Proteomics analysis reveals diabetic kidney as a ketogenic organ in type 2 diabetes

  • Dongjuan Zhang
    Department of Physiology and Pathophysiology, Peking University Health Science Center,
  • Hang Yang
    Department of Physiology and Pathophysiology, Peking University Health Science Center,
  • Xiaomu Kong
    Department of Physiology and Pathophysiology, Peking University Health Science Center,
  • Kang Wang
    Department of Physiology and Pathophysiology, Peking University Health Science Center,
  • Xuan Mao
    National Center of Biomedical Analysis, Beijing, China
  • Xianzhong Yan
    National Center of Biomedical Analysis, Beijing, China
  • Yuan Wang
    Beijing Genomics Institute, Chinese Academy of Sciences, and
  • Siqi Liu
    Beijing Genomics Institute, Chinese Academy of Sciences, and
  • Xiaoyan Zhang
    Department of Physiology and Pathophysiology, Peking University Health Science Center,
  • Jing Li
    Department of Physiology and Pathophysiology, Peking University Health Science Center,
  • Lihong Chen
    Department of Physiology and Pathophysiology, Peking University Health Science Center,
  • Jing Wu
    Department of Physiology and Pathophysiology, Peking University Health Science Center,
  • Mingfen Wei
    Department of Physiology and Pathophysiology, Peking University Health Science Center,
  • Jichun Yang
    Department of Physiology and Pathophysiology, Peking University Health Science Center,
  • Youfei Guan
    Department of Physiology and Pathophysiology, Peking University Health Science Center,

抄録

<jats:p>Diabetic nephropathy (DN) is the leading cause of end-stage renal disease. To date, the molecular mechanisms of DN remain largely unclear. The present study aimed to identify and characterize novel proteins involved in the development of DN by a proteomic approach. Proteomic analysis revealed that 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) synthase 2 (HMGCS2), the key enzyme in ketogenesis, was increased fourfold in the kidneys of type 2 diabetic db/db mice. Consistently, the activity of HMGCS2 in kidneys and 24-h urinary excretion of the ketone body β-hydroxybutyrate (β-HB) were significantly increased in db/db mice. Immunohistochemistry, immunofluorescence, and real-time PCR studies further demonstrated that HMGCS2 was highly expressed in renal glomeruli of db/db mice, with weak expression in the kidneys of control mice. Because filtered ketone bodies are mainly reabsorbed in the proximal tubules, we used RPTC cells, a rat proximal tubule cell line, to examine the effect of the increased level of ketone bodies. Treating cultured RPTC cells with 1 mM β-HB significantly induced transforming growth factor-β1 expression, with a marked increase in collagen I expression. β-HB treatment also resulted in a marked increase in vimentin protein expression and a significant reduction in E-cadherin protein levels, suggesting an enhanced epithelial-to-mesenchymal transition in RPTCs. Collectively, these findings demonstrate that diabetic kidneys exhibit excess ketogenic activity resulting from increased HMGCS2 expression. Enhanced ketone body production in the diabetic kidney may represent a novel mechanism involved in the pathogenesis of DN.</jats:p>

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