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Regulation of pericyte metabolic reprogramming restricts the AKI to CKD transition

Cheng Xu1, Quan Hong2, Kaiting Zhuang2

  • 1Department of Nephrology, The Second Hospital of Jilin University, Nanguan District, Changchun 130041, Jilin, China; Department of Nephrology, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center of Kidney Diseases, Beijing Key Laboratory of Kidney Disease, Haidian District, Beijing 100853, China.

Metabolism: Clinical and Experimental
|May 25, 2023
PubMed

Insights

Metabolic reprogramming drives the transition from acute kidney injury (AKI) to chronic kidney disease (CKD). Targeting pericyte metabolism, specifically enhancing fatty acid oxidation (FAO) and suppressing glycolysis, can prevent this progression.

Area of Science:

  • Nephrology
  • Cell Biology
  • Metabolic Pathways

Background:

  • Acute kidney injury (AKI) significantly increases morbidity and mortality, serving as a precursor to chronic kidney disease (CKD).
  • The AKI to CKD transition involves interstitial fibrosis and myofibroblast proliferation, with pericytes being a primary source.
  • The mechanisms governing pericyte-myofibroblast transition (PMT) remain incompletely understood.

Purpose of the Study:

  • To investigate the role of metabolic reprogramming in the pericyte-myofibroblast transition (PMT).
  • To identify key metabolic pathways and signaling molecules involved in PMT during the AKI to CKD progression.

Main Methods:

  • Utilized a unilateral ischemia/reperfusion-induced AKI to CKD mouse model.
  • Employed TGF-β-treated pericyte-like cells to study metabolic changes (fatty acid oxidation and glycolysis) and signaling pathways during PMT.
  • Administered drugs to modulate metabolic reprogramming.

Main Results:

  • Pericyte-myofibroblast transition (PMT) is characterized by reduced fatty acid oxidation (FAO) and increased glycolysis.
  • Enhancing FAO (e.g., with PGC1α activator ZLN-005) or suppressing glycolysis (e.g., with HK2 inhibitor 2-DG) inhibited PMT and AKI to CKD progression.
  • AMP-activated protein kinase (AMPK) modulates the PGC1α-CPT1A (FAO activation) and HIF1α-HK2 (glycolysis inhibition) pathways, contributing to the inhibition of PMT.

Conclusions:

  • Metabolic reprogramming is a critical determinant of pericyte fate and transdifferentiation.
  • Targeting the abnormal metabolism of pericytes offers a potential therapeutic strategy to prevent the AKI to CKD transition.
Abstract

Keywords:
Acute kidney injuryChronic kidney diseaseFatty acid oxidationFibrosisGlycolysisPericyte-myofibroblast transition

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