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Rapamycin has been reported to have a variety of beneficial pharmacological effects; however, high\u2010doses rapamycin does have side effects such as immunosuppression. The present study investigates whether low\u2010dose rapamycin can reduce the damage caused by hypertension to the testis of spontaneously hypertensive rats (SHRs) and further examines molecular mechanism of low\u2010dose rapamycin in preventing testicular toxicity induced by angiotensin II (Ang II). Low rapamycin dose restores the testicle size, histological alterations, 3\u03b2\u2010hydroxysteroid dehydrogenase (3\u03b2\u2010HSD) expression, and prevents apoptosis in SHR rats. Ang II downregulates angiotensin\u2010converting enzyme\u20102 (ACE2) expression through AT1R, p\u2010ERK, and MAS receptor in LC\u2010540 Leydig cells in a dose\u2010dependent manner. Low doses of rapamycin effectively upregulate steroidogenic enzymes, steroidogenic acute regulatory protein and 3\u03b2\u2010HSD expression in Leydig cells. Rapamycin upregulates ACE2 expression through p\u2010PKAc and p\u2010PI3k in Ang II\u2010treated cells. Further, rapamycin curbs mitochondrial superoxide generation and depleted mitochondrial membrane potential induced by Ang II through activation of Nrf2\u2010mediated Gpx4 and superoxide dismutase 2 expression. Our results revealed the involvement of ACE2, AT1R, AT2R, PKAc, and oxidative stress in Ang\u2010II\u2010induced testicular toxicity, suggesting low\u2010dose rapamycin could be a potential therapeutic candidate to attenuate testicular toxicity.<\/jats:p>","DOI":"10.1002\/jbt.23128","type":"journal-article","created":{"date-parts":[[2022,6,14]],"date-time":"2022-06-14T08:00:20Z","timestamp":1655193620000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Low\u2010dose rapamycin prevents Ang\u2010II\u2010induced toxicity in Leydig cells and testicular dysfunction in hypertensive SHR model"],"prefix":"10.1002","volume":"36","author":[{"given":"Wei\u2010Wen","family":"Kuo","sequence":"first","affiliation":[{"name":"Department of Biological Science and Technology China Medical University Taichung 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