Efficacy of Nrf2 activation in a proteinuric Alport syndrome mouse model.

Activation of nuclear factor erythroid 2-related factor 2 (Nrf2) has shown protective effects in experimental models of acute kidney injury and nonproteinuric chronic kidney disease. However, the efficacy of Nrf2 activation for proteinuric chronic kidney disease with glomerular injury is controversial, as a transient increase in proteinuria is observed. Here, we identified a potent Nrf2 activator UD-051, which inhibits the interaction between Kelch-like ECH-associated protein 1 (Keap1) and Nrf2. UD-051 significantly ameliorated the progressive phenotype of Alport syndrome mouse model in an Nrf2-dependent manner, accompanied by increased proteinuria. Mild Nrf2 activation by genetic Keap1 knockdown or pharmacological Keap1 inhibition with CDDO-imidazolide did not attenuate Alport kidney disease, suggesting that strong Nrf2 activation is essential for clear therapeutic efficacy. In-depth analysis revealed that UD-051 suppressed tubular injury, including oxidative stress, inflammation, and dysregulated metabolism. UD-051 with losartan, a renin-angiotensin system inhibitor that targets glomerular dysfunction, vastly ameliorated Alport kidney disease. Our study provides a comprehensive insight into the efficacy of Nrf2 activation in Alport syndrome and provides a rationale for adding a Keap1-Nrf2 interaction inhibitor to a renin-angiotensin system inhibitor.