Efficacy of Nrf2 activation in a proteinuric Alport syndrome mouse model

PMCID: PMC12174586

PMID: 40527586

DOI: 10.26508/lsa.202503330

Journal: Life science alliance

Publication Date: 2025-6-17

Authors: Kaseda S, Horizono J, Sannomiya Y, Kuwazuru J, Suico MA, et al.

Key Points

• UD-051, a novel Keap1-Nrf2 protein interaction inhibitor, demonstrated kidney protective effects in Alport syndrome by targeting tubular injury
• Combination therapy of UD-051 and losartan extended median survival beyond individual treatment effects
• The study suggests that Nrf2 activation's effectiveness depends on dosage and activation intensity, with strict control of kidney tissue Nrf2 activity being crucial

Summary

This preclinical study investigated novel therapeutic approaches for Alport syndrome, a progressive kidney disease characterized by glomerular basement membrane disruption and kidney dysfunction. Researchers explored Nrf2 activation strategies using genetic and pharmacological interventions in a mouse model, ultimately identifying a promising compound (UD-051) that demonstrated unique kidney protective mechanisms.

The study revealed that while mild Nrf2 activation was ineffective, a potent Nrf2 activator (UD-051) significantly ameliorated kidney disease progression, particularly in tubular injury, inflammation, and fibrosis. Notably, when combined with losartan, UD-051 showed synergistic effects that extended median survival and comprehensively controlled kidney disease progression, challenging conventional therapeutic approaches that focus solely on suppressing proteinuria.