Proteinase-activated Receptor-2 Transactivation of Epidermal Growth Factor Receptor and Transforming Growth Factor-β Receptor Signaling Pathways Contributes to Renal Fibrosis
Proteinase-activated Receptor-2 Transactivation of Epidermal Growth Factor Receptor and Transforming Growth Factor-β Receptor Signaling Pathways Contributes to Renal Fibrosis
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DOI：
10.1074/jbc.m113.492793
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发表时间：
2013-12-27
影响因子：
4.8
通讯作者：
Muruve, Daniel A.
中科院分区：
文献类型：
--
作者：
Chung, Hyunjae;Ramachandran, Rithwik;Muruve, Daniel A.
慢性肾脏疾病在人群中造成很大的发病率和死亡率。在肾脏损伤过程中，定位于肾脏的蛋白水解酶可以通过裂解和激活蛋白酶激活的受体-2(PAR2)来传递信号。PAR2是一种G蛋白偶联受体，参与炎症和纤维化，在肾小管上皮细胞中高表达。与野生型对照组相比，单侧输尿管梗阻后7天，PAR2基因缺陷小鼠的肾小管损伤、纤维化、胶原合成、结缔组织生长因子(CTGF)和-平滑肌肌动蛋白基因表达减少。在体外培养的人近端肾小管上皮细胞中，单独使用PAR2激活肽(PAR2-AP)可显著上调CTGF的表达，CTGF是一种强有力的促纤维化细胞因子。PAR2-AP联合转化生长因子-α(TGF-α)可协同增强CTGF的诱导作用。与这些发现一致的是，用PAR2-AP处理人近端肾小管上皮细胞可以诱导典型的转化生长因子信号通路中Smad2/3的磷酸化。Smad2的磷酸化和CTGF的诱导需要通过转化生长因子受体和表皮生长因子受体的信号，这表明PAR2利用反式激活机制来启动纤维化信号。综上所述，我们的数据支持PAR2与转化生长因子信号通路协同作用导致肾脏损伤和纤维化的假说。
Chronic kidney diseases cause significant morbidity and mortality in the population. During renal injury, kidney-localized proteinases can signal by cleaving and activating proteinase-activated receptor-2 (PAR2), a G-protein-coupled receptor involved in inflammation and fibrosis that is highly expressed in renal tubular cells. Following unilateral ureteric obstruction, PAR2-deficient mice displayed reduced renal tubular injury, fibrosis, collagen synthesis, connective tissue growth factor (CTGF), and -smooth muscle actin gene expression at 7 days, compared with wild-type controls. In human proximal tubular epithelial cells in vitro, PAR2 stimulation with PAR2-activating peptide (PAR2-AP) alone significantly up-regulated the expression of CTGF, a potent profibrotic cytokine. The induction of CTGF by PAR2-AP was synergistically increased when combined with transforming growth factor- (TGF-). Consistent with these findings, treating human proximal tubular epithelial cells with PAR2-AP induced Smad2/3 phosphorylation in the canonical TGF- signaling pathway. The Smad2 phosphorylation and CTGF induction required signaling via both the TGF-receptor and EGF receptor suggesting that PAR2 utilizes transactivation mechanisms to initiate fibrogenic signaling. Taken together, our data support the hypothesis that PAR2 synergizes with the TGF signaling pathway to contribute to renal injury and fibrosis.