Abstract
Renal proximal tubular cells are high energy-demanding cells mainly relying on fatty acid oxidation. In stress conditions, such as transient hypoxia, fatty acid oxidation (FAO) decreases and carbohydrate catabolism fails to compensate for the energy demand. In this scenario, the surviving tubular cells exhibit the peculiar phenotype associated with fibrosis that is the histological manifestation of a process culminating in chronic and end-stage kidney disease. Genome-wide transcriptome analysis revealed that, together with inflammation, FAO is the top dysregulated pathway in kidney diseases with a decreased expression of key FAO enzymes and regulators. Another evidence that links the derangement of FAO to fibrosis is the progressive decrease of the expression of peroxisome proliferator-activated receptor α (PPARα) in aged people, that triggers the age-associated renal fibrosis. To allow FAO completion, a coordinate network of enzymes and transport proteins is required. Indeed, the mitochondrial inner membrane is impermeable to fatty acyl-CoAs and a specialized system, well known as carnitine shuttle, is needed for translocating fatty acids moieties, conjugated with carnitine, into mitochondrial matrix for the β-oxidation. The first component of this system is the carnitine palmitoyltransferase 1 (CPT1) responsible for transfer acyl moieties to carnitine. Several studies indicated that the stimulation of CPT1 activity and expression has a protective effect against renal fibrosis. Therefore, the network of enzymes and transporters linked to FAO may represent potential pharmacological targets deserving further attention in the development of new drugs to attenuate renal dysfunction.
Highlights
The kidney is one of the most energy-demanding organs in the human body, as demonstrated by Elia (Elia, 1992) in a study performed in 1992 describing the specific resting metabolic rates of major organs and tissues in adults
While all kidney districts have a high request for ATP, the mechanism of ATP production is cell type-dependent
The network of transporters and enzymes responsible for the mitochondrial fatty acid oxidation will be dealt with focusing on derangements that underlie kidney injury with special reference to the Acute Kidney Disease (AKI)
Summary
The kidney is one of the most energy-demanding organs in the human body, as demonstrated by Elia (Elia, 1992) in a study performed in 1992 describing the specific resting metabolic rates of major organs and tissues in adults. Proximal tubule cells, which constitute 90% of the outer kidney cortex, are the main ATP consuming cells in the kidney and use fuels such as lactate, glutamine, and fatty acids (Forbes and Thorburn, 2018) These cells are completely dependent on the oxidative phosphorylation, i.e., aerobic respiration, as the primary mechanism of ATP production (Bhargava and Schnellmann, 2017). The fourth step is catalyzed by the long-chain 3-ketoacyl-CoA thiolase (HADHB) with a broad chain-length preference After this first round of reactions, the two carbon shortened Acyl-CoA is recycled through subsequent rounds of β-oxidation reactions generating Acetyl-CoA that enters the TCA cycle allowing the ATP synthesis by the oxidative phosphorylation (Figure 1). Some patients with kidney diseases develop carnitine deficiency (Hedayati, 2006)
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