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<p>Chronic kidney disease (CKD) is associated with dysregulated lipid metabolism, particularly in proximal kidney tubules, where fatty acid oxidation serves as the primary energy source. The proximal tubules’ reliance on fatty acid oxidation rather than glycolysis underscores their unique metabolic profile, consistent with the absence of key glycolytic enzymes. This dysregulation contributes to maladaptive hypertrophy in CKD, where surviving nephrons exhibit compensatory hypertrophy to maintain kidney function. Here, we focus on two key regulators of lipid metabolism: peroxisome proliferator–activated receptor alpha (PPARα) and adenosine monophosphate (AMP)-activated protein kinase (AMPK). Recent multi-omics studies have identified PPARα as an important determinant of proximal tubule cell size and a mediator of compensatory hypertrophy. In CKD models, AMPK activity decreases, impairing cellular responses to energy stress, as indicated by altered AMP/ATP ratios. This defective energy sensing may be exacerbated by uremic metabolites that diminish AMPK function. Unc-51-like autophagy activating kinase 1 (ULK1) has been identified as a regulator of AMPK activity through specific phosphorylation sites that enhance AMP sensitivity. Future research should assess whether targeting these pathways restores metabolic homeostasis and mitigates CKD progression by enhancing AMPK activity and lipid metabolism.</p>

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Energy metabolism in the kidney and its role in chronic kidney disease

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年8月4日

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  • Hiroaki Kikuchi,
  • Tomohiro Tsuboya,
  • Jinming Hu,
  • Mari Sugimoto,
  • Miyu Yoshikawa,
  • Maho Usui,
  • Takefumi Suzuki,
  • Mark A. Knepper,
  • Shinichi Uchida,
  • Eisei Sohara

摘要

Chronic kidney disease (CKD) is associated with dysregulated lipid metabolism, particularly in proximal kidney tubules, where fatty acid oxidation serves as the primary energy source. The proximal tubules’ reliance on fatty acid oxidation rather than glycolysis underscores their unique metabolic profile, consistent with the absence of key glycolytic enzymes. This dysregulation contributes to maladaptive hypertrophy in CKD, where surviving nephrons exhibit compensatory hypertrophy to maintain kidney function. Here, we focus on two key regulators of lipid metabolism: peroxisome proliferator–activated receptor alpha (PPARα) and adenosine monophosphate (AMP)-activated protein kinase (AMPK). Recent multi-omics studies have identified PPARα as an important determinant of proximal tubule cell size and a mediator of compensatory hypertrophy. In CKD models, AMPK activity decreases, impairing cellular responses to energy stress, as indicated by altered AMP/ATP ratios. This defective energy sensing may be exacerbated by uremic metabolites that diminish AMPK function. Unc-51-like autophagy activating kinase 1 (ULK1) has been identified as a regulator of AMPK activity through specific phosphorylation sites that enhance AMP sensitivity. Future research should assess whether targeting these pathways restores metabolic homeostasis and mitigates CKD progression by enhancing AMPK activity and lipid metabolism.