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


METHODS
Adult 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.


RESULTS
In 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.


CONCLUSIONS
Downregulated 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.
Faculty of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
Gui-Lai
GL
Liu
Feng
F
Yu
De-Zai
DZ
Dai
Guo-Lin
GL
Zhang
Can
C
Zhang
Yin
Y
Dai
D015096:3-Hydroxysteroid Dehydrogenases / Q000378:metabolism*; D000818:Animals; D001599:Berberine / Q000031:analogs & derivatives* / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D015536:Down-Regulation; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D005979:Glutathione Peroxidase / Q000097:blood; D007006:Hypogonadism / Q000188:drug therapy* / Q000378:metabolism; D000860:Hypoxia / Q000378:metabolism / Q000662:veterinary; D007770:L-Lactate Dehydrogenase / Q000097:blood; D007986:Luteinizing Hormone / Q000097:blood; D008297:Male; D008315:Malondialdehyde / Q000097:blood; D009543:Nifedipine / Q000494:pharmacology*; D010750:Phosphoproteins / Q000378:metabolism*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013737:Testis / Q000293:injuries / Q000378:metabolism / Q000473:pathology; D013739:Testosterone / Q000096:biosynthesis* / Q000097:blood; D015854:Up-Regulation; D000098682:Steroidogenic Acute Regulatory Protein
C400084:4-chlorobenzyltetrahydroberberine; D002121:Calcium Channel Blockers; D010750:Phosphoproteins; D000098682:Steroidogenic Acute Regulatory Protein; D001599:Berberine; D013739:Testosterone; D008315:Malondialdehyde; D007986:Luteinizing Hormone; D015096:3-Hydroxysteroid Dehydrogenases; D007770:L-Lactate Dehydrogenase; D005979:Glutathione Peroxidase; D009543:Nifedipine; D002118:Calcium