Volume 36, Issue 9 e23128
RESEARCH ARTICLE

Low-dose rapamycin prevents Ang-II-induced toxicity in Leydig cells and testicular dysfunction in hypertensive SHR model

Wei-Wen Kuo

Wei-Wen Kuo

Department of Biological Science and Technology, China Medical University, Taichung, Taiwan

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Rathinasamy Baskaran

Rathinasamy Baskaran

Department of Bioinformatics and Medical Engineering, Asia University, Taichung, Taiwan

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Jing-Ying Lin

Jing-Ying Lin

Department of Medical Imaging and Radiological Science, Central Taiwan University of Science and Technology, Taichung, Taiwan

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Cecilia Hsuan Day

Cecilia Hsuan Day

Department of Nursing, MeiHo University, Pingtung, Taiwan

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Yueh-Min Lin

Yueh-Min Lin

School of Medicine, Chung Shan Medical University, Taichung, Taiwan

Department of Surgical Pathology, Changhua Christian Hospital, Changhua, Taiwan

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Tsung-Jung Ho

Tsung-Jung Ho

Department of Chinese Medicine, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Tzu Chi University, Hualien, Taiwan

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Ray-Jade Chen

Ray-Jade Chen

Department of Surgery, Taipei Medical University, Taipei, Taiwan

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Mei-Yi Lin

Mei-Yi Lin

Department of Food Nutrition and Health Biotechnology, Asia University, Taichung, Taiwan

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Viswanadha Vijaya Padma

Viswanadha Vijaya Padma

Department of Biotechnology, Bharathiar University, Coimbatore, India

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Chih-Yang Huang

Corresponding Author

Chih-Yang Huang

Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan

Center of General Education, Buddhist Tzu Chi Medical Foundation, Tzu Chi University of Science and Technology, Hualien, Taiwan

Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan

Department of Biotechnology, Asia University, Taichung, Taiwan

Cardiovascular and Mitochondrial Related Disease Research Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan

Correspondence Chih-Yang Huang, Cardiovascular and Mitochondrial Related Disease Research Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Tzu Chi University of Science and Technology, Hualien, Taiwan.

Email: [email protected]

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First published: 14 June 2022

Wei-Wen Kuo, Rathinasamy Baskaran, and Jing-Ying Lin contributed equally to this work.

Abstract

Hypertension is a common chronic cardiovascular disease reported among both men and women. Hypertension in males affects the testis and reproduction function; however, the pathogenesis is poorly understood. Rapamycin has been reported to have a variety of beneficial pharmacological effects; however, high-doses rapamycin does have side effects such as immunosuppression. The present study investigates whether low-dose rapamycin can reduce the damage caused by hypertension to the testis of spontaneously hypertensive rats (SHRs) and further examines molecular mechanism of low-dose rapamycin in preventing testicular toxicity induced by angiotensin II (Ang II). Low rapamycin dose restores the testicle size, histological alterations, 3β-hydroxysteroid dehydrogenase (3β-HSD) expression, and prevents apoptosis in SHR rats. Ang II downregulates angiotensin-converting enzyme-2 (ACE2) expression through AT1R, p-ERK, and MAS receptor in LC-540 Leydig cells in a dose-dependent manner. Low doses of rapamycin effectively upregulate steroidogenic enzymes, steroidogenic acute regulatory protein and 3β-HSD expression in Leydig cells. Rapamycin upregulates ACE2 expression through p-PKAc and p-PI3k in Ang II-treated cells. Further, rapamycin curbs mitochondrial superoxide generation and depleted mitochondrial membrane potential induced by Ang II through activation of Nrf2-mediated Gpx4 and superoxide dismutase 2 expression. Our results revealed the involvement of ACE2, AT1R, AT2R, PKAc, and oxidative stress in Ang-II-induced testicular toxicity, suggesting low-dose rapamycin could be a potential therapeutic candidate to attenuate testicular toxicity.

CONFLICT OF INTEREST

The authors declare no conflict of interest.

DATA AVAILABILITY STATEMENT

The data that support the findings of this study are available from the corresponding author, CYH, upon reasonable request.

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