Abstract
Renal proximal tubular cells are the most energy-demanding cells in the body. The ATP that they use is mostly produced in their mitochondrial and peroxisomal compartments, by the oxidation of fatty acids. When those cells are placed under a biological stress, such as a transient hypoxia, fatty acid oxidation (FAO) is shut down for a period of time that outlasts injury, and carbohydrate oxidation does not take over. Facing those metabolic constraints, surviving tubular epithelial cells exhibit a phenotypic switch that includes cytoskeletal rearrangement and production of extracellular matrix proteins, most probably contributing to acute kidney injury-induced renal fibrogenesis, thence to the development of chronic kidney disease. Here, we review experimental evidence that dysregulation of FAO profoundly affects the fate of tubular epithelial cells, by promoting epithelial-to-mesenchymal transition, inflammation, and eventually interstitial fibrosis. Restoring physiological production of energy is undoubtedly a possible therapeutic approach to unlock the mesenchymal reprograming of tubular epithelial cells in the kidney. In this respect, the benefit of the use of fibrates is uncertain, but new drugs that could specifically target this metabolic pathway, and, hopefully, attenuate renal fibrosis merit future research.
Highlights
Renal fibrosis is the final common pathway to all chronic kidney diseases (CKD), suggesting that a biological switch is activated in any context of injury, suppressing noble renal functions long-term and reactivating embryonic-like mesenchymal ones [1]
The aim of this review is to provide an insight into how down-regulation of fatty acid oxidation (FAO) observed during acute kidney injury (AKI) – during ischemic AKI and in other experimental conditions – precedes epithelial-to-mesenchymal transition (EMT) and constitutes a major alteration of cell metabolism, which drives the mesenchymal transition
Kang et al have reported that transforming growth factor β1 (TGF-β1), a major player in kidney fibrosis, and a master inducer of EMT, can inhibit PPAR-α and PPARGC1A, key transcription factors of FAO genes
Summary
Renal fibrosis is the final common pathway to all chronic kidney diseases (CKD), suggesting that a biological switch is activated in any context of injury, suppressing noble renal functions long-term and reactivating embryonic-like mesenchymal ones [1] Such a switch would obviously be a major source of new therapeutics. Three major abnormalities have been found to be associated with the fibrotic outcome of a transient AKI: (a) the epigenetic silencing of RASAL1, a proliferation inhibitor, in myofibroblasts; (b) the cell cycle arrest in G2/M in tubular epithelial cells (the G2/M phase is where the epithelial cell function is closer to a mesenchymal one); and (c) down-regulation of FAO in tubular epithelial cells [14, 17, 18] These mechanisms are not exclusive of each other. The energy yield of FA β-oxidation is very high, with an average of 106 ATP equivalents per FA, as opposed to 36 during the oxidation of carbohydrates
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