Kindlin-2 mediates Peyronie's disease through activation of TGF-β/Smad signaling pathway under the presence of TGF-β1

Abstract

BackgroundPeyronie's disease (PD) causes benign plaques or induration in tunica albuginea (TA). Kindlin-2 regulates the TGF-β1/Smad3 pathway, which accelerates kidney fibrosis. The study is aimed mainly to investigate the impact of Kindlin-2 on PD formation and its signaling pathways, notably the TGF-β/Smad pathway in the presence of TGF-β1. MethodsIn this mouse investigation, adenovirus TGF-β1 was injected into TA to produce PD. The model was successfully induced 45 days later. Western Blot (WB) and immunohistochemistry (IHC) were utilized to measure Kindlin-2 in PD model tissue. WB and immunofluorescence assays were utilized to confirm the impact of TGF-β1 on Kindlin-2 levels in vitro. The interaction among Kindlin-2, TβRI, and Smad3 was detected using immunoprecipitation (IP) experiments. We examined how TGF-β1 affects Smad3 phosphorylation and downstream gene activation process. Finally, Kindlin-2 and the level of tissue fibrosis were examined in PD model. ResultsKindlin-2 levels were elevated in the TGF-β1-induced PD model, confirming that TGF-β1 can increase Kindlin-2 levels in primary PD cells. Moreover, Kindlin-2 mediates Smad3-TβRI interaction, activates p-Smad3, and enhances TGF-β1 target gene expression. In vivo investigations reveal that Kindlin-2 promotes PD development and tissue fibrosis. The regulatory effects of Kindlin-2 need the presence of TGF-β1. Tissue fibrosis can be reduced by downregulating Kindlin-2. ConclusionKindlin-2 does not directly activate Smad3 to induce tissue fibrosis. Instead, it exerts its effect through the combined influence of TGF-β1. Inhibiting Kindlin-2 could potentially be a treatment for PD.