Supplementary Material for: The physiology and pathophysiology of branched-chain amino acids in the kidney

Kidneys require large amounts of energy to maintain function, and are highly metabolically active. Acute kidney injury (AKI) and diseases including chronic kidney disease (CKD), diabetic kidney disease (DKD), and polycystic kidney disease (PKD) are strongly associated with metabolic disturbances. Whilst most research to date has focused on glucose and fatty acid metabolism, the catabolism of the branched-chain amino acids (BCAAs) leucine, isoleucine, and valine, is an emerging area of importance across different kidney pathologies. BCAAs can be used in protein synthesis, or catabolized to provide tricarboxylic acid (TCA) cycle intermediates. BCAAs and their metabolites can also act as signaling molecules. Disturbances of BCAA catabolism have recently been described in AKI, CKD, DKD, and PKD, driven by both transcriptional and post-translational mechanisms. This results in accumulation of BCAAs in the kidney and loss of a source of TCA cycle intermediates. In addition, accumulated BCAAs, especially leucine, can activate mechanistic target of rapamycin complex 1 (mTORC1) signaling. In addition to the described disturbances in BCAA catabolism, recent preclinical studies have shown that reactivation of BCAA catabolism could be a potential therapeutic strategy. This review will describe the process of BCAA catabolism, and its disturbances in AKI, CKD, DKD, and PKD.