ABSTRACT
In chronic kidney disease (CKD), renal fibrosis is an unavoidable result of various manifestations. However, its pathogenesis is not yet fully understood. Here, we revealed the novel role of Homeobox D10 (HOXD10) in CKD-related fibrosis. HOXD10 expression was downregulated in CKD-related in vitro and in vivo fibrosis models. UUO model mice were administered adeno-associated virus (AAV) containing HOXD10, and HOXD10 overexpression plasmids were introduced into human proximal tubular epithelial cells induced by TGF-ß1. The levels of iron, reactive oxygen species (ROS), lipid ROS, the oxidized glutathione/total glutathione (GSSG/GSH) ratio, malonaldehyde (MDA), and superoxide dismutase (SOD) were determined using respective assay kits. Treatment with AAV-HOXD10 significantly attenuated fibrosis and renal dysfunction in UUO model mice by inhibiting NOX4 transcription, ferroptosis pathway activation, and oxidative stress. High levels of NOX4 transcription, ferroptosis pathway activation and profibrotic gene expression induced by TGF-ß1/erastin (a ferroptosis agonist) were abrogated by HOXD10 overexpression in HK-2 cells. Moreover, bisulfite sequencing PCR result determined that HOXD10 showed a hypermethylated level in TGF-ß1-treated HK-2 cells. The binding of HOXD10 to the NOX4 promoter was confirmed by chromatin immunoprecipitation (ChIP) analysis and dual-luciferase reporter assays. Targeting HOXD10 may represent an innovative therapeutic strategy for fibrosis treatment in CKD.
Subject(s)
Ferroptosis , Fibrosis , Homeodomain Proteins , NADPH Oxidase 4 , Renal Insufficiency, Chronic , Ferroptosis/genetics , Animals , NADPH Oxidase 4/metabolism , NADPH Oxidase 4/genetics , Homeodomain Proteins/metabolism , Homeodomain Proteins/genetics , Humans , Mice , Renal Insufficiency, Chronic/pathology , Renal Insufficiency, Chronic/metabolism , Renal Insufficiency, Chronic/genetics , Male , Mice, Inbred C57BL , Disease Models, Animal , Transcription Factors/metabolism , Transcription Factors/genetics , Kidney/pathology , Kidney/metabolism , Transforming Growth Factor beta1/metabolism , Reactive Oxygen Species/metabolism , Oxidative Stress , Cell LineABSTRACT
OBJECTIVE: To study the quality and genetic diversity of Chrysanthemun morifolium, the chemical constituents of 20 medicinal chrysanthemum cultivars in China were compared. METHOD: Chemical constituents of the 20 cultivars were compared in three types of index: chlorogenic acid, flavonoid and volatile oil. RESULT: There are visible differences on the contents of chlorogenic acid, flavonoid and volatile oil between the cultivars. CONCLUSION: Each cultivar has its own internal quality, and it is affected by many factors. The chemical constituents of the cultivars showed the genetic diversity in medicinal chrysanthemums of China.
