TY - JOUR
T1 - Zinc finger protein 24-dependent transcription factor SOX9 up-regulation protects tubular epithelial cells during acute kidney injury
AU - Kim, Ji Young
AU - Silvaroli, Josie A.
AU - Martinez, Gabriela Vasquez
AU - Bisunke, Bijay
AU - Luna Ramirez, Alanys V.
AU - Jayne, Laura A.
AU - Feng, Mei Ji He Ho
AU - Girotra, Bhavya
AU - Acosta Martinez, Shirely M.
AU - Vermillion, Corynne R.
AU - Karel, Isaac Z.
AU - Ferrell, Nicholas
AU - Weisleder, Noah
AU - Chung, Sangwoon
AU - Christman, John W.
AU - Brooks, Craig R.
AU - Madhavan, Sethu M.
AU - Hoyt, Kari R.
AU - Cianciolo, Rachel E.
AU - Satoskar, Anjali A.
AU - Zepeda-Orozco, Diana
AU - Sullivan, Jennifer C.
AU - Davidson, Alan J.
AU - Bajwa, Amandeep
AU - Pabla, Navjot Singh
N1 - Publisher Copyright:
© 2023 International Society of Nephrology
PY - 2023/6
Y1 - 2023/6
N2 - Transcriptional profiling studies have identified several protective genes upregulated in tubular epithelial cells during acute kidney injury (AKI). Identifying upstream transcriptional regulators could lead to the development of therapeutic strategies augmenting the repair processes. SOX9 is a transcription factor controlling cell-fate during embryonic development and adult tissue homeostasis in multiple organs including the kidneys. SOX9 expression is low in adult kidneys; however, stress conditions can trigger its transcriptional upregulation in tubular epithelial cells. SOX9 plays a protective role during the early phase of AKI and facilitates repair during the recovery phase. To identify the upstream transcriptional regulators that drive SOX9 upregulation in tubular epithelial cells, we used an unbiased transcription factor screening approach. Preliminary screening and validation studies show that zinc finger protein 24 (ZFP24) governs 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. Here, we found that tubular epithelial ZFP24 gene ablation exacerbated ischemia, rhabdomyolysis, and cisplatin-associated AKI. Importantly, ZFP24 gene deletion resulted in suppression of SOX9 upregulation in injured tubular epithelial cells. Chromatin immunoprecipitation and promoter luciferase assays confirmed that ZFP24 bound to a specific site in both murine and human SOX9 promoters. Importantly, CRISPR/Cas9-mediated mutation in the ZFP24 binding site in the SOX9 promoter in vivo led to suppression of SOX9 upregulation during AKI. Thus, our findings identify ZFP24 as a critical stress-responsive transcription factor protecting tubular epithelial cells through SOX9 upregulation.
AB - Transcriptional profiling studies have identified several protective genes upregulated in tubular epithelial cells during acute kidney injury (AKI). Identifying upstream transcriptional regulators could lead to the development of therapeutic strategies augmenting the repair processes. SOX9 is a transcription factor controlling cell-fate during embryonic development and adult tissue homeostasis in multiple organs including the kidneys. SOX9 expression is low in adult kidneys; however, stress conditions can trigger its transcriptional upregulation in tubular epithelial cells. SOX9 plays a protective role during the early phase of AKI and facilitates repair during the recovery phase. To identify the upstream transcriptional regulators that drive SOX9 upregulation in tubular epithelial cells, we used an unbiased transcription factor screening approach. Preliminary screening and validation studies show that zinc finger protein 24 (ZFP24) governs 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. Here, we found that tubular epithelial ZFP24 gene ablation exacerbated ischemia, rhabdomyolysis, and cisplatin-associated AKI. Importantly, ZFP24 gene deletion resulted in suppression of SOX9 upregulation in injured tubular epithelial cells. Chromatin immunoprecipitation and promoter luciferase assays confirmed that ZFP24 bound to a specific site in both murine and human SOX9 promoters. Importantly, CRISPR/Cas9-mediated mutation in the ZFP24 binding site in the SOX9 promoter in vivo led to suppression of SOX9 upregulation during AKI. Thus, our findings identify ZFP24 as a critical stress-responsive transcription factor protecting tubular epithelial cells through SOX9 upregulation.
KW - Sox9 (sex-determining region Y [SRY] box 9)
KW - Zinc finger protein (ZFP24)
KW - acute kidney injury (AKI)
KW - cisplatin
KW - ischemia
KW - renal tubular epithelial cells (RTECs)
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UR - http://www.scopus.com/inward/citedby.url?scp=85151284633&partnerID=8YFLogxK
U2 - 10.1016/j.kint.2023.02.026
DO - 10.1016/j.kint.2023.02.026
M3 - Article
C2 - 36921719
AN - SCOPUS:85151284633
SN - 0085-2538
VL - 103
SP - 1093
EP - 1104
JO - Kidney International
JF - Kidney International
IS - 6
ER -