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. 2024 Dec;264(4):396-410.
doi: 10.1002/path.6355. Epub 2024 Oct 29.

Runt-related transcription factor 1 (RUNX1) is a mediator of acute kidney injury

Miguel Fontecha-Barriuso #  1   2 , Natalia Villar-Gomez #  1   2 , Juan Guerrero-Mauvecin  1   2 , Julio M Martinez-Moreno  1 , Susana Carrasco  1 , Diego Martin-Sanchez  1 , María Rodríguez-Laguna  3 , Manuel J Gómez  4 , María D Sanchez-Niño  1   2   5 , Marta Ruiz-Ortega  1   2   6 , Alberto Ortiz  1   2   6   7 , Ana B Sanz  1   2
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Runt-related transcription factor 1 (RUNX1) is a mediator of acute kidney injury

Miguel Fontecha-Barriuso et al. J Pathol. 2024 Dec.

Abstract

Treatment for acute kidney injury (AKI) is suboptimal. A better understanding of the pathogenesis of AKI may lead to new therapeutic approaches. Kidney transcriptomics of folic acid-induced AKI (FA-AKI) in mice identified Runx1 as the most upregulated RUNX family gene. We then examined the expression of RUNX1 in FA-AKI, in bacterial lipopolysaccharide (LPS)-induced cytokine storm-AKI (CS-AKI), and in human AKI. In cultured mouse tubule cells, we explored the expression and role of RUNX1 in response to the cytokine TWEAK or LPS. A chemical inhibitor of RUNX1 (Ro5-3335) was used in animal models of AKI to test its potential as a therapeutic target. RUNX1 overexpression in FA-AKI was validated at the mRNA and protein levels and localized mainly to tubule cell nuclei. CS-AKI also upregulated kidney RUNX1. Increased tubule and interstitial RUNX1 expression were also observed in human AKI. In cultured mouse tubule cells, the pro-inflammatory cytokine TWEAK and LPS increased RUNX1 and IL-6 expression. Mechanistically, RUNX1 bound to the Il6 gene promoter and RUNX1 targeting with the chemical inhibitor Ro5-3335, or a specific small interfering RNA (siRNA), prevented the TWEAK- and LPS-induced upregulation of IL6 through a RUNX1/NFκB1 p50 pathway. In vivo, preventive Ro5-3335 improved kidney function and reduced inflammation in FA-AKI and CS-AKI. However, Ro5-3335 administration after the insult only improved kidney function in CS-AKI. Kidney transcriptomics identified inflammatory genes and transcription factor mRNAs such as Yap1 and Trp53 as key targets of Ro5-3335 in CS-AKI. In conclusion, RUNX1 contributes to AKI by driving the expression of genes involved in inflammation and represents a novel therapeutic target in AKI. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Keywords: LPS; RUNX1; Ro5‐3335; TWEAK; acute kidney injury; inflammation.

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References

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