Sphingosine-1-phosphate acts as a key molecule in the direct mediation of renal fibrosis.
Sphingosine-1-phosphate acts as a key molecule in the direct mediation of renal fibrosis.
复制标题
鞘氨醇1-磷酸在肾纤维化的直接介导中充当关键分子。
DOI：
10.1002/phy2.172
复制
发表时间：
2013-12-01
影响因子：
2.5
通讯作者：
Tsuchiya, Ken
中科院分区：
文献类型：
--
作者：
Shiohira, Shunji;Yoshida, Takumi;Sugiura, Hidekazu;Nishida, Miki;Nitta, Kosaku;Tsuchiya, Ken
鞘脂的主要代谢物鞘脂苷- 1 -磷酸（S1P）具有重要的生物学功能。S1P作为5个G蛋白偶联受体家族的配体，具有不同的信号通路，调节重要的生物学通路。S1P通过炎症途径诱导肾纤维化。然而，其对肾脏的直接纤维化诱导作用尚未被证实。在正常大鼠肾间质成纤维细胞（NRK‐49F）细胞（体外）和单侧输尿管梗阻（UUO）小鼠模型（体内）中，研究了S1P作为肾纤维化的直接介质的作用。为了阐明S1P在肾纤维化中的作用，我们采用免疫反应缺陷的裸UUO小鼠。用不同浓度的外源性S1P和FTY720 （S1P受体激动剂）或N，N -二甲基鞘氨醇（DMS，一种鞘氨醇激酶抑制剂）刺激NRK‐49F细胞。C57BL6和裸UUO小鼠分别用FTY720、DMS或生理盐水预处理。检测α‐平滑肌肌动蛋白（a‐SMA）、E‐钙粘蛋白、1型胶原蛋白（COL1）、4型胶原蛋白（COL4）、基质金属蛋白酶- 1组织抑制剂（TIMP1）和纤溶酶原激活物抑制剂- 1 （PAI1）的表达水平。S1P刺激NRK - 49F细胞和UUO小鼠的纤维化。在S1P刺激的细胞和UUO小鼠中，均观察到a‐SMA、COL1、COL4、TIMP1和PAI1表达水平升高，E‐cadherin表达水平降低。裸UUO小鼠肾脏表达纤维化标志物。UUO和裸UUO小鼠均成功诱导纤维化改变，纤维连接蛋白和COL1染色明显。这些S1P诱导的纤维化变化在体内和体外均被FTY720和DMS抑制。因此，S1P本质上直接介导肾纤维化。鞘氨醇- 1 -磷酸（S1P）在体外和体内均可刺激纤维化。单侧输尿管梗阻（UUO）及单侧输尿管梗阻裸鼠均成功诱导纤维化改变。这些结果表明，S1P在肾纤维化中是一个关键的纤维化介质，部分通过直接的纤维化作用起作用。
The major sphingolipid metabolite, sphingosine‐1‐phosphate (S1P), has important biological functions. S1P serves as a ligand for a family of five G‐protein‐coupled receptors with distinct signaling pathways regulating important biological pathways. S1P induces renal fibrosis through an inflammatory pathway. However, its direct fibrosis‐inducing effect on the kidney has not been shown. The role of S1P as a direct mediator of renal fibrosis was investigated in normal rat kidney interstitial fibroblast (NRK‐49F) cells (in vitro) and kidneys of a unilateral ureteral obstruction (UUO) mouse model (in vivo). To clarify the role of S1P in renal fibrosis, we adopted nude UUO mice with immune response deficits. NRK‐49F cells were stimulated with various concentrations of exogenous S1P and FTY720 (a S1P receptor agonist) or N,N‐dimethylsphingosine (DMS; a sphingosine kinase inhibitor). C57BL6 and nude UUO mice were pretreated with FTY720, DMS, or saline. Expression levels of alpha‐smooth muscle actin (a‐SMA), E‐cadherin, collagen type 1 (COL1), collagen type 4 (COL4), tissue inhibitor of matrix metalloproteinase‐1 (TIMP1), and plasminogen activator inhibitor‐1 (PAI1) were examined. S1P stimulated fibrosis in NRK‐49F cells and UUO mice. Increased a‐SMA, COL1, COL4, TIMP1, and PAI1 and decreased E‐cadherin expression levels were observed in both the S1P‐stimulated cells and UUO mice. Nude UUO mouse kidneys expressed fibrotic markers. Fibrotic changes were successfully induced in both UUO and nude UUO mice, evident through prominent fibronectin and COL1 staining. These S1P‐induced fibrotic changes were suppressed by FTY720 and DMS both in vitro and in vivo. Thus, S1P essentially and directly mediates renal fibrosis. Sphingosine‐1‐phosphate (S1P) stimulated fibrosis both in vitro and in vivo. Fibrotic changes were successfully induced in both unilateral ureteral obstruction (UUO) and nude mice with UUO. These results suggest that S1P is a pivotal fibrotic mediator in renal fibrosis that acts, in part, through direct fibrotic effects.