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Renal Ischaemia Reperfusion Injury: A Mouse Model of Injury and Regeneration
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Methylation in pericytes after acute injury promotes chronic kidney disease

Yu-Hsiang Chou1,2,3, Szu-Yu Pan1,3,4, Yu-Han Shao3

  • 1Renal Division, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.

The Journal of Clinical Investigation
|August 5, 2020
PubMed

Insights

Renal myofibroblasts originate from pericytes after acute kidney injury (AKI). Epigenetic changes in these cells promote chronic kidney disease (CKD) progression, but demethylation therapy can prevent this transition.

Area of Science:

  • Nephrology
  • Cell Biology
  • Epigenetics

Background:

  • The origin and long-term fate of renal myofibroblasts following acute kidney injury (AKI) remain unclear.
  • Pericytes are implicated in kidney repair, but their transformation into myofibroblasts and subsequent role in disease progression require further elucidation.

Purpose of the Study:

  • To investigate the origin and fate of renal myofibroblasts after ischemia/reperfusion injury-induced AKI (IRI-AKI).
  • To explore the epigenetic mechanisms regulating pericyte function and their role in the transition from AKI to chronic kidney disease (CKD).
  • To evaluate the therapeutic potential of demethylation in preventing AKI-CKD transition and mitigating renal fibrosis.

Main Methods:

  • Isolation and gene expression profiling (microarray) of quiescent (qPericytes), activated (aPericytes/myofibroblasts), and inactivated (iPericytes) from kidneys at different time points post-IRI-AKI.
  • Analysis of Acta2 gene regulation, including Ybx2 methylation and transforming growth factor-β1 (TGF-β1) signaling.
  • In vivo administration of 5-azacytidine (a demethylating agent) to assess its effects on renal recovery, fibrosis, and AKI-CKD transition following IRI-AKI and a second AKI.

Main Results:

  • Myofibroblasts are activated from qPericytes post-IRI-AKI, with a subset surviving and proliferating long-term.
  • Hypermethylation of the Acta2 repressor Ybx2 in iPericytes promotes AKI-CKD transition and exacerbates fibrogenesis.
  • TGF-β1 induces Ybx2 hypermethylation, increasing α-smooth muscle actin expression in aPericytes.
  • 5-azacytidine treatment restored microvascular function, reversed profibrotic properties, prevented AKI-CKD transition, and attenuated fibrosis after a second AKI.

Conclusions:

  • Pericyte epigenetic dysregulation, specifically Ybx2 hypermethylation, is a key driver of AKI-CKD transition.
  • Intervention targeting pericyte hypermethylation offers a promising strategy to halt AKI-CKD progression.
  • Demethylation therapy presents a potential therapeutic approach to improve long-term kidney outcomes after AKI.
Keywords:
EpigeneticsNephrologyPericytes

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