Identification of Molecular Markers Associated With the Pathophysiology and Treatment of Lupus Nephritis Based on Integrated Transcriptome Analysis.

Menghui Yao,Wenfang Liang,Zhaohui Zheng,Congcong Gao,Wenbo Sun,Xueqi Di,Chunyi Zhang,Qianqian Wang

doi:10.3389/fgene.2020.583629

Menghui Yao, Wenfang Liang + Show 6 more

Open Access

https://doi.org/10.3389/fgene.2020.583629

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Abstract

Lupus nephritis (LN) is a well-known complication of systemic lupus erythematosus and is its leading cause of morbidity and mortality. Our study aimed to identify the molecular markers associated with the pathophysiology and treatment of LN. The renal tissue gene expression profiles of LN patients in the GSE32591 dataset were downloaded as a discovery cohort from the Gene Expression Omnibus. Differentially expressed genes (DEGs) were identified; weighted gene co-expression network analysis (WGCNA) was used to identify the co-expression modules of DEGs; and gene function enrichment analysis, molecular crosstalk analysis, and immune cell infiltration analysis were performed to explore the pathophysiological changes in glomeruli and tubulointerstitia of LN patients. The crosstalk genes were validated in another RNA-sequencing cohort. DEGs common in RNA-sequencing dataset and GSE32591 were uploaded to the Connectivity Map (CMap) database to find prospective LN-related drugs. Molecular docking was used to verify the targeting association between candidate small molecular compounds and the potential target. In all, 420 DEGs were identified; five modules and two modules associated with LN were extracted in glomeruli and tubulointerstitia, respectively. Functional enrichment analysis showed that type I interferon (IFN) response was highly active, and some biological processes such as metabolism, detoxification, and ion transport were impaired in LN. Gene transcription in glomeruli and tubulointerstitia might affect each other, and some crosstalk genes, such as IRF7, HLA-DRA, ISG15, PSMB8, and IFITM3, play important roles in this process. Immune cell infiltration analysis revealed that monocytes and macrophages were increased in glomeruli and tubulointerstitia, respectively. CMap analysis identified proscillaridin as a possible drug to treat LN. Molecular docking showed proscillaridin forms four hydrogen bonds with the SH2 domain of signal transducer and activator of transcription 1 (STAT1). The findings of our study may shed light on the pathophysiology of LN and provide potential therapeutic targets for LN.

Highlights

Systemic lupus erythematosus (SLE) is an autoimmune disease involving multiple organs and systems, and its pathophysiology remains unclear (Mu et al, 2015)
For the co-expression modules obtained from the weighted gene co-expression network analysis (WGCNA), we focused on the Differentially expressed genes (DEGs) with log2| fold change| > 1 and p < 0.05 due to their significant changes and performed the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses on DEGs using DAVID1
We performed sequencing in Lupus nephritis (LN) renal tissues and healthy renal tissues to identify DEGs and explore their roles in LN

Summary

Introduction

Systemic lupus erythematosus (SLE) is an autoimmune disease involving multiple organs and systems, and its pathophysiology remains unclear (Mu et al, 2015). We performed a retrospective study for 491 LN patients in China and found that the cumulative probability of survival at 10 and 20 years are 77 and 45%, respectively (Zheng et al, 2012). For the treatment of SLE and LN, most clinicians use high-dose glucocorticoids and immunosuppressants to induce remission, followed by long-term maintenance with small doses. Only 30–50% of the patients achieve remission, and 10–20% of LN patients progress to end-stage renal disease (ESRD) (Maria and Davidson, 2020).

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