Transcriptional regulation of proximal tubular metabolism in acute kidney injury

The kidney, and in particular the proximal tubule (PT), has a high demand for ATP, due to its function in bulk reabsorption of solutes. In normal PT, ATP levels are predominantly maintained by fatty acid β-oxidation (FAO), the tricarboxylic acid (TCA) cycle, and oxidative phosphorylation. The normal PT also undertakes gluconeogenesis and metabolism of amino acids. Acute kidney injury (AKI) results in profound PT metabolic alterations, including suppression of FAO, gluconeogenesis, and metabolism of some amino acids, and upregulation of glycolytic enzymes. Recent studies have elucidated new transcriptional mechanisms regulating metabolic pathways in normal PT, as well as the metabolic switch in AKI. A number of transcription factors have been shown to play important roles in FAO, which are themselves downregulated in AKI, while hypoxia-inducible factor 1α, which is upregulated in ischemia-reperfusion injury, is a likely driver of the upregulation of glycolytic enzymes. Transcriptional regulation of amino acid metabolic pathways is less well understood, except for catabolism of branched-chain amino acids, which is likely suppressed in AKI by upregulation of Krüppel-like factor 6. This review will focus on the transcriptional regulation of specific metabolic pathways in normal PT and in AKI, as well as highlighting some of the gaps in knowledge and challenges that remain to be addressed.