Runt-related Transcription Factor 1 (RUNX1) is a mediator of acute kidney injury

Treatment for acute kidney injury (AKI) is suboptimal. A better understanding of its pathogenesis may lead to new therapeutic approaches. Kidney transcriptomics analyses of murine folic acid-induced AKI (FA-AKI) identified Runx1 as the most upregulated RUNX family gene. RUNX1 overexpression in FA-AKI was validated at the mRNA and protein levels and localized mainly to tubular cell nuclei. Bacterial lipopolysaccharide (LPS)-induced cytokine storm-AKI also upregulated kidney RUNX1. Increased tubular and interstitial RUNX1 expression were also observed in human AKI. In cultured murine tubular cells, the proinflammatory cytokine TWEAK and LPS increased RUNX1 and IL-6 expression. Mechanistically, RUNX1 bound to the Il-6 gene promoter while RUNX1 targeting with either the chemical inhibitor Ro5-3335 or a specific small interfering RNA (siRNA) prevented the TWEAK- and LPS-induced upregulation of IL-6 through a RUNX1/NFκB p50 pathway. TWEAK and LPS also induced RUNX1 binding to the promoter of Cdkn1a which encodes the cyclin-dependent kinase inhibitor p21 and increased p21 expression. In vivo, preventive Ro5-3335 improved kidney function and reduced inflammation and p21 expression in both FA-AKI, and in cytokine storm-AKI. However, administration of Ro5-3335 after the insult only improved kidney function in cytokine storm-AKI. Kidney transcriptomics identified inflammatory genes and the transcription factor Yap1 as key targets of Ro5-3335 in cytokine storm-AKI. In conclusion, RUNX1 contributes to AKI by driving the expression of genes involved in inflammation and represents a novel therapeutic target in AKI. To invetigate the role of RUNX1 in cytokine storm-AKI (CS-AKI), we perfomed an animal model of cytokine storm by i.p. LPS injection. One group of mice received a dose of an inhibitor of RUNX1, Ro5-3335, before LPS injection. All mice were sacrificed at 24 hours later. We used C57BL/6 female mice (Charles River Laboratories, Ecully, France), 12- to 14-week-old, and 19-21 gr of weight We then performed gene expression profiling analysis usining data from RNA-seq of 4 different experimental groups: Control, Ro5-3335, CS-AKI and CS-AKI+Ro5-3335.