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| Natura: | Artículo Open Access |
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Wiley
2024
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| Accesso online: | https://pathsocjournals.onlinelibrary.wiley.com/doi/10.1002/path.6355 |
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| author | Miguel Fontecha‐Barriuso Natalia Villar‐Gomez Juan Guerrero‐Mauvecin Julio M Martinez‐Moreno Susana Carrasco Diego Martin‐Sanchez María Rodríguez‐Laguna Manuel J Gómez María D Sanchez‐Niño Marta Ruiz‐Ortega Alberto Ortiz Ana B Sanz |
| author_facet | Miguel Fontecha‐Barriuso Natalia Villar‐Gomez Juan Guerrero‐Mauvecin Julio M Martinez‐Moreno Susana Carrasco Diego Martin‐Sanchez María Rodríguez‐Laguna Manuel J Gómez María D Sanchez‐Niño Marta Ruiz‐Ortega Alberto Ortiz Ana B Sanz Miguel Fontecha‐Barriuso Natalia Villar‐Gomez Juan Guerrero‐Mauvecin Julio M Martinez‐Moreno Susana Carrasco Diego Martin‐Sanchez María Rodríguez‐Laguna Manuel J Gómez María D Sanchez‐Niño Marta Ruiz‐Ortega Alberto Ortiz Ana B Sanz |
| collection | Wiley Open Access |
| contents | Runt‐related transcription factor 1 ( RUNX1 ) is a mediator of acute kidney injury Miguel Fontecha‐Barriuso Natalia Villar‐Gomez Juan Guerrero‐Mauvecin Julio M Martinez‐Moreno Susana Carrasco Diego Martin‐Sanchez María Rodríguez‐Laguna Manuel J Gómez María D Sanchez‐Niño Marta Ruiz‐Ortega Alberto Ortiz Ana B Sanz The Journal of Pathology 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. 10.1002/path.6355 http://creativecommons.org/licenses/by-nc-nd/4.0/ |
| doi_str_mv | 10.1002/path.6355 |
| format | Artículo Open Access |
| id | wiley_oa_10_1002_path_6355 |
| institution | Wiley Open Access |
| license_str_mv | http://creativecommons.org/licenses/by-nc-nd/4.0/ |
| publishDate | 2024 |
| publisher | Wiley |
| record_format | wiley_oa |
| spellingShingle | Runt‐related transcription factor 1 ( RUNX1 ) is a mediator of acute kidney injury Miguel Fontecha‐Barriuso Natalia Villar‐Gomez Juan Guerrero‐Mauvecin Julio M Martinez‐Moreno Susana Carrasco Diego Martin‐Sanchez María Rodríguez‐Laguna Manuel J Gómez María D Sanchez‐Niño Marta Ruiz‐Ortega Alberto Ortiz Ana B Sanz The Journal of Pathology Runt‐related transcription factor 1 ( RUNX1 ) is a mediator of acute kidney injury Miguel Fontecha‐Barriuso Natalia Villar‐Gomez Juan Guerrero‐Mauvecin Julio M Martinez‐Moreno Susana Carrasco Diego Martin‐Sanchez María Rodríguez‐Laguna Manuel J Gómez María D Sanchez‐Niño Marta Ruiz‐Ortega Alberto Ortiz Ana B Sanz The Journal of Pathology 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. 10.1002/path.6355 http://creativecommons.org/licenses/by-nc-nd/4.0/ |
| title | Runt‐related transcription factor 1 ( RUNX1 ) is a mediator of acute kidney injury |
| topic | The Journal of Pathology |
| url | https://pathsocjournals.onlinelibrary.wiley.com/doi/10.1002/path.6355 |