Abstract

Patients with prostate cancer frequently complain of erectile dysfunction (ED) after radical prostatectomy (RP). Corporal fibrosis and apoptosis following cavernous nerve injury (CNI) significantly contribute to RP-induced ED. Klotho is an anti-aging protein, and Klotho-derived peptide (KP) has been introduced as an antagonist of tissue fibrosis and apoptosis. However, it is unknown whether CNI-induced functional and morphological changes in the penis. This study was designed to explore the impact of KP on CNI-induced ED. The rats were randomly divided into three groups: Sham operation, bilateral CNI with saline injection, and bilateral CNI with KP injection. Assessments of erectile function were conducted three weeks post-treatment. Penile tissues were obtained for histopathological examination. Corpus cavernosum smooth muscle cells (CCSMCs) treated with transforming growth factor-beta 1 (TGF-β1) served as an in vitro model to assess the impact of KP. Rats subjected to bilateral CNI developed severe ED. Penile tissues exhibited reduced smooth muscle abundance and nitric oxide synthase expression, alongside increased fibrosis, oxidative stress, apoptosis, and TGF-β1 signaling activation. However, KP ameliorated these functional and morphological damage. Moreover, KP exerted anti-fibrotic and anti-apoptotic effects on TGF-β1-stimulated CCSMCs by downregulating TGF-β type II receptor, which intercepted the Smad2/JNK signaling and activated the AKT pathway. Overall, KP improved CNI-induced ED and corporal remodeling. These beneficial effects were mediated by TGF-β type II receptor downregulation, which rebalanced the TGF-β1-driven Smad2/JNK activation and PI3K/AKT suppression, thereby ameliorating CCSMC dysfunction. Our results establish the potential of KP as a therapy for neurogenic ED.