A Natural Small Molecule Mitigates Kidney Fibrosis by Targeting Cdc42‐mediated GSK‐3β/β‐catenin Signaling

Author:

Hu Xinrong1ORCID,Gan Lu2,Tang Ziwen1,Lin Ruoni1,Liang Zhou1,Li Feng1,Zhu Changjian1,Han Xu1,Zheng Ruilin1,Shen Jiani1,Yu Jing1,Luo Ning1,Peng Wenxing1,Tan Jiaqing1,Li Xiaoyan1,Fan Jinjin1,Wen Qiong1,Wang Xin1,Li Jianbo1,Zheng Xunhua1,Liu Qinghua1,Guo Jianping3,Shi Guo‐Ping4,Mao Haiping1,Chen Wei1,Yin Sheng2,Zhou Yi1ORCID

Affiliation:

1. Department of Nephrology The First Affiliated Hospital Sun Yat‐sen University NHC Key Laboratory of Clinical Nephrology Guangdong Provincial Key Laboratory of Nephrology Sun Yat‐Sen University Guangzhou 510080 China

2. School of Pharmaceutical Sciences Sun Yat‐sen University Guangzhou 510006 China

3. Institute of Precision Medicine The First Affiliated Hospital Sun Yat‐sen University Guangzhou 510080 China

4. Department of Medicine Brigham and Women's Hospital and Harvard Medical School Boston MA 02115 USA

Abstract

AbstractKidney fibrosis is a common fate of chronic kidney diseases (CKDs), eventually leading to renal dysfunction. Yet, no effective treatment for this pathological process has been achieved. During the bioassay‐guided chemical investigation of the medicinal plant Wikstroemia chamaedaphne, a daphne diterpenoid, daphnepedunin A (DA), is characterized as a promising anti‐renal fibrotic lead. DA shows significant anti‐kidney fibrosis effects in cultured renal fibroblasts and unilateral ureteral obstructed mice, being more potent than the clinical trial drug pirfenidone. Leveraging the thermal proteome profiling strategy, cell division cycle 42 (Cdc42) is identified as the direct target of DA. Mechanistically, DA targets to reduce Cdc42 activity and down‐regulates its downstream phospho‐protein kinase Cζ(p‐PKCζ)/phospho‐glycogen synthase kinase‐3β (p‐GSK‐3β), thereby promoting β‐catenin Ser33/37/Thr41 phosphorylation and ubiquitin‐dependent proteolysis to block classical pro‐fibrotic β‐catenin signaling. These findings suggest that Cdc42 is a promising therapeutic target for kidney fibrosis, and highlight DA as a potent Cdc42 inhibitor for combating CKDs.

Funder

National Natural Science Foundation of China

Publisher

Wiley

Subject

General Physics and Astronomy,General Engineering,Biochemistry, Genetics and Molecular Biology (miscellaneous),General Materials Science,General Chemical Engineering,Medicine (miscellaneous)

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