DNA hypermethylation of sFRP5 contributes to indoxyl sulfate-induced renal fibrosis

Journal of Molecular Medicine : Official Organ of the Gesellschaft Deutscher Naturforscher Und Ärzte
Yanlin YuJinghong Zhao

Abstract

Renal fibrosis is the most common outcome of chronic kidney disease (CKD), while the pathogenesis of renal fibrosis is not fully understood. In this study, we first showed that the progress of renal fibrosis was positively related to serum levels of indoxyl sulfate, a typical protein-bound toxin, and that there was a close correlation between serum indoxyl sulfate levels and β-catenin expression in the kidneys (r = 0.908, p < 0.001) of CKD patients. We then demonstrated that intraperitoneal injections of indoxyl sulfate (100 mg/kg/day) for 4 weeks in uninephrectomized mice explicitly induced renal fibrosis, which was accompanied by a significant activation of Wnt/β-catenin signaling. In vitro investigations in human renal tubular HK-2 cells revealed that indoxyl sulfate exhibited a potent ability to induce Wnt/β-catenin activation through the downregulation of sFRP5, a gene that codes for an extracellular antagonist of Wnt signaling, by increasing the DNA methylation level of its promoter CpG islands. The increased expression of DNA methyltransferases following the activation of ROS/ERK1/2 signaling was responsible for the DNA hypermethylation of sFRP5 induced by indoxyl sulfate. Conversely, treatment with 5-aza-2'-deoxycytidin...Continue Reading

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Citations

May 19, 2017·Journal of Molecular Medicine : Official Organ of the Gesellschaft Deutscher Naturforscher Und Ärzte·Jonathan A LindquistPeter R Mertens
Jun 15, 2019·Journal of Interferon & Cytokine Research : the Official Journal of the International Society for Interferon and Cytokine Research·Shan TongYujie Zhou
Oct 2, 2020·Analytical Methods : Advancing Methods and Applications·Wen LiuTong Tong Wang
Jul 16, 2021·Frontiers in Cell and Developmental Biology·Hui XuYou-Shuo Liu

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Methods Mentioned

BETA
PCR
biopsy
immunoprecipitation assay
immunoprecipitation
biopsies
light microscopy

Software Mentioned

SPSS
MethPrimer
GraphPad Prism
Image Pro - Plus
BiQ Analyzer
Quantity One

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