Intermedin Attenuates LPS-induced Inflammation in the Rat Testis

Lei Li,Ping Ma,Fai Tang,Yongjun Liu,Chen Huang,Jian V Zhang,Wai-Sum O,Rajasingh Johnson

doi:10.1371/journal.pone.0065278

Abstract

First reported as a vasoactive peptide in the cardiovascular system, intermedin (IMD), also known as adrenomedullin 2 (ADM2), is a hormone with multiple potent roles, including its antioxidant action on the pulmonary, central nervous, cardiovascular and renal systems. Though IMD may play certain roles in trophoblast cell invasion, early embryonic development and cumulus cell-oocyte interaction, the role of IMD in the male reproductive system has yet to be investigated. This paper reports our findings on the gene expression of IMD, its receptor components and its protein localization in the testes. In a rat model, bacterial lippolysaccharide (LPS) induced atypical orchitis, and LPS treatment upregulated the expression of IMD and one of its receptor component proteins, i.e. receptor activity modifying protein 2 (RAMP2). IMD decreased both plasma and testicular levels of reactive oxygen species (ROS) production, attenuated the increase in the gene expression of the proinflammatory cytokines tumor necrosis factor alpha (TNFα), interleukin 6 (IL6) and interleukin 1 beta (IL1β), rescued spermatogenesis, and prevented the decrease in plasma testosterone levels caused by LPS. The restorative effect of IMD on steroidogenesis was also observed in hydrogen peroxide-treated rat primary Leydig cells culture. Our results indicate IMD plays an important protective role in spermatogenesis and steroidogenesis, suggesting therapeutic potential for IMD in pathological conditions such as orchitis.

Highlights

Male factor infertility accounts for up to 50% of all cases of infertility and affects one out of twenty men [1]
Evidence shows oxidative stress is a common factor in testicular dysfunction, inhibiting both Leydig cell steroidogenesis and spermatogenesis [2,3]
Compared with seminal vehicles and coagulating glands, the gene expression of IMD is relatively low, while those of calcitonin receptorlike receptor (CLR) and receptor activity modifying protein 2 (RAMP2) are relatively high in the testes

Summary

Introduction

Male factor infertility accounts for up to 50% of all cases of infertility and affects one out of twenty men [1]. Evidence shows oxidative stress is a common factor in testicular dysfunction, inhibiting both Leydig cell steroidogenesis and spermatogenesis [2,3]. Oxidative stress results when reactive oxygen species (ROS) produced by the oxidation of lipids in membranes, amino acids in proteins, and carbohydrates within nucleic acids are in excess. Among the factors that cause oxidative stress in the testes are radiation, cryptorchidism, testicular torsion and diabetes [2,3]. Oxidative stress from orchitis/testicular infection may have transient or even permanent effects on male fertility [2,3]. In an experimental model involving the intraperitoneal injection of bacterial lipopolysaccharide (LPS), lipid peroxidation was induced in the testes accompanied by a significant decrease in testosterone production and disruption of spermatogenesis [4,5]

Methods

Results

Conclusion