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Theranostics 2022; 12(16):7158-7179. doi:10.7150/thno.78376 This issue Cite

Research Paper

A new LKB1 activator, piericidin analogue S14, retards renal fibrosis through promoting autophagy and mitochondrial homeostasis in renal tubular epithelial cells

Canzhen Liu1#, Xiaoxu Wang1#, Xiaonan Wang1#, Yunfang Zhang2#, Wenjian Min3, Ping Yu4, Jinhua Miao1, Weiwei Shen1, Shuangqin Chen1, Shan Zhou1, Xiaolong Li1, Ping Meng2, Qinyu Wu1, Fan Fan Hou1, Youhua Liu1, Peng Yang3, Cheng Wang5✉, Xu Lin6✉, Lan Tang4✉, Xuefeng Zhou7✉, Lili Zhou1✉

1. Division of Nephrology, Nanfang Hospital, Southern Medical University; National Clinical Research Center for Kidney Disease; State Key Laboratory of Organ Failure Research; Guangdong Provincial Institute of Nephrology; Guangdong Provincial Key Laboratory of Renal Failure Research, Guangzhou, China.
2. Department of Nephrology, Huadu District People's Hospital, Southern Medical University, Guangzhou, China.
3. State Key Laboratory of Natural Medicines and Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, China.
4. Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China.
5. Division of nephrology, Department of medicine, the Fifth affiliated hospital of Sun Yat-Sen University, Zhuhai, Guangdong, China.
6. Department of Nephrology, The Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, Guangxi, China.
7. CAS Key Laboratory of Tropical Marine Bio-resources and Ecology, Guangdong Key Laboratory of Marine Materia Medica, South China Sea Institute of Oceanology, Chinese Academy of Sciences, Guangzhou, China.
#These authors contributed equally to this work.

✉ Corresponding authors: Dr. Lili Zhou, Division of Nephrology, Nanfang Hospital, 1838 North Guangzhou Ave, Guangzhou 510515, China, E-mail: jinli730edu.cn; or Dr. Xuefeng Zhou, Guangdong Key Laboratory of Marine Materia Medica, South China Sea I More

Citation:
Liu C, Wang X, Wang X, Zhang Y, Min W, Yu P, Miao J, Shen W, Chen S, Zhou S, Li X, Meng P, Wu Q, Hou FF, Liu Y, Yang P, Wang C, Lin X, Tang L, Zhou X, Zhou L. A new LKB1 activator, piericidin analogue S14, retards renal fibrosis through promoting autophagy and mitochondrial homeostasis in renal tubular epithelial cells. Theranostics 2022; 12(16):7158-7179. doi:10.7150/thno.78376. https://www.thno.org/v12p7158.htm
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Abstract

Graphic abstract

Background: Liver kinase B1 (LKB1) is the key regulator of energy metabolism and cell homeostasis. LKB1 dysfunction plays a key role in renal fibrosis. However, LKB1 activators are scarce in commercial nowadays. This study aims to discover a new drug molecule, piericidin analogue S14 (PA-S14), preventing renal fibrosis as a novel activator to LKB1.

Methods: Our group isolated PA-S14 from the broth culture of a marine-derived Streptomyces strain and identified its binding site. We adopted various CKD models or AKI-CKD model (5/6 nephrectomy, UUO, UIRI and adriamycin nephropathy models). TGF-β-stimulated renal tubular cell culture was also tested.

Results: We identified that PA-S14 binds with residue D176 in the kinase domain of LKB1, and then induces the activation of LKB1 through its phosphorylation and complex formation with MO25 and STRAD. As a result, PA-S14 promotes AMPK activation, triggers autophagosome maturation, and increases autophagic flux. PA-S14 inhibited tubular cell senescence and retarded fibrogenesis through activation of LKB1/AMPK signaling. Transcriptomics sequencing and mutation analysis further demonstrated our results.

Conclusion: PA-S14 is a novel leading compound of LKB1 activator. PA-S14 is a therapeutic potential to renal fibrosis through LKB1/AMPK-mediated autophagy and mitochondrial homeostasis pathways.

Keywords: LKB1, PA-S14, renal fibrosis, autophagy, AMPK

Citation styles

APA
Liu, C., Wang, X., Wang, X., Zhang, Y., Min, W., Yu, P., Miao, J., Shen, W., Chen, S., Zhou, S., Li, X., Meng, P., Wu, Q., Hou, F.F., Liu, Y., Yang, P., Wang, C., Lin, X., Tang, L., Zhou, X., Zhou, L. (2022). A new LKB1 activator, piericidin analogue S14, retards renal fibrosis through promoting autophagy and mitochondrial homeostasis in renal tubular epithelial cells. Theranostics, 12(16), 7158-7179. https://doi.org/10.7150/thno.78376.

ACS
Liu, C.; Wang, X.; Wang, X.; Zhang, Y.; Min, W.; Yu, P.; Miao, J.; Shen, W.; Chen, S.; Zhou, S.; Li, X.; Meng, P.; Wu, Q.; Hou, F.F.; Liu, Y.; Yang, P.; Wang, C.; Lin, X.; Tang, L.; Zhou, X.; Zhou, L. A new LKB1 activator, piericidin analogue S14, retards renal fibrosis through promoting autophagy and mitochondrial homeostasis in renal tubular epithelial cells. Theranostics 2022, 12 (16), 7158-7179. DOI: 10.7150/thno.78376.

NLM
Liu C, Wang X, Wang X, Zhang Y, Min W, Yu P, Miao J, Shen W, Chen S, Zhou S, Li X, Meng P, Wu Q, Hou FF, Liu Y, Yang P, Wang C, Lin X, Tang L, Zhou X, Zhou L. A new LKB1 activator, piericidin analogue S14, retards renal fibrosis through promoting autophagy and mitochondrial homeostasis in renal tubular epithelial cells. Theranostics 2022; 12(16):7158-7179. doi:10.7150/thno.78376. https://www.thno.org/v12p7158.htm

CSE
Liu C, Wang X, Wang X, Zhang Y, Min W, Yu P, Miao J, Shen W, Chen S, Zhou S, Li X, Meng P, Wu Q, Hou FF, Liu Y, Yang P, Wang C, Lin X, Tang L, Zhou X, Zhou L. 2022. A new LKB1 activator, piericidin analogue S14, retards renal fibrosis through promoting autophagy and mitochondrial homeostasis in renal tubular epithelial cells. Theranostics. 12(16):7158-7179.

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