Renal tubular PAR2 promotes interstitial fibrosis by increasing inflammatory responses and EMT process

被引:21
|
作者
Ha, Sugyeong [1 ]
Chung, Ki Wung [1 ]
Lee, Jaewon [1 ]
Chung, Hae Young [1 ]
Moon, Hyung Ryong [1 ]
机构
[1] Pusan Natl Univ, Coll Pharm, 2 Busandaehak Ro 63Beon-gil, Busan 48434, South Korea
基金
新加坡国家研究基金会;
关键词
Renal fibrosis; Inflammation; PAR2; Chemokines; Renal tubular epithelial cells; ACTIVATED RECEPTOR 2; NF-KAPPA-B; IGA NEPHROPATHY; MECHANISMS; EXPRESSION; TGF-BETA-1; CHEMOKINES; PATHWAYS; INJURY;
D O I
10.1007/s12272-022-01375-5
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Renal fibrosis is defined by excessive extracellular matrix (ECM) accumulation and is associated with a decreased kidney function. Increased inflammation and infiltration of inflammatory cells are the key features of renal fibrosis development; however, the mechanism of how inflammation starts is still un-known. Here, we show that the activation of epithelial Protease-activating receptor 2 (PAR2) signaling plays an important role in the initiation of inflammation via increased chemokine expression and inflammatory cell induction. In the adenine diet-induced renal fibrosis mouse model, PAR2 expression was significantly increased in the renal tubule region. Kidneys from PAR2-knockout mice were protected from adenine diet-induced renal fibrosis, kidney dysfunction, and inflammation. Using NRK52E kidney epithelial cells, we further elucidated the mechanisms underlying these processes. Activation of PAR2 signaling pathway by PAR2 agonist specifically increased the levels of chemokines, including MCP1 and MCP3, via the MAPK-NF-kappa B signaling pathway. Inhibition of the MAPK signaling pathway attenuated PAR2 agonist-induced NF-kappa B activation, chemokine expression, and macrophage cell induction. Furthermore, PAR2 activation directly increased mesenchymal cell markers in epithelial cells. Taken together, we found that increased PAR2 expression and the PAR2/MAPK signaling pathway promote renal fibrosis by increasing the inflammatory responses and promoting EMT process.
引用
收藏
页码:159 / 173
页数:15
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