Overproduction of nitric oxide by endothelial cells and macrophages contributes to mitochondrial oxidative stress in adrenocortical cells and adrenal insufficiency during endotoxemia.
We have recently demonstrated that lipopolysaccharide (LPS) causes mitochondrial oxidative stress and dysfunction in adrenal glands, thereby leading to adrenocortical insufficiency. Since nitric oxide (NO) produced by inducible nitric oxide synthase (iNOS) leads to mitochondrial damage in various tissues, the present study aims to investigate whether NO contributes to mitochondrial oxidative stress in adrenal cortex and adrenocortical insufficiency during endotoxemia. Systemic administration of LPS increased iNOS expression and NO production in adrenal glands of mice. The specific iNOS inhibitor 1400 W significantly attenuated the LPS-induced mitochondrial superoxide production and dysfunction in adrenal glands, and reversed the LPS-induced adrenocortical hyporesponsiveness to adrenocorticotropic hormone (ACTH). In contrast, administration of the NO donor sodium nitroprusside (SNP) led to mitochondrial oxidative stress and dysfunction in adrenal glands, which resulted in a blunted corticosterone response to ACTH. Using double immunofluorescence staining for iNOS with the vascular endothelial cell marker CD31 or the macrophage marker CD68, we found that increased iNOS expression was found in vascular endothelial cells and macrophages, but not adrenocortical cells in the adrenal gland during endotoxemia. Administration of the hydrogen sulfide (H2S) donor GYY4137 inhibited NO production and reversed LPS-induced adrenocortical hyporesponsiveness. Our data suggest that overproduction of NO, which is mainly generated by endothelial cells and macrophages during endotoxemia, contributes to mitochondrial oxidative stress in adrenocortical cells and subsequently leads to adrenal insufficiency.
Department of Physiology and The Key Laboratory of Molecular Neurobiology of Ministry of Education, Shanghai, 200433, China.
Chang-Nan
CN
Wang
Department of Physiology and The Key Laboratory of Molecular Neurobiology of Ministry of Education, Shanghai, 200433, China; The Eight-year Program on Clinical Medicine, Changhai Hospital, Second Military Medical University, Shanghai, 200433, China.
Guo-Li
GL
Duan
School of Kinesiology, The Key Laboratory of Exercise and Health Sciences of Ministry of Education, Shanghai University of Sport, Shanghai, 200438, China.
Yu-Jian
YJ
Liu
Department of Physiology and The Key Laboratory of Molecular Neurobiology of Ministry of Education, Shanghai, 200433, China.
Qing
Q
Yu
Department of Physiology and The Key Laboratory of Molecular Neurobiology of Ministry of Education, Shanghai, 200433, China.
Xiao-Lu
XL
Tang
Department of Physiology and The Key Laboratory of Molecular Neurobiology of Ministry of Education, Shanghai, 200433, China.
Wei
W
Zhao
Department of Physiology and The Key Laboratory of Molecular Neurobiology of Ministry of Education, Shanghai, 200433, China.
Xiao-Han
XH
Li
Department of Physiology and The Key Laboratory of Molecular Neurobiology of Ministry of Education, Shanghai, 200433, China. Electronic address: xiaoyanzhu@smmu.edu.cn.
Xiao-Yan
XY
Zhu
Department of Physiology and The Key Laboratory of Molecular Neurobiology of Ministry of Education, Shanghai, 200433, China. Electronic address: nixin@smmu.edu.cn.
Xin
X
Ni
D000255:Adenosine Triphosphate / Q000378:metabolism; D000302:Adrenal Cortex / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D000309:Adrenal Insufficiency / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D000324:Adrenocorticotropic Hormone / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D019446:Endotoxemia / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D005455:Fluorescent Antibody Technique; D006862:Hydrogen Sulfide / Q000494:pharmacology; D007124:Immunoenzyme Techniques; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D009569:Nitric Oxide / Q000494:pharmacology*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D009599:Nitroprusside / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
D008070:Lipopolysaccharides; D020030:Nitric Oxide Donors; D012333:RNA, Messenger; D009599:Nitroprusside; D009569:Nitric Oxide; D000255:Adenosine Triphosphate; D000324:Adrenocorticotropic Hormone; D052247:Nitric Oxide Synthase Type II; D006862:Hydrogen Sulfide
Adrenal insufficiency; Hydrogen sulfide; Lipopolysaccharide; Mitochondria; Nitric oxide