Human Tissue Kallikrein 1 Improves Erectile Dysfunction of Streptozotocin-Induced Diabetic Rats by Inhibition of Excessive Oxidative Stress and Activation of the PI3K/AKT/eNOS Pathway

Figure 9

The potential mechanisms of hKLK1’s protective effects on DMED. DM can activate RAGE/NADPH oxidase signaling to induce the generation of ROS. Subsequently, ROS promotes the apoptosis-related protein expression including Bax and cleaved Caspase3, activates the TGFβ1/smad2/3/CTGF signaling to induce the collagen IV expression, and inhibits the NO/cGMP pathway to increase the intracellular Ca²⁺ level in CSMC. By the catalysis of hKLK1, LMWK can be converted into BK and then inhibits RAGE/ROS and TGFβ1 expression and activates the PI3K/AKT/eNOS pathway to improve oxidative stress, apoptosis, fibrosis, and CSMC relaxation. hKLK1: human tissue kallikrein 1; DM: diabetes mellitus; DMED: DM-induced erectile dysfunction; BK: bradykinin; RAGE: receptor for advanced glycation end products; ROS: reactive oxygen species. LMWK: low-molecular-weight kininogen; BK: bradykinin; Bax: Bcl-2-associated X protein; PI3K: phosphatidylinositol 3-kinase; AKT: protein kinase B; eNOS: endothelial nitric oxide synthase; NO: nitric oxide; cGMP: cyclic guanosine monophosphate; TGFβ1: transforming growth factor-β1; CTGF: connective tissue growth factor; CSMC: cavernous smooth muscle cell.