The transcription factor Fosl1 preserves Klotho expression and protects from acute kidney injury
EntityUAM. Departamento de Anatomía Patológica
10.1016/ j.kint.2022.11.023Kidney International 103.4 (2023): 686–701
ISSN1523-1755 (online); 0085-2538 (print)
Funded byThis research was funded by Instituto de Salud Carlos III (ISCIII)–Fondo de Investigacion Sanitaria (FIS)–Fondo Europeo de Desarrollo Regional (FEDER) grants PI18/01366 and PI21/00251 and ISCIII-RETIC REDinREN RD16/0009. We acknowledge Comunidad de Madrid en Biomedicina grant B2017/BMD-3686 CIFRA2-CM and ISCIII FIS/FEDER grants PI19/00588, PI19/00815, European Research Area-PerMedJTC2018 KIDNEY ATTACK AC18/00064, and ISCIII Red de Investigación Cooperativa Orientada a Resultados en Salud (RICORS) program to RICORS2040 (RD21/0005/0001). MDS-N was supported by Spain’s Ministry of Science and Innovation (MICINN) Ramon y Cajal program RYC2018-024461-I. LC was supported by grant FPI-UAM 2018
ProjectGobierno de España. PI18/01366; Gobierno de España. PI21/00251; Comunidad de Madrid. B2017/BMD-3686/CIFRA2; Gobierno de España. PI19/00588; Gobierno de España. PI19/00815
Subjectsacute kidney injury; AP-1; cisplatin; Fosl1; inflammation; klotho; nephrotoxicity; Medicina
Rights© 2022, International Society of Nephrology
Esta obra está bajo una licencia de Creative Commons Reconocimiento-NoComercial-SinObraDerivada 4.0 Internacional.
Increased expression of AP-1 transcription factor components has been reported in acute kidney injury (AKI). However, the role of specific components, such as Fosl1, in tubular cells or AKI is unknown. Upstream regulator analysis of murine nephrotoxic AKI transcriptomics identified AP-1 as highly upregulated. Among AP-1 canonical components, Fosl1 was found to be upregulated in two transcriptomics datasets from nephrotoxic murine AKI induced by folic acid or cisplatin and from proximal tubular cells exposed to TWEAK, a cytokine mediator of AKI. Fosl1 was minimally expressed in the kidneys of control uninjured mice. Increased Fosl1 protein was localized to proximal tubular cell nuclei in AKI. In human AKI, FOSL1 was found present in proximal tubular cells in kidney sections and in urine along with increased urinary FOSL1 mRNA. Selective Fosl1 deficiency in proximal tubular cells (Fosl1Dtub) increased the severity of murine cisplatin- or folate-induced AKI as characterized by lower kidney function, more severe kidney inflammation and Klotho downregulation. Indeed, elevated AP-1 activity was observed after cisplatin-induced AKI in Fosl1Dtub mice compared to wild-type mice. More severe Klotho downregulation preceded more severe kidney dysfunction. The Klotho promoter was enriched in Fosl1 binding sites and Fosl1 bound to the Klotho promoter in cisplatin-AKI. In cultured proximal tubular cells, Fosl1 targeting increased the proinflammatory response and downregulated Klotho. In vivo, recombinant Klotho administration protected Fosl1Dtub mice from cisplatin-AKI. Thus, increased proximal tubular Fosl1 expression during AKI is an adaptive response, preserves Klotho, and limits the severity of tubular cell injury and AKI
Google Scholar:Cuarental Pérez, Leticia - Ribagorda, Marta - Ceballos, Maria I. - Pintor Chocano, Aranzazu - Carriazo, Sol M. - Dopazo, Ana - Vázquez, Enrique - Suárez-Álvarez, Beatriz - Cannata Ortiz, Pablo Javier - Sanz, Ana B. - Ortiz Arduán, Alberto - Sánchez Niño, María Dolores
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Moreno, Juan A.; Izquierdo, María Concepción; Sánchez Niño, María Dolores; Suárez-Álvarez, Beatriz; López-Larrea, Carlos; Jakubowski, Aniela; Blanco-Parra, Jualia A.; Ramírez Tapia, Rafael; Selgas Gutiérrez, Rafael; Ruiz Ortega, Marta; Egido de los Ríos, Jesús; Ortiz Arduán, Alberto; Sanz, Ana Belén