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

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Summary

Introduction

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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