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Int J Biol Sci 2023; 19(9):2860-2878. doi:10.7150/ijbs.82417 This issue Cite

Research Paper

Limonin, a natural ERK2 agonist, protects against ischemic acute kidney injury

Xianke Zhou1*, Yadie Xiang1*, Dier Li1*, Menghua Zhong1, Xue Hong1, Yuan Gui2, Wenjian Min3, Yudan Chen1, Xi Zeng1, Haili Zhu1, Youhua Liu1, Shijia Liu4, Peng Yang3, Fanfan Hou1, Dong Zhou2, Haiyan Fu1✉

1. Division of Nephrology, Nanfang Hospital, Southern Medical University; State Key Laboratory of Organ Failure Research; National Clinical Research Center for Kidney Disease; Guangdong Provincial Institute of Nephrology; Guangdong Provincial Key Laboratory of Renal Failure Research, Guangzhou, 510515, China.
2. Division of Nephrology, Department of Medicine, University of Connecticut School of Medicine, Farmington, CT, 06030, USA.
3. State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, 210009, China.
4. Department of Clinical Pharmacology, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, China.
* These authors contributed equally to this work.

✉ Corresponding author: Haiyan Fu, MD/Ph.D, Division of Nephrology, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou, 510515, China. E-mail: fuhyanedu.cn.

Citation:
Zhou X, Xiang Y, Li D, Zhong M, Hong X, Gui Y, Min W, Chen Y, Zeng X, Zhu H, Liu Y, Liu S, Yang P, Hou F, Zhou D, Fu H. Limonin, a natural ERK2 agonist, protects against ischemic acute kidney injury. Int J Biol Sci 2023; 19(9):2860-2878. doi:10.7150/ijbs.82417. https://www.ijbs.com/v19p2860.htm
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Abstract

Graphic abstract

Acute kidney injury (AKI) is a refractory clinical syndrome with limited effective treatments. Amid AKI, activation of the extracellular signal-regulated kinase (ERK) cascade plays a critical role in promoting kidney repair and regeneration. However, a mature ERK agonist in treating kidney disease remains lacking. This study identified limonin, a member of the class of compounds known as furanolactones, as a natural ERK2 activator. Employing a multidisciplinary approach, we systemically dissected how limonin mitigates AKI. Compared to vehicles, pretreatment of limonin significantly preserved kidney functions after ischemic AKI. We revealed that ERK2 is a significant protein linked to the limonin's active binding sites through structural analysis. The molecular docking study showed a high binding affinity between limonin and ERK2, which was confirmed by the cellular thermal shift assay and microscale thermophoresis. Mechanistically, we further validated that limonin promoted tubular cell proliferation and reduced cell apoptosis after AKI by activating ERK signaling pathway in vivo. In vitro and ex vivo, blockade of ERK abolished limonin's capacity of preventing tubular cell death under hypoxia stress. Our results indicated that limonin is a novel ERK2 activator with strong translational potential in preventing or mitigating AKI.

Keywords: limonin, acute kidney injury, extracellular signal-regulated kinase 2, cell death, cell proliferation

Citation styles

APA
Zhou, X., Xiang, Y., Li, D., Zhong, M., Hong, X., Gui, Y., Min, W., Chen, Y., Zeng, X., Zhu, H., Liu, Y., Liu, S., Yang, P., Hou, F., Zhou, D., Fu, H. (2023). Limonin, a natural ERK2 agonist, protects against ischemic acute kidney injury. International Journal of Biological Sciences, 19(9), 2860-2878. https://doi.org/10.7150/ijbs.82417.

ACS
Zhou, X.; Xiang, Y.; Li, D.; Zhong, M.; Hong, X.; Gui, Y.; Min, W.; Chen, Y.; Zeng, X.; Zhu, H.; Liu, Y.; Liu, S.; Yang, P.; Hou, F.; Zhou, D.; Fu, H. Limonin, a natural ERK2 agonist, protects against ischemic acute kidney injury. Int. J. Biol. Sci. 2023, 19 (9), 2860-2878. DOI: 10.7150/ijbs.82417.

NLM
Zhou X, Xiang Y, Li D, Zhong M, Hong X, Gui Y, Min W, Chen Y, Zeng X, Zhu H, Liu Y, Liu S, Yang P, Hou F, Zhou D, Fu H. Limonin, a natural ERK2 agonist, protects against ischemic acute kidney injury. Int J Biol Sci 2023; 19(9):2860-2878. doi:10.7150/ijbs.82417. https://www.ijbs.com/v19p2860.htm

CSE
Zhou X, Xiang Y, Li D, Zhong M, Hong X, Gui Y, Min W, Chen Y, Zeng X, Zhu H, Liu Y, Liu S, Yang P, Hou F, Zhou D, Fu H. 2023. Limonin, a natural ERK2 agonist, protects against ischemic acute kidney injury. Int J Biol Sci. 19(9):2860-2878.

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