Soluble Receptor for Advanced Glycation End Product Ameliorates Chronic Intermittent Hypoxia Induced Renal Injury, Inflammation, and Apoptosis via P38/JNK Signaling Pathways.

Xu Wu,Yaodong Tang,Hui Xu,Chengying Liu,Chuan Shao,Huan Lu,Jian Zhou,Shanqun Li,Wenyu Gu,Biyun Yu

doi:10.1155/2016/1015390

Abstract

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.

Highlights

Obstructive sleep apnea (OSA) is characterized by repetitive upper airway collapse and recurrent hypoxia during sleep
In histological examination of kidney stained with hematoxylin-eosin, normal air (NA) group rats showed normal glomerular and tubular structures, while chronic intermittent hypoxia (CIH) resulted in prominent tubular atrophy and inflammatory cell infiltration (Figure 1(a))
Animals treated with soluble RAGE (sRAGE) before each hypoxia circle seldom displayed extensive features of tubule epithelial swelling and narrowed tubular lumens, without significant changes in distal convoluted tubule (Figure 1(a))

Summary

Introduction

Obstructive sleep apnea (OSA) is characterized by repetitive upper airway collapse and recurrent hypoxia during sleep. Emerging evidence indicates that chronic kidney disease (CKD) is highly prevalent complication of untreated OSA with symptoms of polyuria and proteinuria [1, 2]. The prevalence of OSA in CKD patients ranges severalfold higher than the general population [3]. Two mechanisms are responsible for the loss of kidney function in OSA patients: chronic nocturnal intrarenal hypoxia and activation of sympathetic nervous system in response to oxidative stress, resulting in tubulointerstitial injury and leading common pathway to end-stage renal disease (ESKD) [4, 5]. As the foremost pathophysiological change in the process of OSA, chronic intermittent hypoxia (CIH) often causes oxidative stress and inflammations, contributing to damage of various tissue and organs [6].

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