Soluble Receptor for Advanced Glycation End Product Ameliorates Chronic Intermittent Hypoxia Induced Renal Injury, Inflammation, and Apoptosis via P38/JNK Signaling Pathways.
Obstructive sleep apnea (OSA) associated chronic kidney disease is mainly caused by chronic intermittent hypoxia (CIH) triggered tissue damage. Receptor for advanced glycation end product (RAGE) and its ligand high mobility group box 1 (HMGB1) are expressed on renal cells and mediate inflammatory responses in OSA-related diseases. To determine their roles in CIH-induced renal injury, soluble RAGE (sRAGE), the RAGE neutralizing antibody, was intravenously administered in a CIH model. We also evaluated the effect of sRAGE on inflammation and apoptosis. Rats were divided into four groups: (1) normal air (NA), (2) CIH, (3) CIH+sRAGE, and (4) NA+sRAGE. Our results showed that CIH accelerated renal histological injury and upregulated RAGE-HMGB1 levels involving inflammatory (NF-κB, TNF-α, and IL-6), apoptotic (Bcl-2/Bax), and mitogen-activated protein kinases (phosphorylation of P38, ERK, and JNK) signal transduction pathways, which were abolished by sRAGE but p-ERK. Furthermore, sRAGE ameliorated renal dysfunction by attenuating tubular endothelial apoptosis determined by immunofluorescence staining of CD31 and TUNEL. These findings suggested that RAGE-HMGB1 activated chronic inflammatory transduction cascades that contributed to the pathogenesis of the CIH-induced renal injury. Inhibition of RAGE ligand interaction by sRAGE provided a therapeutic potential for CIH-induced renal injury, inflammation, and apoptosis through P38 and JNK pathways.
Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Clinical Center for Sleep Breathing Disorder and Snoring, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
Xu
X
Wu
Department of Urology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China.
Wenyu
W
Gu
Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Clinical Center for Sleep Breathing Disorder and Snoring, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
Huan
H
Lu
Department of Respiratory Medicine, Affiliated Jiangyin Hospital of Southeast University, Jiangyin 214400, China.
Chengying
C
Liu
Department of Respiratory Medicine, Ningbo Medical Center Lihuili Eastern Hospital, Taipei Medical University Ningbo Medical Center, Ningbo 315040, China.
Biyun
B
Yu
Department of Respiratory Medicine, Ningbo Medical Center Lihuili Eastern Hospital, Taipei Medical University Ningbo Medical Center, Ningbo 315040, China.
Hui
H
Xu
Department of Respiratory Medicine, Ningbo Medical Center Lihuili Eastern Hospital, Taipei Medical University Ningbo Medical Center, Ningbo 315040, China.
Yaodong
Y
Tang
Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Clinical Center for Sleep Breathing Disorder and Snoring, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
Shanqun
0000-0002-8096-9780
S
Li
Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Clinical Center for Sleep Breathing Disorder and Snoring, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
Jian
0000-0003-4736-9457
J
Zhou
Department of Respiratory Medicine, Ningbo Medical Center Lihuili Eastern Hospital, Taipei Medical University Ningbo Medical Center, Ningbo 315040, China.
Chuan
0000-0001-9073-219X
C
Shao
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