Involvement of Activation of Mitogen-Activated Protein Kinase (MAPK)/Extracellular Signal-Regulated Kinase (ERK) Signaling Pathway in Proliferation of Urethral Plate Fibroblasts in Finasteride-Induced Rat Hypospadias
Nini An, Jinpu Peng, Guoqing He, Xia Fan, Fei Li, Hui Chen
Department of Pediatric Surgery, Guizhou Provincial People’s Hospital, Guiyang, Guizhou, China (mainland)
Med Sci Monit 2018; 24:8984-8992
We investigated the role of the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) signaling pathway in finasteride-induced hypospadias rats and explored the mechanisms involved.
MATERIAL AND METHODS: The hypospadias model was established by intragastric administration of finasteride and confirmed by hematoxylin and eosin (HE) staining. The urethral plate fibroblasts (UPF) were obtained from normal and modeled rats and identified based upon vimentin expression. Thereafter, UPF were divided into a normal control group, a model group, a model + MAPK inhibitor group, and a model + ERK inhibitor group. Cell proliferation, apoptosis, and cell cycling of UPF were assessed. Quantitative real-time PCR and Western blot analysis were used to evaluate expression of the MAPK signaling pathway and apoptosis-related genes.
RESULTS: HE staining confirmed that 10 mg/kg finasteride caused severe hypospadias in rats. UPFs obtained from the 10 mg/kg finasteride group showed higher proliferation and cell cycling and lower apoptosis compared with those obtained from the normal control group (P<0.05). Interestingly, a MAPK inhibitor or an ERK inhibitor could attenuate the abnormalities of cell proliferation, cycling, and apoptosis of UPF induced by finasteride. Compared with controls, the relative expression of p-MEK1/MEK1, caspase 3, and P53 in the UPF of the model group were reduced, while the relative expression of p-MAPK14/MAPK14 was increased in the cells of the model group. By contrast, a MAPK inhibitor or an ERK inhibitor could alleviate the abnormalities of MAPK/ERK signaling pathway and apoptosis-related gene expression induced by finasteride.
CONCLUSIONS: Our study reveals that the MAPK/ERK signaling pathway is involved in the regulation of proliferation, apoptosis, and cell cycling of UPFs in finasteride-induced hypospadias.
Keywords: Finasteride, MAP Kinase Kinase Kinases, Urethral Neoplasms