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The Nrf2 pathway in the progression of renal disease

Carlamaria Zoja1, Ariela Benigni, Giuseppe Remuzzi

  • 1IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy.

Nephrology, Dialysis, Transplantation : Official Publication of the European Dialysis and Transplant Association - European Renal Association
|June 14, 2013
PubMed

Insights

Bardoxolone methyl, a Nrf2/Keap1 inducer, showed potential for chronic kidney disease (CKD) but led to serious adverse events. Further animal studies are crucial for understanding risks before clinical use.

Area of Science:

  • Biochemistry
  • Pharmacology
  • Nephrology

Background:

  • The Nrf2/Keap1 pathway regulates antioxidant and cytoprotective genes.
  • Oxidative stress and inflammation are implicated in chronic kidney disease (CKD) progression.
  • Bardoxolone methyl and its analogues are potent Nrf2/Keap1 inducers explored for renoprotection.

Purpose of the Study:

  • To evaluate the efficacy and safety of bardoxolone methyl in patients with CKD and type 2 diabetes.
  • To investigate the mechanisms and side effects of bardoxolone methyl analogues in preclinical models.
  • To inform future clinical trial design for Nrf2/Keap1 inducers in CKD.

Main Methods:

  • Phase II (BEAM) and Phase III (BEACON) clinical trials were conducted.
  • Preclinical studies involved treating rats with type 2 diabetic nephropathy using bardoxolone methyl analogues.
  • Analysis focused on estimated glomerular filtration rate (eGFR) and adverse event profiles.

Main Results:

  • Bardoxolone methyl increased eGFR in the BEAM trial, generating interest.
  • Bardoxolone methyl analogues in rats reproduced some adverse effects observed in humans.
  • The BEACON trial was terminated early due to excess serious adverse events and mortality.

Conclusions:

  • While bardoxolone methyl showed initial promise in increasing eGFR, its safety profile is a significant concern.
  • Preclinical models can offer insights into potential adverse effects of Nrf2/Keap1 inducers.
  • Carefully designed animal studies are essential for elucidating pathogenetic mechanisms and unexpected side effects before widespread clinical application.
Keywords:
Keap1bardoxolonediabetic nephropathy

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