DUSP1 downregulation induces immunochemokines expression and promotes ferroptosis in human mesangial cells, contributing to IgA nephropathy pathogenesis

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DUSP1 downregulation induces immunochemokines expression and promotes ferroptosis in human mesangial cells, contributing to IgA nephropathy pathogenesis

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Co-author 1

Yuanhao Chen chenyh515400@163.com The First Affiliated Hospital of Jinan University Nephrology Guangzhou China *

Co-author 2

Liangmei Chen lmchen526@126.com The First Affiliated Hospital of Jinan University Nephrology Guangzhou China -

Co-author 3

Zekun Si awhisky@126.com The First Affiliated Hospital of Jinan University Nephrology Guangzhou China -

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Introduction

Immunoglobulin A nephropathy (IgAN) is a common glomerular disease that often progresses to end-stage renal disease. Its pathogenesis, partially explained by the "multi-hit" hypothesis, remains unclear. Ferroptosis, an iron-dependent cell death process, has been recently implicated in IgAN.

To investigate the link between IgAN and ferroptosis, we conducted a bioinformatic analysis and identified Dual Specificity Phosphatase 1 (DUSP1) as a key gene. DUSP1 is known to be protective in kidney injury and induced during ferroptosis. Using an in vitro IgAN model with Gd-IgA1-stimulated human mesangial cells, we aimed to explore the role of DUSP1 and the mechanism of ferroptosis in IgAN.

Methods

We analyzed glomerular tissues from 47 patients with IgAN and 31 normal controls using data obtained from the GEO database. Differentially expressed genes (DEGs) were identified and subjected to enrichment analysis Weighted gene co-expression network analysis (WGCNA) was utilized to identify key gene modules. The least absolute shrinkage and selection operator (LASSO and random forest were used to identify hub genes. We also analyzed immune cell infiltration using ClBERSORT. Additionally, we investigated the relationships between hub genes and clinicopathological features, as well as examined the distribution and expression of hub genes in the kidney.

Results

A key down-regulated gene, DUSP1, was selected as a potential IgAN-related signature gene via comprehensive bioinformatic analysis and machine learning model and estimation of diagnostic effect from inner and outer datasets. In HMC with Gd-IgA1 stimulation, mRNA expression levels of DUSP1 and GPX4 were reduced, HMC viability was decreased，ROS was increased, and a series of immune chemokines was which could be reversed by Fer-1 or overexpression of DUSP1.

Conclusion

Hence, DUSP1 has emerged as a promising candidate driver gene for IgAN, which has the potential to offer valuable insights into the molecular diagnosis and treatment of IgAN on way of ferroptosis and immune chamokines .

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