SOX9 promotes stress-responsive transcription of VGF nerve growth factor inducible gene in kidney epithelial cells

Abstract

<jats:title>Abstract</jats:title><jats:p>Acute kidney injury (AKI) is a common clinical condition associated with diverse etiologies and abrupt loss of renal function. In patients with sepsis, rhabdomyolysis, cancer, as well as cardiovascular disorders, the underlying disease or associated therapeutic interventions can cause hypoxic, cytotoxic, and inflammatory insults to renal tubular epithelial cells (RTECs) resulting in the onset of AKI. To uncover stress-responsive disease-modifying genes, here we have carried out renal transcriptome profiling in three distinct murine models of AKI. We find that Vgf nerve growth factor inducible gene upregulation is a common transcriptional stress response in RTECs to ischemia, cisplatin, and rhabdomyolysis-associated renal injury. The Vgf gene encodes a secretory peptide precursor protein that has critical neuro-endocrine functions; however, its role in the kidneys remains unknown. Our functional studies show that RTEC-specific Vgf gene ablation exacerbates ischemia, cisplatin, and rhabdomyolysis-associated AKI in vivo and cisplatin-induced RTEC cell death in vitro. Importantly, addback experiments showed that aggravation of cisplatin-induced renal injury caused by Vgf gene ablation is partly reversed by TLQP-21, a Vgf-derived peptide. Finally, in vitro and in vivo mechanistic studies showed that injury-induced Vgf upregulation in RTECs is driven by the transcriptional regulator Sox9. These findings reveal a crucial downstream target of the Sox9-directed transcriptional program and identify Vgf as a stress-responsive protective gene in kidney epithelial cells.</jats:p>

Identification and validation of the diagnostic signature associated with immune microenvironment of acute kidney injury based on ferroptosis-related genes through integrated bioinformatics analysis and machine learning

“…In the present study, we aimed to identify novel diagnostic FRGs genes for AKI based on bioinformatics and machine learning. We analyzed our previously uploaded dataset GSE192883 (Chen et al, 2022) and another mouse dataset GSE153625 (Kim et al, 2020) from GEO database using limma and WGCNA analysis, and identified 885 coDEGs. Enrichment analysis showed that these genes were mainly enriched in Complement and Coagulation Cascades, Cell Cycle, and Oxidoreductase Activity.…”

“…In the present study, we aimed to identify novel diagnostic ferroptosis-related genes (FRGs) for AKI based on bioinformatics and machine learning. We analyzed our previously uploaded dataset GSE192883 (Chen et al, 2022) and another mouse dataset GSE153625 (Kim et al, 2020) from Gene Expression Omnibus (GEO) database to determine common differentially expressed genes (DEGs) and hub FRGs between AKI and Control specimens. Then, we analyzed their diagnostic value in AKI using machine learning and receiver operator characteristic (ROC) curve analysis.…”

Bibliometric and visualization analysis of kidney repair associated with acute kidney injury from 2002 to 2022

“…Furthermore, multiple upstream and downstream molecules or mechanisms are involved in the renal repair process via Sox9 in AKI. Sox9 drives the upregulation of VGF nerve growth factor in multiple AKI models and acts as a stress-responsive protective gene in TECs (Kim et al, 2020). In IRI and folic acid (FA)-induced AKI models, early growth response 1 (EGR1) can increase Sox9 expression in kidney TECs by directly binding to the promoter of the Sox9 gene, consequently promoting Sox9 cell proliferation by activating the Wnt/β-catenin pathway (Chen et al, 2022).…”