Bardoxolone Methyl in Chronic Kidney Disease (CKD)
Bardoxolone methyl is an Nrf2 activator currently being investigated in clinical trials for the treatment of patients with different forms of chronic kidney disease.
Inflammation—initiated by a variety of pathogenic processes, including diabetes, systemic hypertension, IgA deposition, and genetic mutations—drives kidney function decline (43). At the molecular level, these pathogenic processes induce mitochondrial dysfunction, decrease ATP production, and promote production of ROS and pro-inflammatory signaling mediators that initiate and amplify inflammatory pathways in glomerular endothelial cells, mesangial cells, and podocytes, while also recruiting activated macrophages and other inflammatory effector cells to the renal interstitium. At the physiological level, chronic activation of pro-inflammatory pathways in these kidney cells leads to a reduction in the glomerular filtration rate (GFR) (44-46).
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In preclinical models, bardoxolone methyl suppresses inflammatory pathways that contribute to kidney function loss by increasing Nrf2 activity (4, 32-36). The beneficial activity of bardoxolone methyl and analogs has been observed in several nonclinical models of CKD, including CKD caused by diabetes, hypertension, autoimmune disease, nephron loss, and nephrosis (32, 34-36, 47, 48). In these models, bardoxolone methyl and analogs suppress inflammation and fibrosis (32, 34-36), reduce glomerulosclerosis (35, 36, 48), prevent tubulointerstitial damage (32, 34-36), and improve kidney function (32, 35, 47, 48).
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