Although AS is caused by mutations in the genes encoding type IV collagen, a major structural component of the GBM in the kidney, mitochondrial dysfunction and chronic inflammation play a central role in the progression of AS. Mitochondrial dysfunction in AS is associated with the genetic insult and results in the development of chronic inflammation in the kidney. The activation of proinflammatory pathways promotes kidney tissue remodeling, tubular atrophy, interstitial scarring, and fibrosis, which manifests clinically as progressive loss of kidney function that can eventually lead to ESRD.8,9
Bardoxolone Methyl Mechanism of Action
Through Nrf2 induction and inhibition of NF-κB, bardoxolone methyl activates molecular pathways that promote the resolution of inflammation by restoring mitochondrial function and redox balance and inhibiting proinflammatory signaling. In preclinical models, bardoxolone methyl reverses endothelial dysfunction and chronic, disease-related mesangial cell contraction, resulting in an increased surface area of the glomerulus and increased glomerular filtration rate (GFR). Bardoxolone methyl also inhibits activation of proinflammatory and profibrotic pathways that lead to structural remodeling and glomerulosclerosis. Thus, bardoxolone methyl targets multiple pathways that contribute to GFR loss in AS.