Fluvastatin protects Leydig cells in orchitis through direct activation of Peroxiredoxin 1
Orchitis caused by infection is one of the most important causes of male infertility, which can cause an imbalance of the oxidation/antioxidation system. Appropriate antioxidant therapy may be effective in alleviating testicular damage. Previous studies found that peroxiredoxin 1 (PRDX1) is involved in the regulation of oxidative stress and inflammation, and is highly expressed in testis. Therefore, selecting an effective PRDX1 agonist might become an attractive strategy in the treatment of orchitis related to oxidative stress. In the current study, we identified the effective agonist of PRDX1. Leydig cells were used to find the antioxidant role and mechanisms of the agonist in vitro. Models of orchitis in wild-type and Prdx1-/- mice were employed to confirm the anti-orchitis effect of the agonist. We found that fluvastatin (FV), a classical cholesterol-lowering drug, could directly bind PRDX1 to activate its enzyme activity. FV played a protective and antioxidant role on H2O2-treated Leydig cells by improving cell viability and testosterone level, inhibiting apoptosis, and reducing reactive oxygen species level and inflammatory factors in a PRDX1-dependent manner. FV could also decrease oxidative stress and inflammation levels of testes in mice models, thereby reducing the damage on testicular steroidogenesis and spermatogenesis caused by orchitis. FV was an effective agonist of PRDX1, which showed antioxidant and anti-inflammatory impact in orchitis. Our results may shed light on the antioxidant treatment of orchitis and male infertility. Overall design: We analyzed the gene expression profiling of H2O2-treated primary mouse Leydig cells followed by fluvastatin (FV) treatment with or without the transfection of PRDX1 small interfering RNA (siprdx1). The primary mouse Leydig cells were divided into six groups with different treatments before RNA-seq. In brief, primary mouse Leydig cells were transfected with either siprdx1 or siNC, and then treated with or without 200 µM H2O2 for 30min, followed by 5 µM FV or 0.1% DMSO treatment for 6 hours. Consequently, groups (1) siNC; (2) siNC+H2O2; (3) siNC+H2O2+FV; (4) siprdx1; (5) siprdx1+H2O2; (6) siprdx1+H2O2+FV were employed for RNA-seq (each n=3).