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AMPK activation coupling SENP1-Sirt3 axis protects against acute kidney injury

Minyan Zhu1, Jianli He2, Yao Xu1

  • 1Department of Nephrology, Molecular Cell Lab for Kidney Disease, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 201207, China.

Molecular Therapy : the Journal of the American Society of Gene Therapy
|August 23, 2023
PubMed

Insights

Targeting the SENP1-Sirt3 pathway protects against acute kidney injury (AKI) and subsequent fibrosis. Activating this axis reduces mitochondrial damage and inflammation, offering a potential therapeutic strategy for kidney disease.

Area of Science:

  • Nephrology
  • Mitochondrial Biology
  • Molecular Signaling

Background:

  • Acute kidney injury (AKI) is a significant clinical issue leading to kidney fibrosis with limited treatments.
  • Mitochondrial dysfunction in proximal tubular epithelial cells (PTECs) plays a crucial role in AKI pathogenesis.
  • The SENP1-Sirt3 signaling pathway's role in AKI requires further investigation.

Purpose of the Study:

  • To investigate the role of the SENP1-Sirt3 signaling pathway in AKI.
  • To explore the correlation between this pathway and mitochondrial dysfunction in PTECs.
  • To identify potential therapeutic targets for AKI-induced kidney fibrosis.

Main Methods:

  • Utilized folic acid (FA) and ischemia-reperfusion-induced (IRI) AKI mouse models.
  • Investigated Sirt3 SUMOylation site mutation (Sirt3 KR) and pharmacological stimulation (metformin, NAC, MitoQ).
  • Performed metabolomics analysis and assessed mitochondrial function, oxidative stress, and apoptosis markers.

Main Results:

  • Sirt3 KR mutation or metformin treatment protected against AKI, inflammation, and fibrosis.
  • These interventions reduced mitochondrial acetylation of SOD2, decreased mitochondrial reactive oxygen species (mtROS), and restored ATP levels.
  • Metformin activated the AMPK pathway, promoting the SENP1-Sirt3 axis and protecting PTECs.

Conclusions:

  • Augmented mitochondrial deSUMOylation of Sirt3, via the AMPK pathway, protects against AKI.
  • The Sirt3-SOD2-mtROS axis is a key mediator in mitigating renal inflammation and fibrosis.
  • Targeting the SENP1-Sirt3 pathway presents a promising therapeutic strategy for AKI.
Keywords:
SENP1-Sirt3acute kidney injurydeSUMOylationdeacetylationmitochondrionproximal tubule

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