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Pharmacological activation of nuclear factor erythroid 2-related factor-2 prevents hyperglycemia-induced renal

Rafael M Costa1, Mayara C Dias2, Juliano V Alves1

  • 1Institute of Health Sciences, Federal University of Jatai, Jatai, GO, Brazil; Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, SP, Brazil.

Biochemical Pharmacology
|December 14, 2023
PubMed

Insights

Hyperglycemia damages kidneys by increasing oxidative stress and reducing the protective Nrf2 pathway. L-sulforaphane (SFN) treatment restores Nrf2 activity, mitigating kidney injury and suggesting O-GlcNAcylation as a key mechanism.

Area of Science:

  • Nephrology
  • Molecular Biology
  • Biochemistry

Background:

  • Hyperglycemia is a significant risk factor for kidney disease progression.
  • Oxidative stress, driven by reactive oxygen species, is a primary contributor to hyperglycemia-induced kidney damage.
  • The nuclear factor erythroid 2-related factor-2 (Nrf2) pathway is critical for cellular defense against oxidative stress via antioxidant gene activation.

Purpose of the Study:

  • To investigate the impact of hyperglycemia on Nrf2 activity and antioxidant defenses in the kidney.
  • To explore the role of O-linked β-N-acetylglucosamine (O-GlcNAc) modification in regulating Nrf2 activity under hyperglycemic conditions.
  • To evaluate the renoprotective effects of L-sulforaphane (SFN), an Nrf2 activator, in a model of hyperglycemia.

Main Methods:

  • Utilized hyperglycemic Wistar rats and HEK 293 cells cultured in high-glucose medium to model hyperglycemia.
  • Assessed Nrf2 nuclear translocation, antioxidant enzyme expression and activity, renal function markers, oxidative stress indicators, and cell apoptosis.
  • Investigated the effect of hyperglycemia and O-GlcNAc levels on Nrf2 modification and activity, including pharmacological inhibition of O-GlcNAcase (OGA).

Main Results:

  • Hyperglycemia led to decreased Nrf2 nuclear translocation, reduced antioxidant enzyme expression/activity, impaired renal function, increased oxidative stress, and cell death.
  • SFN treatment reversed these detrimental effects, enhancing Nrf2 activity and improving renal outcomes.
  • Hyperglycemia increased O-GlcNAc modification of Nrf2, and elevated O-GlcNAc levels (via OGA inhibition) decreased Nrf2 activity.

Conclusions:

  • Hyperglycemia impairs Nrf2 activity, exacerbating oxidative stress, apoptosis, and renal damage.
  • SFN demonstrates significant renoprotective potential by activating Nrf2.
  • O-GlcNAcylation negatively regulates Nrf2 activity, representing a key mechanism in hyperglycemia-associated kidney injury.
Keywords:
HyperglycemiaKidneyL-sulforaphaneNuclear factor erythroid 2-related factor-2Oxidative stress

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