ZFP24 drives SOX9 upregulation and protects tubular epithelial cells during acute kidney injury

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SOX9 is a transcription factor that controls cell-fate determination during embryonic development and adult tissue homeostasis in multiple organs including the kidneys. SOX9 expression is low in the adult kidneys, however, stress conditions can trigger its transcriptional upregulation in tubular epithelial cells. Functionally, SOX9 plays a protective role during the early phase of acute kidney injury (AKI) and facilitates repair during the recovery phase. To identify the upstream transcriptional regulators that drive SOX9 upregulation in tubular epithelial cells, here we have used an unbiased transcription factor screening approach. Our preliminary screening and validation studies show that Zinc finger protein 24 (ZFP24) controls injury induced SOX9 upregulation in tubular epithelial cells. ZFP24, a Cys2-His2 (C2H2) zinc finger protein is essential for oligodendrocyte maturation and myelination, however its role in the kidneys or in SOX9 regulation remains unknown. We find that tubular epithelial ZFP24 gene ablation exacerbates ischemia, rhabdomyolysis, and cisplatin-associated AKI. Importantly, ZFP24 gene deletion results in suppression of SOX9 upregulation in injured tubular epithelial cells. Chromatin immunoprecipitation and promoter luciferase assays confirmed that ZFP24 binds to a specific site in both murine and human SOX9 promoter. Importantly, CRISPR/Cas9 mediated introduction of mutations in the ZFP24 binding site in the SOX9 promoter in vivo led to suppression of SOX9 upregulation during AKI. These findings identify ZFP24 as a critical stress-responsive transcription factor that protects tubular epithelial cells during AKI in part through SOX9 upregulation. The current study was supported by NIDDK 1R01DK132230 grant to N.P. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.