MO285: FOSL1 Preserves Klotho Expression and Limits Acute Kidney Injury

Abstract

Abstract BACKGROUND AND AIMS Fosl1 (FRA1, Fos-related-antigen 1) is a transcription factor of the AP-1 complex (activator protein 1) that regulates the expression of genes that regulates processes involved in acute kidney injury (AKI) such differentiation, inflammation, proliferation and cell death. We have now explored the role of Fosl1 in AKI and repair. METHOD The function of Fosl1 was explored in murine nephrotoxic AKI induced by folic acid or cisplatin in wild type and genetically modified mice tubular cell Fosl1 deficient mice (Fosl1Δtub). RT-qPCR, western blot, and immunohistochemistry were used to assess gene and protein expression. Direct regulation of Klotho by Fosl1 was explored by chromatin immunoprecipitation (ChIP). Murine tubular cells were cultured in an inflammatory milieu promoted by TWEAK and Fosl1 was targeted by siRNA. RESULTS Fosl1 was one of the most upregulated transcription factors in experimental nephrotoxic AKI transcriptomics and also one the transcription factors binding to the Klotho promoter (Panel A). Fosl1 upregulation was confirmed in experimental nephrotoxic AKI and in human AKI and localized to tubular cell nuclei at early times points (panel B). Fosl1 deficient (Fosl1Δtub) mice developed more severe folic acid- or cisplatin-induced AKI and higher proinflammatory cytokine expression and kidney macrophage infiltration (Panel C). Additionally, kidney expression of the nephroprotective and antiaging factor Klotho was more severely depressed in Fosl1Δtub mice (Panel D). Enrichment of AP1 binding sites was found in the Klotho promoter and we confirmed direct Fosl1 binding to the Klotho promoter in a ChIP assay. Moreover, Fosl1Δtub mice had disturbed expression of cell cycle regulators and PCNA expression, suggesting a dysregulation in kidney repair. In tubular cells cultured in an inflammatory milieu, Fosl1 expression was also upregulated. Fosl1 siRNA targeting in cultured tubular cells increased inflammatory gene expression and cell death and decreased Klotho expression. CONCLUSION Fosl1 contributes to an adaptive kidney response during AKI that limits kidney injury and includes Klotho expression and Fosl1 deficiency promotes an accelerated loss of klotho and more severe AKI.