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

Yang Luan,Kai Cui,Zhong Chen,Shaogang Wang,Jihong Liu,Zhe Tang,Yajun Ruan,Kang Liu,Tao Wang

doi:10.1155/2020/6834236

Yang Luan, Kai Cui + Show 7 more

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https://doi.org/10.1155/2020/6834236

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Journal: Oxidative Medicine and Cellular Longevity	Publication Date: Feb 28, 2020
Citations: 16	License type: CC BY 4.0

Affiliation: Tongji Hospital

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 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 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.

Highlights

According to the latest report from International Diabetes Federation, diabetes mellitus (DM) affects approximately 425 million people globally, and this number is expected to increase to 629 million by 2045
Our results provided an experimental basis for the therapeutic effects of human tissue kallikrein 1 (hKLK1) as a promising alternative target for DM-induced ED (DMED)
erectile dysfunction (ED) is one of earliest and frequent complications of DM, which affects the normal quality of life and presages underlying vasculopathy and serious cardiovascular diseases [1]. 12 weeks after establishment of STZ-induced DM rat model, we found that DM seriously impaired the normal erectile response, while the hKLK1 could obviously preserve it, and this protective effect could be diminished by inhibitor of hKLK1 pathway

Summary

Introduction

According to the latest report from International Diabetes Federation, diabetes mellitus (DM) affects approximately 425 million people globally, and this number is expected to increase to 629 million by 2045. DM can induce the accumulation of advanced glycation end products (AGEs) and a series of downstream oxidative stress (OS) reactions, followed by damage of endothelial function, apoptosis of functional cells, tissue morphological changes, and occurrence of multiple vascular system complications. DM-induced ED (DMED) is considered as the result of multiple pathogenetic factors, such as excessive cavernous OS, endothelial dysfunction, autonomic neuropathy, and penile fibrosis [1, 3, 4]. The first-line oral phosphodiesterase-5 (PDE5) inhibitors can neither increase cyclic guanosine monophosphate (cGMP) level if the bioavailability or formation of endogenous nitric oxide (NO) is restricted, nor reverse morphological changes. Oxidative Medicine and Cellular Longevity of corpus cavernosum, which explains the poor responsiveness of DMED patients to PDE5 inhibitors [5].

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