Restoration of branched chain amino acid catabolism improves kidney function in preclinical cardiovascular-kidney-metabolic syndrome models

Patients with metabolic syndrome and heart failure (HF) often have accompanying kidney dysfunction, which was recently defined as cardiovascular-kidney-metabolic (CKM) syndrome. Prior metabolomics profiling of metabolic syndrome patients identified a plasma branched chain amino acid (BCAA) signature, and BCAAs are elevated in HF patient myocardium. The rate limiting step of BCAA catabolism is decarboxylation by branched chain ketoacid dehydrogenase enzyme (BCKDH), which is negatively regulated by BCKDH kinase (BCKDK or BDK), and BDK inhibitors improve metabolism and heart failure preclinically. Here we show that BCAA catabolic impairment is associated with and may be causal to CKM as treatment with the BDK inhibitor BT2 improved urine protein content, glomerular filtration rate, kidney hypertrophy, and kidney pathology in CKM models. Coadministration of BT2 and empagliflozin restored renal function and gene expression signatures and improved mitochondrial density and function, suggesting that BDK inhibition could represent a therapeutic avenue for CKM.代谢综合征与心力衰竭（heart failure, HF）患者常伴随肾功能不全，该病症近期被定义为心血管-肾脏-代谢（cardiovascular-kidney-metabolic, CKM）综合征。既往针对代谢综合征患者的代谢组学分析已鉴定出血浆支链氨基酸（branched chain amino acid, BCAA）特征谱，且心力衰竭患者的心肌组织中支链氨基酸水平升高。支链氨基酸分解代谢的限速步骤为支链酮酸脱氢酶（branched chain ketoacid dehydrogenase enzyme, BCKDH）催化的脱羧反应，该酶的活性可被支链酮酸脱氢酶激酶（BCKDH kinase, BCKDK或BDK）负向调控，而BDK抑制剂在临床前研究中可改善代谢与心力衰竭表型。本研究证实，支链氨基酸分解代谢受损与心血管-肾脏-代谢综合征存在关联，且可能为其致病诱因：使用BDK抑制剂BT2干预心血管-肾脏-代谢综合征模型动物，可改善其尿蛋白含量、肾小球滤过率、肾脏肥大及肾脏病理损伤。联合使用BT2与恩格列净（empagliflozin）可恢复肾功能与基因表达特征，并改善线粒体密度与功能，这提示BDK抑制有望成为心血管-肾脏-代谢综合征的治疗新途径。