined kidney injury molecule-1 (KIM-1) at d3 after IR in injured WT and Ddr1-null (Ddr1KO) mice
Both WT and Ddr1KO mice showed increased blood urea nitrogen (BUN) at d9 compared to d-1, it was significantly lower in the injured Ddr1KO mice
Summary
Severe acute kidney injury (AKI) has been linked to progression to chronic kidney disease (CKD) [1]. Multiple factors influence the secretion of pro-inflammatory and pro-fibrotic cytokines by the injured RPTECs including extracellular matrix receptors Among these receptors, discoidin domain receptor 1 (DDR1) is a receptor tyrosine kinase that binds to and is activated by collagen. In CKD, DDR1 promotes inflammatory cell infiltration, secretion of pro-fibrotic cytokines and tissue fibrosis [5,6,7,8,9]. Consistent with this study, DDR1 expression on macrophages was not detected in subjects with interstitial nephritis [4] These findings, together with the observation that DDR1 expression is detected in proximal tubules of kidneys transplant subjects with AKI [11], suggest that DDR1 expressed on injured resident tubular epithelial cells, rather than on infiltrating macrophages, is responsible for regulating DDR1-dependent pro-inflammatory effects
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