Inhibition of BRD4 Attenuates ER Stress-induced Renal Ischemic-Reperfusion Injury

Diaz-Bulnes, Paula; Rodríguez, Ramon M; Banon-Maneus, Elisenda; Saiz, María Laura; Bernet, Cristian Ruiz; Corte-Iglesias, Viviana; Ramirez-Bajo, Maria Jose; Lazo-Rodriguez, Marta; Tamargo-Gómez, Isaac; Rodrigues-Diez, Raúl R.; Sanz, Ana B; Diaz-Corte, Carmen; Ruiz-Ortega, Marta; Diekmann, Fritz; Aransay, Ana M; Lopez-Larrea, Carlos; Suarez-Alvarez, Beatriz

doi:10.7150/ijbs.83040

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Int J Biol Sci 2024; 20(5):1547-1562. doi:10.7150/ijbs.83040 This issue Cite

Research Paper

Inhibition of BRD4 Attenuates ER Stress-induced Renal Ischemic-Reperfusion Injury

Paula Diaz-Bulnes^1,2, Ramon M Rodríguez^1,3, Elisenda Banon-Maneus^2,4, María Laura Saiz^1,2, Cristian Ruiz Bernet^1,2, Viviana Corte-Iglesias^1,2, Maria Jose Ramirez-Bajo^2,4, Marta Lazo-Rodriguez⁴, Isaac Tamargo-Gómez⁵, Raúl R. Rodrigues-Diez^1,2, Ana B Sanz^6,2, Carmen Diaz-Corte^1,2,7, Marta Ruiz-Ortega^8,2, Fritz Diekmann^2,4,9, Ana M Aransay^10,11, Carlos Lopez-Larrea^1,2,✉, Beatriz Suarez-Alvarez^1,2,✉

1. Translational Immunology, Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), 33011 Oviedo, Spain.
2. RICORS2040 (Kidney Disease), Instituto de Salud Carlos III, 28029 Madrid, Spain.
3. Lipids in Human Pathology, Health Research Institute of the Balearic Islands (IdISBa), Research Unit, University Hospital Son Espases, 07120 Palma, Spain.
4. Laboratori Experimental de Nefrologia i Trasplantament (LENIT), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
5. Autophagy and Metabolism Laboratory, Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Spain.
6. Laboratorio de Nefrología Experimental, Instituto de Investigación Sanitaria-Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Madrid, Spain.
7. Servicio de Nefrología, Hospital Universitario Central de Asturias, Oviedo, Asturias, Spain.
8. Cellular Biology in Renal Diseases Laboratory, IIS-Fundación Jiménez Díaz, Universidad Autónoma Madrid, 28040 Madrid, Spain.
9. Departmento de Nefrologia y Transplante Renal, Institut Clínic de Nefrologia i Urologia, Hospital Clínic Barcelona, Barcelona, Spain
10. Genome Analysis Platform, CIC bioGUNE-BRTA, Derio, Spain.
11. Centro de Investigación Biomédica en Red en el Área Temática de Enfermedades Hepáticas (CIBERehd), Madrid, Spain.

Citation:

Diaz-Bulnes P, Rodríguez RM, Banon-Maneus E, Saiz ML, Bernet CR, Corte-Iglesias V, Ramirez-Bajo MJ, Lazo-Rodriguez M, Tamargo-Gómez I, Rodrigues-Diez RR, Sanz AB, Diaz-Corte C, Ruiz-Ortega M, Diekmann F, Aransay AM, Lopez-Larrea C, Suarez-Alvarez B. Inhibition of BRD4 Attenuates ER Stress-induced Renal Ischemic-Reperfusion Injury. Int J Biol Sci 2024; 20(5):1547-1562. doi:10.7150/ijbs.83040. https://www.ijbs.com/v20p1547.htm

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Abstract

Renal ischemia-reperfusion injury (IRI) leads to endoplasmic reticulum (ER) stress, thereby initiating the unfolded protein response (UPR). When sustained, this response may trigger the inflammation and tubular cell death that acts to aggravate the damage. Here, we show that knockdown of the BET epigenetic reader BRD4 reduces the expression of ATF4 and XBP1 transcription factors under ER stress activation. BRD4 is recruited to the promoter of these highly acetylated genes, initiating gene transcription. Administration of the BET protein inhibitor, JQ1, one hour after renal damage induced by bilateral IRI, reveals reduced expression of ATF4 and XBP1 genes, low KIM-1 and NGAL levels and recovery of the serum creatinine and blood urea nitrogen levels. To determine the molecular pathways regulated by ATF4 and XBP1, we performed stable knockout of both transcription factors using CRISPR-Cas9 and RNA sequencing. The pathways triggered under ER stress were mainly XBP1-dependent, associated with an adaptive UPR, and partially regulated by JQ1. Meanwhile, treatment with JQ1 downmodulated most of the pathways regulated by ATF4 and related to the pathological processes during exacerbated UPR activation. Thus, BRD4 inhibition could be useful for curbing the maladaptive UPR activation mechanisms, thereby ameliorating the progression of renal disease.

Keywords: BRD4, ER stress, UPR, renal damage, Hypoxia

Citation styles

APA

Diaz-Bulnes, P., Rodríguez, R.M., Banon-Maneus, E., Saiz, M.L., Bernet, C.R., Corte-Iglesias, V., Ramirez-Bajo, M.J., Lazo-Rodriguez, M., Tamargo-Gómez, I., Rodrigues-Diez, R.R., Sanz, A.B., Diaz-Corte, C., Ruiz-Ortega, M., Diekmann, F., Aransay, A.M., Lopez-Larrea, C., Suarez-Alvarez, B. (2024). Inhibition of BRD4 Attenuates ER Stress-induced Renal Ischemic-Reperfusion Injury. International Journal of Biological Sciences, 20(5), 1547-1562. https://doi.org/10.7150/ijbs.83040.

ACS

Diaz-Bulnes, P.; Rodríguez, R.M.; Banon-Maneus, E.; Saiz, M.L.; Bernet, C.R.; Corte-Iglesias, V.; Ramirez-Bajo, M.J.; Lazo-Rodriguez, M.; Tamargo-Gómez, I.; Rodrigues-Diez, R.R.; Sanz, A.B.; Diaz-Corte, C.; Ruiz-Ortega, M.; Diekmann, F.; Aransay, A.M.; Lopez-Larrea, C.; Suarez-Alvarez, B. Inhibition of BRD4 Attenuates ER Stress-induced Renal Ischemic-Reperfusion Injury. Int. J. Biol. Sci. 2024, 20 (5), 1547-1562. DOI: 10.7150/ijbs.83040.

NLM

CSE

Diaz-Bulnes P, Rodríguez RM, Banon-Maneus E, Saiz ML, Bernet CR, Corte-Iglesias V, Ramirez-Bajo MJ, Lazo-Rodriguez M, Tamargo-Gómez I, Rodrigues-Diez RR, Sanz AB, Diaz-Corte C, Ruiz-Ortega M, Diekmann F, Aransay AM, Lopez-Larrea C, Suarez-Alvarez B. 2024. Inhibition of BRD4 Attenuates ER Stress-induced Renal Ischemic-Reperfusion Injury. Int J Biol Sci. 20(5):1547-1562.

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