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Published on: November 10, 2021
Identification of fibroblast activation-related genes in two acute kidney injury models
Weiming Deng1, Xiangling Wei1, Zhanwen Dong1
1Department of Kidney Transplantation, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong Province, China.
Background:
Ischemia-reperfusion injury and drug-induced nephrotoxicity are the two most common reasons for acute kidney injury (AKI). However, little attention has been paid to early activation of fibroblasts in the progression of AKI to chronic kidney disease (CKD). The present study aimed to identify related genes and pathways on fibroblast activation in two mouse models of AKI: ischemia-reperfusion injury (IRI) model and folic acid (FA)-induced injury model.
Methods:
The microarray expression profiles of GSE62732 and GSE121190 were downloaded from the GEO database, and the differentially expressed genes (DEGs) was analyzed using the Limma package of R software. Principal component analysis (PCA) was also performed using R. The functional information of gene products was annotated by Gene Ontology (GO) and DAVID online database, and the pathway analysis was carried out by using the Kyoto Encyclopedia of Genes and Genomes pathway (KEGG) database. Protein-protein interactions (PPI) network was constructed by STRING and Cytoscape. Furthermore, in the Hypoxia/Reoxygenation (H/R) model, the morphological changes of cells were observed under microscope and the expression of the hub genes in NRK-49F cells were validated by qRT-PCR assays.
Results:
A total of 457 DEGs were identified. Among these, 215 DEGs were upregulated and 242 DEGs were downregulated in the acute injured samples compared with uninjured samples. The GO enrichment analysis indicated that these DEGs were mainly involved in transport, the oxidation-reduction process, the metabolic process, metal ion binding, hydrolase activity, and oxidoreductase activity. The KEGG analysis revealed that these DEGs were significantly enriched in the PI3K-Akt signaling pathway, protein digestion and absorption pathway, and focal adhesion pathway. The hub genes including Hnf4α, Pck1 and Timp1 were validated by the qRT-PCR assay in NRK-49F cells in the H/R model.
Conclusions:
Hnf4α, Pck1 and Timp-1 may play a pivotal role in the early activation of fibroblasts, providing novel therapeutic strategies for early prediction and treatment of renal fibrosis.
Insights
This study identifies key genes like Hnf4α, Pck1, and Timp-1 involved in fibroblast activation during acute kidney injury (AKI). These findings offer potential therapeutic targets for preventing renal fibrosis progression.
Area of Science:
- Nephrology
- Molecular Biology
- Genomics
Background:
- Acute kidney injury (AKI) from ischemia-reperfusion or nephrotoxicity can progress to chronic kidney disease (CKD).
- Early fibroblast activation is a critical but understudied factor in AKI to CKD transition.
- This study investigates gene expression changes related to fibroblast activation in AKI models.
Purpose of the Study:
- To identify genes and pathways associated with fibroblast activation in AKI.
- To explore the role of fibroblast activation in the progression from AKI to CKD.
- To find potential biomarkers for early AKI detection and therapeutic targets.
Main Methods:
- Analysis of microarray expression profiles (GSE62732, GSE121190) to identify differentially expressed genes (DEGs).
- Utilized R software, Gene Ontology (GO), DAVID, KEGG, STRING, and Cytoscape for data analysis and network construction.
- Validated hub gene expression in a Hypoxia/Reoxygenation (H/R) cell model using qRT-PCR.
Main Results:
- Identified 457 DEGs, with 215 upregulated and 242 downregulated in injured kidney samples.
- GO analysis revealed DEGs involved in transport, oxidation-reduction, and metabolic processes.
- KEGG pathway analysis highlighted enrichment in PI3K-Akt signaling, protein digestion/absorption, and focal adhesion pathways.
- Validated Hnf4α, Pck1, and Timp1 as hub genes in the H/R model.
Conclusions:
- Hnf4α, Pck1, and Timp-1 are identified as key players in early fibroblast activation.
- These genes may serve as novel therapeutic targets for early prediction and treatment of renal fibrosis.
- Understanding fibroblast activation pathways is crucial for managing AKI progression to CKD.
Related Concept Videos
Acute Kidney Injury II: Pathophysiology
Acute Kidney Injury I: Introduction
Acute Kidney Injury IV: Diagnostic Studies and Prevention
Introduction to Fibroblasts
Acute Kidney Injury III: Clinical Manifestations

