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

• Main Authors: Mingsheng Zhu (Author), Xian Ling (Author), Shan Zhou (Author), Ping Meng (Author), Qiyan Chen (Author), Shuangqin Chen (Author), Kunyu Shen (Author), Chao Xie (Author), Yaozhong Kong (Author), Maosheng Wang (Author), Lili Zhou (Author)
• Format: Book
• Published: Karger Publishers, 2022-09-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.
• Notes: 2296-9381; 2296-9357; 10.1159/000526139
• Keywords: kya1797k; mitochondrial dysfunction; kidney aging; β-catenin; icg-001; Internal medicine; RC31-1245
• Source: Kidney Diseases, Pp 1-16 (2022)

Introduction: Aged kidney is characterized by mitochondrial dysfunction, cellular senescence, and fibrogenesis. The activation of Wnt/β-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 β-catenin inhibitors, KYA1797K and ICG-001, to assess their superiority. Methods: Two-month-old male C57BL/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 β-catenin pathway through blocking the binding of β-catenin and cAMP response element-binding protein (CREB)-binding protein (CBP), KYA1797K, a novel small molecule destabilizing β-catenin through activating Axin-GSK3β complex, possesses the superior effects on protecting against kidney aging. In D-gal-treated accelerated aging mice, KYA1797K could greatly inhibit β-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 β-catenin is a necessity to target against age-related kidney injury, suggesting the multiple transcriptional regulation of β-catenin in kidney aging besides T-cell factor/lymphoid enhancer-binding factor family of transcription factors (TCF/LEF-1).