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

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.

TDB protects vascular endothelial cells against oxygen-glucose deprivation/reperfusion-induced injury by targeting miR-34a to increase Bcl-2 expression

“…Moreover, the apoptotic ratio of cerebrovascular cells was calculated in red fluorescence stained with CD31 and brown in TUNEL assay. CD31 was a marker of vascular cells43. Thus, vascular cells were marked in red fluorescence and counted.…”

ERK and p38 Upregulation versus Bcl-6 Downregulation in Rat Kidney Epithelial Cells Exposed to Prolonged Hypoxia

“… 50 It is also reported that chronic inflammatory and apoptotic cascades that are stimulated by p38 and JNK, but not ERK pathways, contribute to the pathogenesis of the chronic intermittent hypoxia-induced renal injury. 51 These studies suggest that MAPKs are differentially involved in cellular responses to hypoxic stress, depending on cell type and cell conditions. However, the precise functions of ERK1/2 and p38 are still debatable, especially in the kidney under hypoxic conditions.…”

The δ-Opioid Receptor Differentially Regulates MAPKs and Anti-inflammatory Cytokines in Rat Kidney Epithelial Cells Under Hypoxia

“…et al, 2017) and protective role of ERK1/2 (Hung et al, 2003;Chen et al, 2015;Li et al, 2018) in cell survival under stress, the up-regulation of P-ERK1/2 in hypoxic renal cells is probably an adaptive response to overcome the hypoxia-induced increase in P-p38, rendering the cells a new balance between ERK1/2 and p38. Indeed, there is solid evidence indicating that P-ERK1/2 is a mediator of controlling cell survival in response to many stimuli including hypoxia in the kidney (di Mari et al, 1999;Kunduzova et al, 2002;Yang et al, 2003;Zou et al, 2016), while the p38 is considered as the major stress-activated protein kinases (Kyriakis and Avruch, 2012) and mediate a pro-inflammation effect in hypoxic condition (Wu et al, 2016). Based on our previous work, we believe that DOR, which was tolerant to hypoxia and was not down-regulated in the renal cells after hypoxia, plays a positive effect in the upstream signaling of P-ERK1/2 and a negative influence on p38, at least partially.…”