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Published on: May 26, 2022
Low-dose rapamycin prevents Ang-II-induced toxicity in Leydig cells and testicular dysfunction in hypertensive SHR
Wei-Wen Kuo1, Rathinasamy Baskaran2, Jing-Ying Lin3
1Department of Biological Science and Technology, China Medical University, Taichung, Taiwan.
Insights
Low-dose rapamycin protects male reproductive function from hypertension-induced testicular damage by restoring key molecular pathways and reducing oxidative stress. This suggests rapamycin as a potential therapeutic for male infertility associated with hypertension.
Area of Science:
- Cardiovascular Pharmacology
- Reproductive Biology
- Molecular Medicine
Background:
- Hypertension is a prevalent cardiovascular disease impacting male reproductive health, yet its underlying mechanisms remain unclear.
- High-dose rapamycin offers benefits but carries risks like immunosuppression.
- Understanding protective strategies against hypertension-induced testicular toxicity is crucial.
Purpose of the Study:
- To investigate the efficacy of low-dose rapamycin in mitigating hypertension-induced testicular damage in spontaneously hypertensive rats (SHRs).
- To elucidate the molecular mechanisms by which low-dose rapamycin prevents testicular toxicity induced by angiotensin II (Ang II).
Main Methods:
- Assessment of testicular parameters (size, histology, apoptosis) in SHR rats treated with low-dose rapamycin.
- In vitro studies using LC-540 Leydig cells to analyze the effects of Ang II and rapamycin on gene/protein expression (ACE2, 3β-HSD, steroidogenic enzymes).
- Evaluation of mitochondrial function (superoxide generation, membrane potential) and related molecular pathways (Nrf2, Gpx4, SOD2).
Main Results:
- Low-dose rapamycin restored testicular size, improved histology, normalized 3β-hydroxysteroid dehydrogenase (3β-HSD) expression, and prevented apoptosis in SHR rats.
- Angiotensin II (Ang II) downregulated angiotensin-converting enzyme-2 (ACE2) expression via AT1R, p-ERK, and MAS receptor pathways.
- Rapamycin upregulated ACE2, steroidogenic enzymes, and 3β-HSD in Leydig cells, while also mitigating Ang II-induced mitochondrial dysfunction and oxidative stress via Nrf2 activation.
Conclusions:
- Low-dose rapamycin effectively protects against Ang II-induced testicular toxicity in rats.
- The protective effects involve upregulation of ACE2, steroidogenic pathways, and antioxidant mechanisms, alongside curbing oxidative stress.
- Low-dose rapamycin presents a promising therapeutic candidate for attenuating testicular toxicity associated with hypertension.
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.
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