Impact of impaired branched-chain amino acid metabolism on kidney disease

Abstract

Acute kidney injury (AKI) and chronic kidney disease (CKD) are the two primary forms of kidney disease that significantly contribute to increased mortality and progression to end-stage renal disease. To effectively treat AKI and CKD, elucidating the detailed mechanisms underlying their onset and progression is essential for the development of novel therapeutic strategies. Impaired cellular function resulting from the altered metabolism of energy-producing nutrients, such as fatty acids, glucose, and amino acids, is closely involved in the pathogenesis of both AKI and CKD. Among these nutrients, branched-chain amino acids (BCAAs), such as leucine, isoleucine, and valine, are essential amino acids in humans and animals because they cannot be synthesized de novo. BCAAs play a crucial role in protein synthesis and energy production in various metabolic tissues, including skeletal muscle, liver, brown adipose tissue, pancreas, heart, and the kidney. Maintaining an appropriate balance between BCAA catabolism and anabolism is vital for optimal cellular function. Alterations in BCAA homeostasis have emerged as key contributors to the pathophysiology of several metabolic disorders, including obesity-related insulin resistance, type 2 diabetes, heart failure, kidney disease, and sarcopenia. In the present review, we provide a comprehensive overview of BCAA metabolism, with a particular focus on the molecular mechanisms linking disrupted BCAA homeostasis in proximal tubular cells to kidney disease. We also discuss the potential of targeting BCAA metabolism as a novel therapeutic strategy to suppress kidney disease progression.