Role of bardoxolone methyl, a nuclear factor erythroid 2-related factor 2 activator, in aldosterone- and salt-induced renal injury

Hypertens Res. 2018 Jan;41(1):8-17. doi: 10.1038/hr.2017.83. Epub 2017 Oct 5.

Abstract

The aim of this study was to investigate the renoprotective effect of bardoxolone methyl (BM), a nuclear factor erythroid 2-related factor 2 (Nrf2) activator with an antioxidant effect, in a salt-sensitive hypertension model induced by aldosterone (Ald) and salt. Tubulointerstitial damage with urinary liver-type fatty acid-binding protein (L-FABP) was evaluated using human L-FABP chromosomal transgenic (L-FABP+/-) male mice. The mice in the Ald group (n=7) received systemic Ald infusions via an osmotic minipump and were given 1% NaCl water for 35 days. Those in the Ald-BM group (n=8) were administered BM intraperitoneally in addition to an injection of Ald and salt. The dose of BM was gradually increased every 7 days up to 10 mg kg-1 per day, which was maintained for 14 days. The administration of BM significantly increased renal expression of the Nrf2 target antioxidant gene. Tubulointerstitial damage was significantly ameliorated in the Ald-BM group compared to the Ald group. The increase in reactive oxygen species (ROS) and upregulation of angiotensinogen expression in the kidneys of the Ald group was significantly prevented in the Ald-BM group. The upregulation of human L-FABP expression induced in the kidneys and increase in urinary L-FABP in the Ald group were significantly suppressed by BM administration. In conclusion, BM ameliorated tubulointerstitial damage in the Ald- and salt-induced hypertension model through suppression of both ROS production and intrarenal renin-angiotensin system activation. Urinary L-FABP may be a useful marker reflecting the therapeutic efficacy of BM.

MeSH terms

  • Aldosterone / adverse effects
  • Angiotensinogen / metabolism
  • Animals
  • Blood Pressure / drug effects
  • Disease Models, Animal
  • Fatty Acid-Binding Proteins / urine*
  • Hypertension, Renal / chemically induced
  • Hypertension, Renal / metabolism
  • Hypertension, Renal / prevention & control*
  • Kidney / drug effects
  • Kidney / metabolism
  • Mice
  • NF-E2-Related Factor 2 / metabolism*
  • Oleanolic Acid / analogs & derivatives*
  • Oleanolic Acid / pharmacology
  • Oleanolic Acid / therapeutic use
  • Oxidative Stress / drug effects
  • Protective Agents / pharmacology
  • Protective Agents / therapeutic use*
  • Reactive Oxygen Species / metabolism
  • Renin-Angiotensin System / drug effects*
  • Renin-Angiotensin System / physiology
  • Sodium Chloride / adverse effects
  • Up-Regulation / drug effects

Substances

  • Fabp1 protein, mouse
  • Fatty Acid-Binding Proteins
  • NF-E2-Related Factor 2
  • Protective Agents
  • Reactive Oxygen Species
  • Angiotensinogen
  • Sodium Chloride
  • Aldosterone
  • Oleanolic Acid
  • methyl 2-cyano-3,12-dioxoolean-1,9-dien-28-oate