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

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

doi:10.1074/jbc.ra120.015110

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, 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.

Highlights

Acute kidney injury (AKI) is a common clinical condition associated with diverse etiologies and abrupt loss of renal function
We find that Vgf nerve growth factor inducible gene up-regulation is a common transcriptional stress response in renal tubular epithelial cells (RTEC) to ischemia, cisplatin, and rhabdomyolysis-associated renal injury
We found that TLQP-21 levels were increased in the renal tissues of WT mice challenged with ischemia, cisplatin, and rhabdomyolysis-associated AKI (Fig. 5A)

Summary

Introduction

Acute kidney injury (AKI) is a common clinical condition associated with diverse etiologies and abrupt loss of renal function. 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. 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. Patients who survive an episode of AKI are at increased risk for major adverse cardiovascular events and progression to chronic kidney disease [8] Disorders such as sepsis, cancer, and rhabdomyolysis and therapeutic interventions such as cardiac surgery and chemotherapy are associated with inflammatory, toxic, and hypoxic insults to renal tubular epithelial cells (RTECs).

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