Endoplasmic reticulum stress mediating downregulated StAR and 3-beta-HSD and low plasma testosterone caused by hypoxia is attenuated by CPU86017-RS and nifedipine

Gui-Lai Liu,Can Zhang,De-Zai Dai,Yin Dai,Guo-Lin Zhang,Feng Yu

doi:10.1186/1423-0127-19-4

Gui-Lai Liu, Can Zhang + Show 4 more

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https://doi.org/10.1186/1423-0127-19-4

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Abstract

BackgroundHypoxia exposure initiates low serum testosterone levels that could be attributed to downregulated androgen biosynthesizing genes such as StAR (steroidogenic acute regulatory protein) and 3-beta-HSD (3-beta-hydroxysteroid dehydrogenase) in the testis. It was hypothesized that these abnormalities in the testis by hypoxia are associated with oxidative stress and an increase in chaperones of endoplasmic reticulum stress (ER stress) and ER stress could be modulated by a reduction in calcium influx. Therefore, we verify that if an application of CPU86017-RS (simplified as RS, a derivative to berberine) could alleviate the ER stress and depressed gene expressions of StAR and 3-beta-HSD, and low plasma testosterone in hypoxic rats, these were compared with those of nifedipine.MethodsAdult male Sprague-Dawley rats were randomly divided into control, hypoxia for 28 days, and hypoxia treated (mg/kg, p.o.) during the last 14 days with nifedipine (Nif, 10) and three doses of RS (20, 40, 80), and normal rats treated with RS isomer (80). Serum testosterone (T) and luteinizing hormone (LH) were measured. The testicular expressions of biomarkers including StAR, 3-beta-HSD, immunoglobulin heavy chain binding protein (Bip), double-strand RNA-activated protein kinase-like ER kinase (PERK) and pro-apoptotic transcription factor C/EBP homologous protein (CHOP) were measured.ResultsIn hypoxic rats, serum testosterone levels decreased and mRNA and protein expressions of the testosterone biosynthesis related genes, StAR and 3-beta-HSD were downregulated. These changes were linked to an increase in oxidants and upregulated ER stress chaperones: Bip, PERK, CHOP and distorted histological structure of the seminiferous tubules in the testis. These abnormalities were attenuated significantly by CPU86017-RS and nifedipine.ConclusionDownregulated StAR and 3-beta-HSD significantly contribute to low testosterone in hypoxic rats and is associated with ER stress which mediates testis damage caused by oxygen deprivation. CPU86017-RS is potential in ameliorating hypoxia-induced testicular injuries, possibly by its calcium antagonist effects on the testis.

Highlights

Hypoxia exposure initiates low serum testosterone levels that could be attributed to downregulated androgen biosynthesizing genes such as Steroidogenic acute regulatory protein (StAR) and 3-beta-HSD (3-betahydroxysteroid dehydrogenase) in the testis
This study was aimed to verify whether Endoplasmic reticulum (ER) stress is responsible for low expression of StAR and 3-beta-HSD, and low testosterone involved in hypoxia-damaged testes and could be blunted by CPU86017-RS, compared to those of nifedipine
The results indicated that the rat was suffering from oxidative insults leading to an increment in lipid peroxidation and reduced antioxidant activity both in serum and the testis, and a deficiency of energy supply in the testis was indicative of decreased activity of testicular lactate dehydrogenase (LDH) responsible for the decreased production of androgen and spermatogenesis in the seminiferous tubules

Summary

Introduction

Hypoxia exposure initiates low serum testosterone levels that could be attributed to downregulated androgen biosynthesizing genes such as StAR (steroidogenic acute regulatory protein) and 3-beta-HSD (3-betahydroxysteroid dehydrogenase) in the testis. A low level of inflammation exists in the testis affecting adversely expressions of the androgen production genes such as StAR and 3-beta-HSD. Along with the further development of ER stress, the signals such as IRE1 (inositol-requiring enzyme-1), PERK (double-strand RNA-activated protein kinase-like ER kinase), ATF6 (activating transcription factor-6) and CHOP (C/EBP homologous protein) are exaggerated, the dialogue between the endoplasmic reticulum and the nucleus is altered, triggering the signaling cascades to induce adverse events in cells, resulting in apoptosis, cell death and disease [8]

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