title: Downregulation of kidney protective factors by inflammation: role of transcription factors and epigenetic mechanisms.
abstract: Chronic kidney disease (CKD) is associated to an increased risk of death, CKD progression, and acute kidney injury (AKI) even from early stages, when glomerular filtration rate (GFR) is preserved. The link between early CKD and these risks is unclear, since there is no accumulation of uremic toxins. However, pathological albuminuria and kidney inflammation are frequent features of early CKD, and the production of kidney protective factors may be decreased. Indeed, Klotho expression is already decreased in CKD category G1 (normal GFR). Klotho has anti-aging and nephroprotective properties, and decreased Klotho levels may contribute to increase the risk of death, CKD progression, and AKI. In this review, we discuss the downregulation by mediators of inflammation of molecules with systemic and/or renal local protective functions, exemplified by Klotho and peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), a transcription factor that promotes mitochondrial biogenesis. Cytokines such as TWEAK, TNF-α, or transforming growth factor -β1 produced locally during kidney injury or released from inflammatory sites at other organs may decrease kidney expression of Klotho and PGC-1α or lead to suboptimal recruitment of these nephroprotective proteins. Transcription factors (e.g., Smad3 and NF-κB) and epigenetic mechanisms (e.g., histone acetylation or methylation) contribute to downregulate the expression of Klotho and/or PGC-1α, while histone crotonylation promotes PGC-1α expression. NF-κBiz facilitates the repressive effect of NF-κB on Klotho expression. A detailed understanding of these mediators may contribute to the development of novel therapeutic approaches to prevent CKD progression and its negative impact on mortality and AKI.
authors.affiliation: IIS-Fundación Jiménez Díaz, School of Medicine, Universidad Autónoma de Madrid.|REDINREN, Madrid, Spain; and.
authors.forename: Olga
authors.initials: O
authors.lastname: Ruiz-Andres
authors.affiliation: IIS-Fundación Jiménez Díaz, School of Medicine, Universidad Autónoma de Madrid.|REDINREN, Madrid, Spain; and.
authors.forename: Maria Dolores
authors.initials: MD
authors.lastname: Sanchez-Niño
authors.affiliation: IIS-Fundación Jiménez Díaz, School of Medicine, Universidad Autónoma de Madrid.
authors.forename: Juan Antonio
authors.initials: JA
authors.lastname: Moreno
authors.affiliation: IIS-Fundación Jiménez Díaz, School of Medicine, Universidad Autónoma de Madrid.|REDINREN, Madrid, Spain; and.
authors.forename: Marta
authors.initials: M
authors.lastname: Ruiz-Ortega
authors.affiliation: IIS-Fundación Jiménez Díaz, School of Medicine, Universidad Autónoma de Madrid.|REDINREN, Madrid, Spain; and.
authors.forename: Adrian Mario
authors.initials: AM
authors.lastname: Ramos
authors.affiliation: IIS-Fundación Jiménez Díaz, School of Medicine, Universidad Autónoma de Madrid.|REDINREN, Madrid, Spain; and.
authors.forename: Ana Belen
authors.initials: AB
authors.lastname: Sanz
authors.affiliation: IIS-Fundación Jiménez Díaz, School of Medicine, Universidad Autónoma de Madrid; aortiz@fjd.es.|REDINREN, Madrid, Spain; and.|Fundación Renal Iñigo Alvarez de Toledo-IRSIN, Madrid, Spain.
authors.forename: Alberto
authors.identifier: 0000-0002-9805-9523
authors.initials: A
authors.lastname: Ortiz
mesh_terms: D000818:Animals; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation; D044127:Epigenesis, Genetic; D005966:Glucuronidase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000378:metabolism* / Q000473:pathology; D007668:Kidney / Q000378:metabolism* / Q000473:pathology; D000090265:Klotho Proteins; D065840:Protective Factors; D051436:Renal Insufficiency, Chronic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D016207:Cytokines; D014157:Transcription Factors; D005966:Glucuronidase; D000090265:Klotho Proteins
keywords: Klotho; NF-κB; NF-κBiz; PGC-1α; TWEAK; acetylation; acute kidney injury; aging; chronic kidney disease; crotonylation; epigenetic; inflammation; mitochondria; phosphate