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HOXD10 attenuates renal fibrosis by inhibiting NOX4-induced ferroptosis
Xin Li1, Tian-Kui Ma2, Pu Wang3
1Nephrology Department, Fourth Hospital of China Medical University, Shenyang, China.
Insights
Homeobox D10 (HOXD10) is downregulated in chronic kidney disease (CKD) fibrosis. Restoring HOXD10 levels in mice and cells reduced fibrosis by inhibiting oxidative stress and ferroptosis, suggesting a new therapeutic target.
Area of Science:
- Nephrology
- Molecular Biology
- Biochemistry
Background:
- Renal fibrosis is a common complication in chronic kidney disease (CKD), but its underlying mechanisms remain incompletely understood.
- Homeobox D10 (HOXD10) has emerged as a potential factor in fibrotic diseases.
- HOXD10 expression is reduced in established models of CKD-related fibrosis.
Purpose of the Study:
- To investigate the role of Homeobox D10 (HOXD10) in the pathogenesis of chronic kidney disease (CKD)-related renal fibrosis.
- To explore the potential of HOXD10 as a therapeutic target for mitigating fibrosis in CKD.
Main Methods:
- Utilized unilateral ureter obstruction (UUO) mouse models and TGF-β1-induced human proximal tubular epithelial cells (HK-2).
- Overexpressed HOXD10 using adeno-associated virus (AAV) in vivo and plasmid transfection in vitro.
- Assessed markers of oxidative stress (ROS, lipid ROS, GSSG/GSH ratio, MDA, SOD), ferroptosis, and fibrosis.
- Employed bisulfite sequencing PCR, chromatin immunoprecipitation (ChIP), and dual-luciferase reporter assays to confirm molecular interactions.
Main Results:
- HOXD10 expression was significantly downregulated in both in vitro and in vivo models of CKD fibrosis.
- HOXD10 overexpression attenuated renal fibrosis, improved renal function, and reduced oxidative stress and ferroptosis activation in UUO mice.
- HOXD10 abrogated TGF-β1/erastin-induced NOX4 transcription, ferroptosis, and profibrotic gene expression in HK-2 cells.
- HOXD10 was found to be hypermethylated in TGF-β1-treated cells and directly binds to the NOX4 promoter.
Conclusions:
- HOXD10 plays a protective role against renal fibrosis in CKD by inhibiting NOX4 transcription, ferroptosis, and oxidative stress.
- HOXD10 acts as a suppressor of fibrosis, potentially through epigenetic regulation and direct promoter interaction with NOX4.
- Targeting HOXD10 represents a promising and novel therapeutic strategy for treating fibrosis in chronic kidney disease.
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-β1. 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-β1/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-β1-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.
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