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. Bulk RNA-seq was performed on the whole heart or on the whole kidney and kidney cortex, respectively, of 30-week-old ZSF1 obese and ZSF1 lean rats. Rats were treated with vehicle, BDK inhibitor (BT2), SGLT2 inhibitor (emplagliflozin) or combination BT2 + SGLT2 treatment. Sequencing was performed on 10 rats per condition.