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

Abstract

Objective. To investigate the protective effects and mechanisms of human tissue kallikrein 1 (hKLK1) on type 1 diabetes mellitus- (DM-) induced erectile dysfunction in rats. Materials and Methods. The homozygous transgenic rats (TGR) harboring the hKLK1 gene and age-matched wild-type Sprague Dawley rats (WTR) were involved, and intraperitoneal injection of streptozotocin was utilized to induce diabetes in rats. Forty-eight-week-old male rats were randomly divided into a WTR group, TGR group, diabetic WTR group (WTDM), diabetic TGR group (TGDM), and TGDM with HOE140 group (TGDMH), with eight rats in each group. Twelve weeks later, the erectile response of all rats was detected by cavernous nerve electric stimulation, and corpus cavernosums were harvested to evaluate the levels of cavernous oxidative stress (OS), apoptosis, fibrosis, and involved pathways. Moreover, cavernous smooth muscle cells (CSMC) and endothelial cells (EC) were primarily isolated to build a coculture system for a series of in vitro verification. Results. The hKLK1 gene only existed and was expressed in TGR. Compared to the WTR group, the WTDM group showed a lower erectile response, overactivated OS and apoptosis, inhibited PI3K/AKT/eNOS pathway, and aggravated cavernous fibrosis. However, hKLK1 in the TGDM group could improve these pathological changes induced by DM, while its protective effects could be weakened by HOE140 in the TGDMH group. In the coculture system, hKLK1 could induce CSMC relaxation through activating PI3K/eNOS/cGMP signaling and inhibiting calcium ion influx under physiological condition. It could also resist the increased reactive oxygen species, apoptosis level, and reduced cGMP level in CSMC under high-glucose condition. Conclusions. hKLK1 preserves erectile function of DM rats through its antitissue excessive OS, apoptosis, and fibrosis effects, as well as activation of the PI3K/AKT/eNOS/cGMP pathway in the penis. Moreover, hKLK1 promotes relaxation and prevents high glucose-induced injuries of CSMC mediated by EC-CSMC crosstalk.

A Bioinformatic Investigation of the Mechanism Underlying Migraine-Induced Erectile Dysfunction

“…In addition to the regulation of blood vessels, nerves, the endocrine system, and other factors, abnormalities in penile erection can also be closely related to the vasomotor function of the vascular smooth muscle. Previous studies have found that during the occurrence of ED, there is an increase in the number of collagen fibers in the penile cavernous body; fibrotic changes can also occur, along with limitations in smooth muscle relaxation and contraction [ 10 ]. The PI3K/Akt/mTOR pathway is widely distributed in the penile vascular smooth muscle and facilitates the regulation of diastolic function in the smooth muscle.…”

“…Some studies have confirmed that PI3K and AKT undergo significant activation in brainstem tissue from rat models of migraine [ 9 ]. Furthermore, the levels of essential neurotransmitters in the brain, such as serotonin, were significantly reduced, thus proving that the PI3K/Akt/mTOR signaling pathway is one of the dominant mechanisms underlying migraine [ 10 ]. The occurrence of ED is due to a combination of factors, including blood vessels, nerves, and endocrine factors.…”

Co‑expression of tissue kallikrein 1 and tissue inhibitor of matrix metalloproteinase 1 improves myocardial ischemia‑reperfusion injury by promoting angiogenesis and inhibiting oxidative stress

“…Previous research has reported that any treatment that can reduce oxidative stress may attenuate myocardial I/R injury ( 34 – 36 ). It has been previously reported that hTK1 can improve erectile dysfunction of streptozotocin-induced diabetic model rats and attenuate salt-induced renal fibrosis via inhibition of oxidative stress ( 8 , 37 ). Furthermore, a previous study demonstrated that free TIMP1 and magnetic nanoparticle-bound TIMP1 significantly reduced ROS production in HIV-infected neuroblastoma cells ( 38 ).…”

“…Tissue kallikrein 1 (TK1), a glycoprotein that belongs to the serine proteinase superfamily, can cleave low-molecular-weight kininogen into a number of bioactive kinin peptides, including kininogens and kallikreins ( 7 ). Vasoactive kinins serve a beneficial role in a number of cardiovascular, cerebrovascular and renal diseases ( 8 ). A previous study revealed that hTK1 gene-modified mesenchymal stem cells display protective effects against cardiac injury following MI via suppressing apoptosis and inflammation, and promoting neovascularization ( 9 ).…”

Berberine ameliorates erectile dysfunction in rats with streptozotocin‐induced diabetes mellitus through the attenuation of apoptosis by inhibiting the SPHK1/S1P/S1PR2 and MAPK pathways

“…According to the published method, 24 corpus cavernosum smooth muscle cells (CCSMCs) were extracted and purified via the differential wall adhesion method from the CC of 8-week-old healthy male SD rats. CCSMCs were cultured in Dulbecco's modified Eagle's medium (DMEM, low-glucose, HyClone, USA) containing 10% fetal bovine serum (FBS; Gibco, USA), 1% 100 ng/ml streptomycin, and 1% 100 U/ml penicillin under standardized conditions (5% CO2, 37 • C).…”