KYA1797K, a Novel Small Molecule Destabilizing β-Catenin, Is Superior to ICG-001 in Protecting against Kidney Aging

作者：Zhu, Mingsheng^*; Ling, Xian; Zhou, Shan; Meng, Ping; Chen, Qiyan; Chen, Shuangqin; Shen, Kunyu; Xie, Chao; Kong, Yaozhong; Wang, Maosheng; Zhou, Lili^*

来源：Kidney Diseases, 2022, 8(5): 408-423.

DOI：10.1159/000526139

• KYA1797K
• Mitochondrial dysfunction
• Kidney aging
• beta-Catenin
• ICG-001

Introduction: Aged kidney is characterized by mitochondrial dysfunction, cellular senescence, and fibrogenesis. The activation of Wnt/beta-catenin signaling plays an important role in the initiation of kidney aging. However, the inhibiting strategies have not been discovered in detail. Here, we compared the therapeutic effects of two beta-catenin inhibitors, KYA1797K and ICG-001, to assess their superiority. Methods: Two-month-old male CS7BL/6 mice which had undergone unilateral nephrectomy and received D-galactose (D-gal) injection were co-treated with KYA1797K or ICG-001 at 10 mg/kg/day for 4 weeks. Human proximal renal tubular cells were treated with D-gal and KYA1797K/ICG-001 to compare their effects. Results: Compared with ICG-001, which inhibits beta-catenin pathway through blocking the binding of beta-catenin and cAMP response element-binding protein (CREB)-binding protein (CBP), KYA1797K, a novel small molecule destabilizing beta-catenin through activating Axin-GSK3 beta complex, possesses the superior effects on protecting against kidney aging. In D-gal-treated accelerated aging mice, KYA1797K could greatly inhibit beta-catenin pathway, preserve mitochondrial homeostasis, repress cellular senescence, and retard age-related kidney fibrosis. In cultured proximal tubular cells, KYA1797K shows a better effect on inhibiting cellular senescence and could better suppress mitochondrial dysfunction and ameliorate the fibrotic changes, at the same dose as that in ICG-001. Conclusion: These results show that effectively eliminating beta-catenin is a necessity to target against age-related kidney injury, suggesting the multiple transcriptional regulation of beta-catenin in kidney aging besides T-cell factor/ lymphoid enhancer-binding factor family of transcription factors (TCF/LEF-1).

• 单位
  佛山市第一人民医院; 南方医科大学