尿毒症毒素硫酸吲哚酚通过诱导sFRP5甲基化活化Wnt/β-catenin信号通路在肾纤维化中的作用

Renal fibrosis is the significant pathological basis of chronic renal failure(CRF),and the massive accumulation of uremic toxins is one of the most important clinical features. Our previous studies showed that the indoxyl sufate(IS) could promote the renal fibrosis ,but the specific mechanism was still unclear. Our early results indicated that when IS induced the renal fibrosis of the unilateral nephrectomy mice, the β-catenin of the Wnt signal expression increased. Our in vitro studies showed that IS could decrease the secreted frizzled-related protein 5(SFRP5)of the Wnt signal inhibiting factor expression, and the methyltransferase inhibitor could reverse the effect of IS. Thus, it is supposed that IS may promote renal fibrosis through inducing the Wnt/β-catenin signal pathway, which may be associated with the induction of SFRP5 gene methylation. therefore , we plan to choose HK-2 cells and unilateral nephrectomy mice as the object of study in this research, and we can further discuss the important role of the Wnt/β-catenin signal pathway in the process of the renal fibrosis, which can help us to analysis what is the effect of IS on binding abilities and inhibiting effect of sFRP5 with Wnt. then we can make clear if SFRP5 methylation is the key mechanism that IS activate Wnt/β-catenin signal pathway. The purpose of this study provides us new idea to reveal the development of renal fibrosis and find the control measures.

肾纤维化是慢性肾衰竭（CRF）的重要病理基础，而尿毒症毒素蓄积是CRF的主要临床特点。我们既往研究发现尿毒症毒素硫酸吲哚酚（IS）可以促进肾纤维化，但机制并不明确。我们前期研究提示IS诱导肾纤维化的同时Wnt信号核心分子β-catenin表达增高；体外研究表明，IS可以降低Wnt信号抑制因子分泌型卷曲相关蛋白sFRP5的表达，甲基化转移酶抑制剂却可以逆转IS的作用。故推测IS可能通过激活Wnt/β-catenin信号通路促进了肾纤维化，其作用可能与诱导sFRP5基因甲基化有关。为此，本项目拟以HK-2细胞和单侧肾切除小鼠为研究对象，探讨Wnt/β-catenin信号通路在IS诱导肾纤维化过程中的重要作用，分析IS对sFRP5与Wnt结合能力和抑制作用的影响，明确sFRP5甲基化是否是IS激活Wnt/β-catenin信号通路的关键机制。为揭示肾纤维化持续进展的机制及寻找防治措施提供新思路。

肾纤维化是慢性肾衰竭（CRF）的重要病理基础，而尿毒症毒素蓄积是CRF的主要临床特点。我们既往研究发现尿毒症毒素硫酸吲哚酚（IS）可以促进肾纤维化，但机制并不明确。我们前期研究提示IS诱导肾纤维化的同时Wnt信号核心分子β-catenin表达增高；体外研究表明，IS可以降低Wnt信号抑制因子分泌型卷曲相关蛋白sFRP5的表达，甲基化转移酶抑制剂却可以逆转IS的作用。故推测IS可能通过激活Wnt/β-catenin信号通路促进了肾纤维化，其作用可能与诱导sFRP5基因甲基化有关。为此，本项目拟以HK-2细胞和单侧肾切除小鼠为研究对象，探讨Wnt/β-catenin信号通路在IS诱导肾纤维化过程中的重要作用，分析IS对sFRP5与Wnt结合能力和抑制作用的影响，明确sFRP5甲基化是否是IS激活Wnt/β-catenin信号通路的关键机制。为揭示肾纤维化持续进展的机制及寻找防治措施提供新思路。