Lysophosphatidic acid signaling through its receptor initiates profibrotic epithelial cell fibroblast communication mediated by epithelial cell derived connective tissue growth factor.
Lysophosphatidic acid signaling through its receptor initiates profibrotic epithelial cell fibroblast communication mediated by epithelial cell derived connective tissue growth factor.
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DOI：
10.1016/j.kint.2016.09.030
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发表时间：
2017-03
影响因子：
19.6
通讯作者：
Tager AM
中科院分区：
文献类型：
--
作者：
Sakai N;Chun J;Duffield JS;Lagares D;Wada T;Luster AD;Tager AM
成纤维细胞库的扩增是器官纤维化的关键步骤，但驱动扩增的机制仍有待充分阐明。我们以前表明，溶血磷脂酸（LPA）信号通过其受体LPA 1表达成纤维细胞直接诱导这些细胞的招聘。在这里，我们测试了LPA-LPA 1信号传导是否在肾纤维化的发展过程中驱动成纤维细胞增殖和活化。将LPA 1缺陷（LPA 1-/-）或LPA 1充足（LPA 1 +/+）小鼠与具有由I型前胶原启动子（Col-GFP）驱动的绿色荧光蛋白表达（GFP）的小鼠杂交以鉴定成纤维细胞。在LPA 1 −/−Col-GFP小鼠中，单侧输尿管梗阻诱导的肾脏胶原蛋白增加显著减弱，但不完全减弱，成纤维细胞和肌成纤维细胞的积累也是如此。结缔组织生长因子主要在肾小管上皮细胞中检测到，其水平在LPA 1 −/−Col-GFP小鼠中受到抑制。LPA-LPA 1信号通过肌心蛋白相关转录因子-血清反应因子途径直接诱导原代近端肾小管上皮细胞中结缔组织生长因子的表达。近端肾小管上皮细胞衍生的结缔组织生长因子介导的肾成纤维细胞增殖和肌成纤维细胞分化。肌红蛋白相关转录因子/血清反应因子抑制剂的管理抑制阻塞诱导的肾纤维化。因此，靶向LPA-LPA 1信号传导和/或心肌素相关转录因子/血清反应因子诱导的转录可能是肾纤维化的有希望的治疗策略。
The expansion of the fibroblast pool is a critical step in organ fibrosis, but the mechanisms driving expansion remain to be fully clarified. We previously showed that lysophosphatidic acid (LPA) signaling through its receptor LPA1 expressed on fibroblasts directly induces the recruitment of these cells. Here we tested whether LPA-LPA1 signaling drives fibroblast proliferation and activation during the development of renal fibrosis. LPA1-deficient (LPA1−/−) or -sufficient (LPA1+/+) mice were crossed to mice with green fluorescent protein expression (GFP) driven by the type I pro-collagen promoter (Col-GFP) to identify fibroblasts. Unilateral ureteral obstruction-induced increases in renal collagen were significantly, though not completely, attenuated in LPA1−/−Col-GFP mice, as were the accumulations of both fibroblasts and myofibroblasts. Connective tissue growth factor was detected mainly in tubular epithelial cells, and its levels were suppressed in LPA1 −/−Col-GFP mice. LPA-LPA1 signaling directly induced connective tissue growth factor expression in primary proximal tubular epithelial cells, through a myocardin-related transcription factor-serum response factor pathway. Proximal tubular epithelial cell derived connective tissue growth factor mediated renal fibroblast proliferation and myofibroblast differentiation. Administration of an inhibitor of myocardin-related transcription factor/serum response factor suppressed obstruction-induced renal fibrosis. Thus, targeting LPA-LPA1 signaling and/or myocardin-related transcription factor/serum response factor-induced transcription could be promising therapeutic strategies for renal fibrosis.