Exploring Transglutaminase 2 as a potential therapeutic target for diabetes-induced sexual dysfunction
▶Summary
Diabetes impairs blood supply and disrupts the integrity of the nervous system in genital organs, leading to sexual dysfunction (SD) and genital tissue fibrosis in both sexes. SD is strongly correlated with depression, reduced social well-being, and a diminished quality of life. Current therapeutic options for SD are inadequate, have important side effects, and no effective treatments exist for vaginal/penile fibrosis, underscoring an urgent need for advanced mechanistic studies to identify new therapeutic targets and develop effective and safe treatments. Transglutaminase-2 (TG2) is a multifunctional enzyme that operates in two conformations: in its open conformation, it exerts transamidase activity, which has a pro-fibrotic effect; in its closed conformation, it regulates vascular tone. It has been reported that TG2 is involved in vascular dysfunction and fibrosis, and pharmacological inhibition of TG2 improves endothelial function and shows great promise for treating fibrotic diseases. However, its role in the pathophysiology of diabetes-induced SD (DISD) remains unexplored.We hypothesize that TG2 may play a crucial role in DISD and erectile tissue fibrosis. Promoting the closed conformation of TG2 with an allosteric reversible inhibitor could improve sexual function by enhancing vascular function and preventing fibrosis.We will test this hypothesis by investigating: i) TG2 expression/activity in primary fibroblasts isolated from healthy rat erectile tissues and the involvement of TG2 in the fibrotic process; ii) the acute effect of TG2 inhibition on sexual function in healthy rats; and iii) the role of TG2 and the therapeutic effect of allosteric TG2 inhibitors in the rat model of DISD and vaginal/penile fibrosis. Furthermore, our project will address a significant gap in the current literature by investigating female SD, contributing to a more comprehensive understanding and management of the impact of diabetes on women’s sexual health.