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

Abstract

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).

• Authors: Mingsheng Zhu, Xian Ling, Shan Zhou, Ping Meng, Qiyan Chen, Shuangqin Chen, Kunyu Shen, Chao Xie, Yaozhong Kong, Maosheng Wang, Lili Zhou
• Journal: Kidney diseases (Basel, Switzerland) (Kidney Dis (Basel)) Vol. 8 Issue 5 Pg. 408-423 (Nov 2022) ISSN: 2296-9381 [Print] Switzerland
• PMID: 36466073 (Publication Type: Journal Article)
• Copyright: Copyright © 2022 by The Author(s). Published by S. Karger AG, Basel.