Kaseda Shota, Horizono Jun, Sannomiya Yuya, Kuwazuru Jun, Suico Mary Ann, Sato Ryoichi, Fukiya Hirohiko, Sunamoto Hidetoshi, Ogi Sayaka, Matsushita Takashi, Koyama Yuimi, Owaki Aimi, Tsuhako Haruki, Shiraga Masahiro, Watanabe Hiroshi, Nakano Takehiro, Davenport Bernard, Nozu Kandai, Yamamoto Masayuki, Shuto Tsuyoshi, Tokunaga Yasunori, Lennon Rachel, Onuma Kazuhiro, Kai Hirofumi
Department of Molecular Medicine, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan
Wellcome Centre for Cell-Matrix Research, University of Manchester, Manchester, UK.
Life Sci Alliance. 2025 Jun 17;8(8). doi: 10.26508/lsa.202503330. Print 2025 Aug.
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 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.
核因子红细胞2相关因子2（Nrf2）的激活在急性肾损伤和非蛋白尿性慢性肾脏病的实验模型中已显示出保护作用。然而，Nrf2激活对伴有肾小球损伤的蛋白尿性慢性肾脏病的疗效存在争议，因为会观察到蛋白尿短暂增加。在此，我们鉴定出一种强效的Nrf2激活剂UD-051，它可抑制 Kelch样ECH相关蛋白1（Keap1）与Nrf2之间的相互作用。UD-051以Nrf2依赖的方式显著改善了Alport综合征小鼠模型的进行性表型，同时伴有蛋白尿增加。通过基因敲低或用CDDO-咪唑化物进行药理学Keap1抑制实现的轻度Nrf2激活并未减轻Alport肾病，这表明强烈的Nrf2激活对于明确的治疗效果至关重要。深入分析表明，UD-051可抑制肾小管损伤，包括氧化应激、炎症和代谢失调。UD-051与氯沙坦（一种针对肾小球功能障碍的肾素-血管紧张素系统抑制剂）联合使用，可极大地改善Alport肾病。我们的研究全面深入地了解了Nrf2激活在Alport综合征中的疗效，并为在肾素-血管紧张素系统抑制剂中添加Keap1-Nrf2相互作用抑制剂提供了理论依据。
