Sirt6-mediated Nrf2/HO-1 activation alleviates angiotensin II-induced DNA DSBs and apoptosis in podocytes

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Yanqin Fan1, Jing Cheng, Qian Yang

  • 1Division of Nephrology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China. ghxding@gmail.com.

Food & Function
|July 9, 2021
PubMed

Insights

Sirtuin6 (Sirt6) protects against kidney damage by reducing DNA double-strand breaks (DSBs) and cell injury in podocytes. The Sirt6-Nrf2-HO-1 pathway is key to this protective mechanism against angiotensin II-induced harm.

Area of Science:

  • Nephrology
  • Molecular Biology
  • Genetics

Background:

  • DNA double-strand breaks (DSBs) are implicated in chronic kidney disease (CKD) pathogenesis.
  • Sirtuin6 (Sirt6) is a histone deacetylase involved in DNA damage repair.

Purpose of the Study:

  • To investigate Sirtuin6's role in angiotensin II-induced DNA DSBs and podocyte injury.
  • To elucidate the underlying mechanism involving Sirt6 in kidney disease.

Main Methods:

  • Assessed Sirt6 expression in human hypertensive nephropathy (HN) glomeruli.
  • Utilized angiotensin II infusion in rats and cultured podocytes.
  • Investigated the effects of Sirt6 overexpression and Nrf2 knockdown.

Main Results:

  • Reduced Sirt6 expression correlated with increased DSBs in HN patients, Ang II-infused rats, and podocytes.
  • Sirt6 overexpression mitigated Ang II-induced reactive oxygen species (ROS), DSBs, and apoptosis in podocytes.
  • Sirt6 activation upregulated Nrf2 and HO-1 expression, with Nrf2 knockdown partially reversing protective effects.

Conclusions:

  • The Sirt6-Nrf2-HO-1 pathway is crucial for mitigating angiotensin II-mediated oxidative DNA damage.
  • Sirt6 activation protects podocytes from injury, suggesting a therapeutic target for kidney disease.

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