Losartan inhibits methotrexate-induced testicular damage via anti-inflammatory and anti-apoptotic effects

BACKGROUND: Methotrexate (MTX), a potent chemotherapy drug, has restricted clinical utility owing to its capacity to cause significant gonadal damage. OBJECTIVE: This study investigated the preventive effect of the angiotensin II type 1 receptor (AT1R) antagonist, losartan, against methotrexate-induced testicular damage in rats. METHODS: = 6). The animals were administered MTX (20 mg/kg) with or without losartan treatment (10 mg/kg/day) via intraperitoneal injection. Histopathological examination and ELISA-based assessment of Ang II, AKT, p-AKT, NF-κB, IL-1, TNF-α, and caspase-3 were performed. Furthermore, MTX suppressed the pAKT/AKT survival pathway by 37.6%, decreasing the ratio from 1.25 to 0.78, hence facilitating apoptosis. The co-administration of Losartan (10 mg/kg/day for seven days) markedly mitigated these effects. Losartan brought Ang II levels back to normal, reduced the inflammatory response (IL-1 went up by only 83.3% and TNF-α by 44.4% compared to the control), lowered NF-κB activity, and raised the pAKT/AKT ratio by 62.8% (to 1.27, which is similar to control levels). CONCLUSION: The findings indicate that the Ang II/AT1R axis is a significant upstream mediator of MTX-induced gonadotoxicity. It connects inflammatory and pro-apoptotic signaling with structural damage to the testes. Our data collectively demonstrate that AT1R inhibition using Losartan successfully mitigates MTX-induced testicular damage by addressing this upstream mechanistic pathway. Losartan has been identified as a viable treatment strategy for preserving male reproductive function following cytotoxic therapy.