Imperatorin ameliorates ferroptotic cell death, inflammation, and renal fibrosis in a unilateral ureteral obstruction mouse model

Jr-Di Yang; Ssu Chia Lin; Huey Liang Kuo; Yu Syuan Chen; Pei Yu Weng; Chang Mu Chen; Shing-Hwa Liu; Chun Fa Huang; Siao Syun Guan; Po Lin Liao; Yen Hao Su; Kuan-I Lee; Pei Yun Wang; Haw Ling Chuang; Cheng Tien Wu

doi:10.1016/j.phymed.2024.156066

Imperatorin ameliorates ferroptotic cell death, inflammation, and renal fibrosis in a unilateral ureteral obstruction mouse model

Phytomedicine. 2024 Sep 16:135:156066. doi: 10.1016/j.phymed.2024.156066. Online ahead of print.

Authors

Jr-Di Yang¹, Ssu Chia Lin², Huey Liang Kuo³, Yu Syuan Chen², Pei Yu Weng², Chang Mu Chen⁴, Shing-Hwa Liu⁵, Chun Fa Huang⁶, Siao Syun Guan⁷, Po Lin Liao⁸, Yen Hao Su⁹, Kuan-I Lee¹⁰, Pei Yun Wang², Haw Ling Chuang¹¹, Cheng Tien Wu¹²

Affiliations

¹ Division of Urology, Department of Surgery, National Yang-Ming Chiao Tung University Hospital, Yilan, Taiwan.
² Department of Nutrition, China Medical University, Taichung 40402, Taiwan.
³ Division of Nephrology, Department of Internal Medicine, China Medical University Hospital, Taichung 40402, Taiwan; School of Medicine, College of Medicine, China Medical University, Taichung 40402, Taiwan; Clinical Nutrition, China Medical University Hospital, Taichung 40402, Taiwan.
⁴ Division of Neurosurgery, Department of Surgery, College of Medicine and Hospital, National Taiwan University, Taipei 10051, Taiwan.
⁵ Institute of Toxicology, College of Medicine, National Taiwan University, Taipei 10051, Taiwan.
⁶ School of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung 40402, Taiwan; Department of Nursing, College of Medical and Health Science, Asia University, Taichung, 413, Taiwan.
⁷ Institute of Nuclear Energy Research, Atomic Energy Council, Taoyuan 32546, Taiwan.
⁸ Institute of Food Safety and Health Risk Assessment, National Yang Ming Chiao Tung University-Yang ming Campus, 155, Sec. 2, Linong Street, Taipei 11221, Taiwan.
⁹ Department of Surgery, Division of General Surgery, Shuang Ho Hospital, Taipei Medical University, Taipei 235, Taiwan; Department of General Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan.
¹⁰ Department of Emergency, Taichung Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taichung 427, Taiwan.
¹¹ Department of Emergency, Taichung Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taichung 427, Taiwan. Electronic address: tc2050403@tzuchi.com.tw.
¹² Department of Nutrition, China Medical University, Taichung 40402, Taiwan. Electronic address: ct-wu@mail.cmu.edu.tw.

PMID: 39341130
DOI: 10.1016/j.phymed.2024.156066

Abstract

Background: Imperatorin is a naturally occurring furocoumarin derivative found in traditional Chinese medicine Angelica dahurica for its anticancer, antihypertensive, and antidiabetic properties. Chronic kidney disease (CKD) is a global health issue, characterized by a high prevalence, significant morbidity and mortality, and a range of related complications.

Objective: This study aims to investigate the protective effects of imperatorin treatment and the specific underlying mechanisms in progressive CKD.

Methods: Imperatorin was orally administrated for 14 consecutive days to mice with unilateral ureteral obstruction (UUO) to investigate the renal pathological alternations, pro-inflammatory mediators, antioxidant response, and ferroptotic death signaling. Imperatorin was also tested in the erastin-induced injury of renal proximal tubular cells (NRK-52E). Cell viability, ferroptosis protein markers, erastin-induced oxidative stress, and lipid peroxidation were assessed.

Results: In vivo, imperatorin treatment alleviated kidney histology alternations and attenuated the protein expression of fibrotic markers. Furthermore, imperatorin administration reduced inflammatory cell infiltration, and alleviated the oxidative stress burden by downregulating protein markers such as catalase, superoxide dismutase 2 (SOD-2), NADPH oxidase 4 (NOX-4), and thioredoxin reductase 1 (Trxr-1). It also mitigated ferroptosis markers such as glutathione peroxidase 4 (GPX4), solute carrier family 7 member 11/cystine transporter (SLC7A11/xCT), and transferrin receptor 1 (TFR-1), and attenuated renal cell apoptosis. In vitro, imperatorin treatment effectively decreased erastin-induced feroptotic cell death, restored the antioxidant enzyme levels, and mitigated lipid peroxidation as well as the expression of ferroptosis-related markers (XCT, GPX4, and p-p53) in a dose-dependent manner.

Conclusion: Our finding demonstrated for the first time, that imperatorin treatment holds therapeutic potential in a UUO mouse model of CKD and inhibits the erastin-induced oxidative stress, ferroptosis, and subsequent lipid peroxidation in vitro. This highlights the potential of imperatorin as a future therapeutic target for ferroptosis to improve the progression of CKD.

Keywords: Chronic kidney disease; Ferroptosis; Fibrosis; Imperatorin; Oxidative stress.