Downregulation of kidney protective factors by inflammation: role of transcription factors and epigenetic mechanisms

作者：Ruiz Andres Olga; Dolores Sanchez Nino Maria; Antonio Moreno Juan; Ruiz Ortega Marta; Mario Ramos Adrian; Belen Sanz Ana; Ortiz Alberto^*

来源：American Journal of Physiology - Renal Fluid and Electrolyte Physiology, 2016, 311(6): F1329-F1340.

DOI：10.1152/ajprenal.00487.2016

• acute kidney injury
• chronic kidney disease
• aging
• epigenetic
• inflammation
• NF-kappa B
• NF-kappa Biz
• acetylation
• crotonylation
• TWEAK
• Klotho
• phosphate
• mitochondria
• PGC-1 alpha

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 gamma coactivator-1 alpha (PGC-1 alpha), a transcription factor that promotes mitochondrial biogenesis. Cytokines such as TWEAK, TNF-alpha, or transforming growth factor -beta 1 produced locally during kidney injury or released from inflammatory sites at other organs may decrease kidney expression of Klotho and PGC-1 alpha or lead to suboptimal recruitment of these nephroprotective proteins. Transcription factors (e.g., Smad3 and NF-kappa B) and epigenetic mechanisms (e.g., histone acetylation or methylation) contribute to downregulate the expression of Klotho and/or PGC-1 alpha, while histone crotonylation promotes PGC-1 alpha expression. NF-kappa Biz facilitates the repressive effect of NF-kappa B 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.

• 出版日期2016-12-1