Patients born with congenital porto-systemic shunts have been shown to have a high risk of benign and malignant liver tumors in otherwise healthy livers. This study aimed to evaluate the genetic lands Show more
Patients born with congenital porto-systemic shunts have been shown to have a high risk of benign and malignant liver tumors in otherwise healthy livers. This study aimed to evaluate the genetic landscape of liver tumors in patients with congenital porto-systemic shunts (CPSS) and correlate genotype with histological findings. Nodules from patients with CPSS and sporadic pediatric focal nodular hyperplasia (FNH) or FNH-like nodules were evaluated histologically and sequenced for a panel of 50 genes using next-generation sequencing. Thirty-eight nodules from 17 patients with CPSS were histologically classified as hepatoblastomas ( CPSS is strongly associated with nodules containing variants in Show less
Kidney tubular cell injury is largely responsible for the pathophysiological features of diabetic kidney disease (DKD). Increased leucine levels in individuals with DKD have been associated with the p Show more
Kidney tubular cell injury is largely responsible for the pathophysiological features of diabetic kidney disease (DKD). Increased leucine levels in individuals with DKD have been associated with the progression of diabetes to end-stage renal failure, yet a comprehensive understanding of leucine metabolism in kidney tubules during the progression of DKD is lacking. Human kidney biopsies and mouse models were used to assess leucine metabolism during DKD progression. Enhancement of leucine degradation was achieved through genetic ablation or pharmacological inhibition of branched-chain ketoacid dehydrogenase kinase (BCKDK). Cultured kidney tubular epithelial cells were used to analyse the underlying cellular mechanisms. The association of urinary leucine with progression of DKD was determined in individuals with diabetes. Measurements of metabolites and enzymes suggested defective leucine degradation and increased BCKDK expression in kidney tubules during DKD progression. Enhancement of leucine degradation relieved glucose-induced metabolic remodelling in tubular cells and mitigated DKD in mouse models. Accumulation of leucine stimulated metabolic remodelling via the mTOR signalling pathway; this was relieved by blocking leucine uptake or enhancing its degradation. Restricting dietary leucine significantly decreased albuminuria, kidney hypertrophy and lipid accumulation in mouse models of diabetes. Additionally, we observed that rapid decline in kidney function correlated with a higher urinary leucine-to-creatinine ratio in both female and male individuals with diabetes. In summary, we identify defective leucine degradation in renal tubules of diabetic individuals and propose leucine as a causative factor for DKD, highlighting its potential as a therapeutic target for further investigation. The transcriptomic data supporting the findings of this study are openly available at the National Center for Biotechnology Information Sequence ReadArchive (SRA) ( https://www.ncbi.nlm.nih.gov/sra , identifiers: PRJNA1180888 and PRJNA1180923). The metabolomics data associated with the manuscript are available in the ESM. Show less