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Aims/hypothesis <p>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.</p> Methods <p>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.</p> Results <p>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.</p> Conclusions/interpretation <p>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.</p> Data availability <p>The transcriptomic data supporting the findings of this study are openly available at the National Center for Biotechnology Information Sequence ReadArchive (SRA) (<a href="https://www.ncbi.nlm.nih.gov/sra">https://www.ncbi.nlm.nih.gov/sra</a>, identifiers: PRJNA1180888 and PRJNA1180923). The metabolomics data associated with the manuscript are available in the ESM.</p> Graphical Abstract <p></p>

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BCKDK accelerates the progression of diabetic kidney disease by regulating leucine-mediated metabolic remodelling in renal tubular cells

  • 期刊论文

  • 发表日期：

    2025年8月16日

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  • Caifeng Shi,
  • Xingyue Wang,
  • Songyan Qin,
  • Aiqin He,
  • Xiaomei Wu,
  • Qingqing Ke,
  • Rui Shen,
  • Yemeng Wan,
  • Lulu Wang,
  • Yu Xiao,
  • Dandan Liu,
  • Xin Yu,
  • Xinjia Shen,
  • Yuting Sheng,
  • Xueting Zhu,
  • Lei Jiang,
  • Ke Zen,
  • Chunsun Dai,
  • Yang Zhou

摘要

Aims/hypothesis

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.

Methods

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.

Results

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.

Conclusions/interpretation

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.

Data availability

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.

Graphical Abstract