Role of the Nrdp1 in Brain Injury Induced by Chronic Intermittent Hypoxia in Rats via Regulating the Protein Levels of ErbB3

Abstract

Obstructive sleep apnea syndrome (OSAS) is known as a repeated obstruction of the upper airway during sleep, leading to generalized hypoxia episodes and associated with cardiovascular and cerebrovascular diseases. We mainly explored the role of neuregulin receptor degradation protein-1 (Nrdp1, also known as FLRF) in brain injury induced by chronic intermittent hypoxia (CIH) in rats. Wistar rats were randomly divided into 4 groups (n = 12 per group), including the sham + adeno-associated virus-NC (AAV-NC) group, the sham + AAV-siNrdp1 group, the IH-4w (intermittent hypoxia for 4 weeks) + AAV-NC group, and the IH-4w + AAV-siNrdp1 group. Morphologic changes in brain tissue were observed by hematoxylin and eosin (HE) staining. Apoptosis in the hippocampus was detected by terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) staining. Spatial learning and memory were assessed by the Morris water maze test. The expression of Nrdp1 mRNA and protein in the hippocampus was detected by qualitative real-time polymerase chain reaction (qRT-PCR) and Western blotting. The concentration of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) in serum was detected via enzyme-linked immunosorbent assay (ELISA) kits. Nrdp1 expression was increased after intermittent hypoxia exposure over time. Western blotting and H&E results showed that pathological changes of hippocampus neurons in chronic intermittent hypoxia rat were diminished by shNrdp1. Western blotting and TUNEL staining showed that apoptotic cells in the hippocampus of CIH rats were decreased by shNrdp1. The Morris water maze results proved that shNrdp1 improved spatial learning performance of chronic intermittent hypoxia rats. ELISA kits results showed that CIH-induced inflammatory response was decreased by shNrdp1. Western blotting and qRT-PCR results showed protein expression of ErbB3 in the hippocampus of CIH rats. Nrdp1 could regulate ErbB3 protein levels in brain-injured rats with CIH, which demonstrates that Nrdp1 is a potential therapeutic target in the cognition deficits associated with OSAS.

Keywords: Apoptosis; Brain injury; Chronic intermittent hypoxia (CIH); Nrdp1.