Low-dose rapamycin prevents Ang-II-induced toxicity in Leydig cells and testicular dysfunction in hypertensive SHR model
Wei-Wen Kuo
Department of Biological Science and Technology, China Medical University, Taichung, Taiwan
Search for more papers by this authorRathinasamy Baskaran
Department of Bioinformatics and Medical Engineering, Asia University, Taichung, Taiwan
Search for more papers by this authorJing-Ying Lin
Department of Medical Imaging and Radiological Science, Central Taiwan University of Science and Technology, Taichung, Taiwan
Search for more papers by this authorCecilia Hsuan Day
Department of Nursing, MeiHo University, Pingtung, Taiwan
Search for more papers by this authorYueh-Min Lin
School of Medicine, Chung Shan Medical University, Taichung, Taiwan
Department of Surgical Pathology, Changhua Christian Hospital, Changhua, Taiwan
Search for more papers by this authorTsung-Jung Ho
Department of Chinese Medicine, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Tzu Chi University, Hualien, Taiwan
Search for more papers by this authorRay-Jade Chen
Department of Surgery, Taipei Medical University, Taipei, Taiwan
Search for more papers by this authorMei-Yi Lin
Department of Food Nutrition and Health Biotechnology, Asia University, Taichung, Taiwan
Search for more papers by this authorViswanadha Vijaya Padma
Department of Biotechnology, Bharathiar University, Coimbatore, India
Search for more papers by this authorCorresponding 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]
Search for more papers by this authorWei-Wen Kuo
Department of Biological Science and Technology, China Medical University, Taichung, Taiwan
Search for more papers by this authorRathinasamy Baskaran
Department of Bioinformatics and Medical Engineering, Asia University, Taichung, Taiwan
Search for more papers by this authorJing-Ying Lin
Department of Medical Imaging and Radiological Science, Central Taiwan University of Science and Technology, Taichung, Taiwan
Search for more papers by this authorCecilia Hsuan Day
Department of Nursing, MeiHo University, Pingtung, Taiwan
Search for more papers by this authorYueh-Min Lin
School of Medicine, Chung Shan Medical University, Taichung, Taiwan
Department of Surgical Pathology, Changhua Christian Hospital, Changhua, Taiwan
Search for more papers by this authorTsung-Jung Ho
Department of Chinese Medicine, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Tzu Chi University, Hualien, Taiwan
Search for more papers by this authorRay-Jade Chen
Department of Surgery, Taipei Medical University, Taipei, Taiwan
Search for more papers by this authorMei-Yi Lin
Department of Food Nutrition and Health Biotechnology, Asia University, Taichung, Taiwan
Search for more papers by this authorViswanadha Vijaya Padma
Department of Biotechnology, Bharathiar University, Coimbatore, India
Search for more papers by this authorCorresponding 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]
Search for more papers by this authorWei-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.
Open Research
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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