Impact of lisinopril on cisplatin-induced inflammation, oxidative stress, apoptosis, and impaired steroidogenesis in rat testis: involvement of Nrf2/Keap1/HO-1 and PPARγ signaling

Testicular dysfunction is a significant long-term side effect of the chemotherapeutic drug cisplatin (CDDP), primarily due to DNA damage and oxidative stress. Lisinopril (LSP), an angiotensin-converting enzyme (ACE) inhibitor commonly used for hypertension treatment, has a debated impact on reproductive function. This study investigates, for the first time, the ability of LSP to counteract CDDP-induced inflammation, oxidative stress, apoptosis, and steroidogenic disturbances in rat testis. In addition, LSP’s effect on testicular Nrf2/Keap1/HO-1 and PPARγ signaling is examined. Rats were divided into Control, LSP, CDDP, and LSP + CDDP groups. Rats were treated with 10 mg/kg of LSP orally for 10 days, and blood and testis samples were collected after sacrifice for histopathological, biochemical, and genetic analysis. Our results revealed that LSP administration with CDDP effectively increased luteinizing, follicle-stimulating, and testosterone hormone levels (effect size f = 2.56, 2.32, and 3.02; respectively, and power = 1.00) and upregulated testicular expression of CYP11a1, HSD17B3, and StAR genes. LSP counteracted the histopathological aberrations induced by CDDP. The LSP + CDDP group also showed increased levels of reduced glutathione and superoxide dismutase (effect size f = 1.72 and power = 0.99) and decreased levels of malondialdehyde (effect size f = 3.07 and power = 1), interleukin-1β, tumor necrosis factor-α, interleukin-6, nuclear factor kappa B, cyclooxygenase-2, and cleaved caspase 3 (effect size f = 4.61 and power = 1). On the molecular level, the LSP + CDDP group showed a reduction in Keap1 protein level but an increase in Nrf2 (effect size f = 5.50 and power = 1), HO-1 (effect size f = 3.66 and power = 1), and PPARγ protein levels, compared to the CDDP group. In conclusion, LSP revealed prominent anti-oxidant, anti-apoptotic, and anti-inflammatory effects protecting against CDDP-induced testicular damage. Moreover, it preserved the steroidogenic process and testicular tissue characteristics. LSP modulated the expression of Nrf2/Keap1/HO-1 and PPARγ signaling. Therefore, our data presents LSP as a promising candidate for enhancing reproductive health in patients undergoing CDDP treatment.