DDR1 contributes to kidney inflammation and fibrosis by promoting the phosphorylation of BCR and STAT3.
DDR1 contributes to kidney inflammation and fibrosis by promoting the phosphorylation of BCR and STAT3.
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DOI：
10.1172/jci.insight.150887
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发表时间：
2022-02-08
期刊：
影响因子：
8
通讯作者：
Pozzi A
中科院分区：
文献类型：
--
作者：
Borza CM;Bolas G;Bock F;Zhang X;Akabogu FC;Zhang MZ;de Caestecker M;Yang M;Yang H;Lee E;Gewin L;Fogo AB;McDonald WH;Zent R;Pozzi A
盘状结构域受体1（DDR 1）是一种由胶原蛋白激活的受体酪氨酸激酶，与慢性肾脏疾病有关。然而，其在急性肾损伤和随后的肾纤维化发展中的作用尚不清楚。因此，我们在WT和Ddr 1缺失小鼠中建立了严重缺血/再灌注诱导的急性肾损伤模型，该模型进展为肾纤维化。我们发现，Ddr 1基因敲除小鼠急性肾小管损伤、炎症和肾小管间质纤维化减少，肾脏单核细胞趋化蛋白（MCP-1）水平和STAT 3活化总体下降。我们将断点簇区（BCR）蛋白鉴定为DDR 1的磷酸化靶点，该靶点控制肾近端小管上皮细胞中MCP-1的产生。DDR 1诱导的BCR磷酸化或BCR下调增加MCP-1分泌，表明BCR负调节MCP-1水平。从机制上讲，BCR的磷酸化或下调增加了β-连环蛋白的活性，进而增加了MCP-1的产生。最后，我们发现DDR 1介导的STAT 3激活是刺激TGF-β分泌所必需的。因此，DDR 1通过调节BCR和STAT 3磷酸化，进而调节MCP-1和TGF-β的产生，导致急性和慢性肾损伤。这些发现确定DDR 1是改善肾脏疾病中促炎和促纤维化信号传导的有吸引力的治疗靶点。
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.
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