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DUSP26 protects against acute kidney injury by dephosphorylating p53 at serine 312

ABSTRACT: Acute kidney injury (AKI) remains a leading cause of morbidity and mortality, yet the molecular pathways driving kidney tubule damage in AKI are not fully understood. Here, we report dual-specificity phosphatase 26 (DUSP26) as a critical regulator of kidney tubule injury in AKI. In our study, DUSP26 expression was markedly reduced in kidney biopsies from AKI patients and in murine models of cisplatin nephrotoxic and ischemic AKI. This down-regulation was driven by hypermethylation of the gene promoter of DUSP26 in kidney tubular cells. Loss of DUSP26 exacerbated tubular damage, whereas knock-in of DUSP26 specifically in kidney proximal tubule cells conferred protection. Mechanistically, DUSP26 directly bound to p53 to dephosphorylate it at serine 312, dampening the transcriptional activity of p53 towards cell death genes. Pharmacologic inhibition of DUSP26 sensitized kidneys to AKI, whereas DUSP26 overexpression was protective. Pharmacologic inhibition of DUSP26 also exacerbated ischemia-reperfusion injury in the liver. These findings uncover DUSP26 as a key phosphatase guarding against tissue injury by dephosphorylating p53 at serine 312, and highlight the DUSP26-p53 axis as a promising therapeutic target.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Cell Culture

SUBMITTER: Ying Fu

LAB HEAD: Zheng Dong

PROVIDER: PXD070789 | Pride | 2026-02-15

REPOSITORIES: Pride

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Project description:Microarray analysis of human kidneys with acute kidney injury (AKI) has been limited because such kidneys are seldom biopsied. However, all kidney transplants experience AKI, and early kidney transplants without rejection are an excellent model for human AKI: they are screened to exclude chronic kidney disease, frequently biopsied, and have extensive follow-up. We used histopathology and microarrays to compare indication biopsies from 28 transplants with AKI to 11 pristine protocol biopsies of stable transplants. Kidneys with AKI showed increased expression of 394 injury-repair response associated transcripts, including many known epithelial injury molecules (e.g. ITGB6, LCN2), tissue remodeling molecules (e.g. VCAN), and inflammation molecules (S100A8, ITGB3). Many other genes also predict the phenotype, depending on statistical filtering rules, including AKI biomarkers as HAVCR1 and IL18. Most mouse orthologs of the top injury-repair transcripts were increased in published mouse AKI models. Pathway analysis of the injury-repair transcripts revealed similarities to cancer, development, and cell movement. The injury-repair transcript score AKI kidneys correlated with reduced function, future recovery, brain death, and need for dialysis, but not future graft loss. In contrast, histologic features of "acute tubular injury" did not correlate with function or with the molecular changes. Thus the injury-repair associated transcripts represent a massive coordinate injury-repair response of kidney parenchyma to AKI, similar to mouse AKI models, and provide an objective measure for assessing the severity of AKI in kidney biopsies and validation for the use of many AKI biomarkers. AKI biopsies sample names and CEL files are from GSE21374. All consenting renal transplant patients undergoing biopsies for cause as standard of care between 09/2004 and 10/2007 at the university of Alberta or between 11/2006 and 02/2007 at the University of Illinois were included in the analysis. In addition to the cores required for standard histopathology, we collected one core for gene expression studies. the relationship between gene expression in the biopsy and subsequent graft loss was analyzed. This dataset is part of the TransQST collection.

			Action	DRS
	EM-CIS.raw	Raw
	LV-CIS.raw	Raw
	Phospho-STY-Sites.txt	Txt
	SI-DU-CIS.raw	Raw
	SI-NC-CIS.raw	Raw

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DUSP26 protects against acute kidney injury by dephosphorylating p53 at serine 312

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