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

Abstract

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 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 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, 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 tubular epithelial cells.

Downregulation of SOX9 suppresses breast cancer cell proliferation and migration by regulating apoptosis and cell cycle arrest

“…SOX9 is a member of the SOX family, which controls the expression of numerous genes, such as VGF nerve growth factor inducible ( 22 , 23 ). Since it is a transcriptional factor, drugs to inhibit SOX may have highly toxic side effects ( 22 ).…”

Nephrotoxicity of the BRAF-kinase inhibitor Vemurafenib is driven by off-target Ferrochelatase inhibition

“…2 D&F) showed significant tubular epithelial cell-death. In C57B6/J mice, several injury 30 , repair 31 and inflammatory genes [32][33][34][35] are upregulated during ischemia, cisplatin, and rhabdomyolysis associated AKI 36 . We found a similar increase in injury, repair, and inflammation-related genes during vemurafenib nephrotoxicity (Fig.…”

Mouse Models of Acute Kidney Injury

“…Rhabdomyolysis-associated AKI can be mimicked in murine models through glycerol injection in the hind-leg muscles [27]. In this model, a single bilateral intramuscular injection (7.5 mL/kg 50% glycerol) results in development of AKI within 24 hours.…”

“…On day three post-cisplatin injection, sacrifice the mice by carbon dioxide euthanasia followed by serum and renal tissue collection for further analysis. Kidney injury can then be evaluated by serum analysis [blood urea nitrogen (BUN) and creatinine], histological analysis [hematoxylin-eosin (H&E) staining], and examination of renal expression of injury biomarkers [kidney injury molecule-1 (KIM1) and neutrophil gelatinase-associated lipocalin (NGAL)] [26,27]. Blood urine nitrogen and enzymatic assay-based creatinine measurements can be performed in serum or plasma samples using commercially available kits.…”