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

Kim, Ji Young; Bai, Yuntao; Jayne, Laura A; Abdulkader, Ferdos; Gandhi, Megha; Perreau, Tayla; Parikh, Samir V; Gardner, David S.; Davidson, Alan J; Sander, Veronika; Song, Min Ae; Bajwa, Amandeep; Pabla, Navjot Singh

Abstract

© 2020 Kim et al. 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, and cardiovascular disorders, the underlying disease or associated therapeutic interventions can cause hypoxia, cytotoxicity, 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 up-regulation 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 neuroendocrine 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, 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 up-regulation 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 tubular epithelial cells.

Citation

Kim, J. Y., Bai, Y., Jayne, L. A., Abdulkader, F., Gandhi, M., Perreau, T., …Pabla, N. S. (2020). SOX9 promotes stress-responsive transcription of VGF nerve growth factor inducible gene in renal tubular epithelial cells. Journal of Biological Chemistry, 295(48), 16328-16341. https://doi.org/10.1074/jbc.RA120.015110

• Journal Article Type: Article
• Acceptance Date: Sep 3, 2020
• Online Publication Date: Sep 4, 2020
• Publication Date: Nov 27, 2020
• Deposit Date: Sep 14, 2020
• Publicly Available Date: Sep 5, 2021
• Journal: The Journal of biological chemistry
• Print ISSN: 0021-9258
• Electronic ISSN: 1083-351X
• Publisher: American Society for Biochemistry and Molecular Biology
• Peer Reviewed: Peer Reviewed
• Volume: 295
• Issue: 48
• Article Number: jbc.RA120.015110
• Pages: 16328-16341
• DOI: https://doi.org/10.1074/jbc.RA120.015110
• Keywords: Cell Biology; Biochemistry; Molecular Biology
• Public URL: https://nottingham-repository.worktribe.com/output/4903608
• Publisher URL: https://www.jbc.org/content/early/2020/09/04/jbc.RA120.015110