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Abstract：
Obstructive sleep apnoea (OSA) induced chronic kidney disease is mainly caused by chronic intermittent hypoxia (CIH). Our study investigate the mechanism underlying CIH-induced renal damage and whether the cannabinoid receptor 1 (CB1R) antagonist rimonabant (Ri) alleviates CIH-induced renal injury.
Male Sprague-Dawley rats were randomly divided into five groups: one normal control (NC) group, two chronic intermittent hypoxia (CIH) groups, and two CIH + Ri groups. Rats in the NC groups were exposed to room air, while the CIH groups were exposed to a CIH environment for 4 weeks (4w CIH group) and 6 weeks (6w CIH group), respectively. Additionally, rats in the CIH + Ri groups were administered 1.5 mg/kg/day Ri for 4 weeks (4w CIH + Ri group) and 6 weeks (6w CIH + Ri group), respectively. Following this, the rats were euthanized and kidneys were excised for downstream analysis. In the renal tissues, the morphological alterations were examined via haematoxylin eosin (HE) staining and periodic acid schiff (PAS) staining, CB1R, Fis1, Mfn1, and p66Shc expression was assessed through western blot and immunohistochemistry, and the mitochondrial ultrastructural changes in kidney sections were assessed by electron microscopy.
CB1R expression in the 4w and 6w CIH groups was significantly elevated, and further increased with prolonged hypoxia; however, Ri prevented the increase in CIH-induced CB1R expression. Fis1 and p66Shc expression in the CIH groups were increased, but Mfn1 expression decreased. Ri decreased Fis1 and p66Shc expression and increased Mfn1 expression. Renal damage in the 4w or 6w CIH + Ri group was evidently improved compared with that in the 4w or 6w CIH group. CB1R expression was positively correlated with Fis1 and p66Shc and negatively correlated with Mfn1. Meanwhile, electron microscopy showed that the percentage of fragmented mitochondria in the tubular cells in each group was consistent with the trend of CB1R expression.
CIH causes endocannabinoid disorders and induces abnormal mitochondrial dynamics, resulting in renal injury. Treatment with CB1R antagonists reduces CIH-induced renal damage by inhibiting dysregulated renal mitochondrial dynamics.
Male Sprague-Dawley rats were randomly divided into five groups: one normal control (NC) group, two chronic intermittent hypoxia (CIH) groups, and two CIH + Ri groups. Rats in the NC groups were exposed to room air, while the CIH groups were exposed to a CIH environment for 4 weeks (4w CIH group) and 6 weeks (6w CIH group), respectively. Additionally, rats in the CIH + Ri groups were administered 1.5 mg/kg/day Ri for 4 weeks (4w CIH + Ri group) and 6 weeks (6w CIH + Ri group), respectively. Following this, the rats were euthanized and kidneys were excised for downstream analysis. In the renal tissues, the morphological alterations were examined via haematoxylin eosin (HE) staining and periodic acid schiff (PAS) staining, CB1R, Fis1, Mfn1, and p66Shc expression was assessed through western blot and immunohistochemistry, and the mitochondrial ultrastructural changes in kidney sections were assessed by electron microscopy.
CB1R expression in the 4w and 6w CIH groups was significantly elevated, and further increased with prolonged hypoxia; however, Ri prevented the increase in CIH-induced CB1R expression. Fis1 and p66Shc expression in the CIH groups were increased, but Mfn1 expression decreased. Ri decreased Fis1 and p66Shc expression and increased Mfn1 expression. Renal damage in the 4w or 6w CIH + Ri group was evidently improved compared with that in the 4w or 6w CIH group. CB1R expression was positively correlated with Fis1 and p66Shc and negatively correlated with Mfn1. Meanwhile, electron microscopy showed that the percentage of fragmented mitochondria in the tubular cells in each group was consistent with the trend of CB1R expression.
CIH causes endocannabinoid disorders and induces abnormal mitochondrial dynamics, resulting in renal injury. Treatment with CB1R antagonists reduces CIH-induced renal damage by inhibiting dysregulated renal mitochondrial dynamics.
摘要：
阻塞性睡眠呼吸暂停(OSA)诱发的慢性肾脏病主要由慢性间歇性缺氧(CIH)引起。我们的研究探讨了CIH引起的肾损伤的机制以及大麻素受体1（CB1R）拮抗剂利莫那班（Ri）是否减轻了CIH引起的肾损伤。
雄性SD大鼠随机分为5组:正常对照组(NC),两个慢性间歇性缺氧（CIH）组，和两个H+Ri基团。NC组大鼠暴露于室内空气，而CIH组暴露于aCIH环境4周(4wCIH组)和6周(6wCIH组),分别。此外,CIH+Ri组大鼠给予1.5mg/kg/天Ri4周(4wCIH+Ri组)和6周(6wCIH+Ri组),分别。在此之后,对大鼠实施安乐死,切除肾脏进行下游分析.在肾组织中，通过苏木精伊红（HE）染色和高碘酸希夫（PAS）染色检查形态学改变，CB1R,Fis1、Mfn1和p66Shc的表达通过蛋白质印迹和免疫组织化学进行评估，电镜观察肾脏切片线粒体超微结构变化。
CB1R在4w和6wCIH组中的表达显著升高，并随着长期缺氧而进一步增加；然而，Ri阻止了CIH诱导的CB1R表达的增加。Fis1和p66Shc在CIH组的表达增加，但Mfn1表达下降。Ri降低Fis1和p66Shc表达并增加Mfn1表达。与4w或6wCIH组相比，4w或6wCIH组的肾脏损伤明显改善。CB1R表达与Fis1、p66Shc呈正相关,与Mfn1呈负相关。同时,电镜显示各组肾小管细胞中片段化线粒体百分比与CB1R表达趋势一致。
CIH引起内源性大麻素紊乱并诱导线粒体动力学异常，导致肾损伤。用CB1R拮抗剂治疗可通过抑制肾脏线粒体动力学失调来减轻CIH诱导的肾损伤。
雄性SD大鼠随机分为5组:正常对照组(NC),两个慢性间歇性缺氧（CIH）组，和两个H+Ri基团。NC组大鼠暴露于室内空气，而CIH组暴露于aCIH环境4周(4wCIH组)和6周(6wCIH组),分别。此外,CIH+Ri组大鼠给予1.5mg/kg/天Ri4周(4wCIH+Ri组)和6周(6wCIH+Ri组),分别。在此之后,对大鼠实施安乐死,切除肾脏进行下游分析.在肾组织中，通过苏木精伊红（HE）染色和高碘酸希夫（PAS）染色检查形态学改变，CB1R,Fis1、Mfn1和p66Shc的表达通过蛋白质印迹和免疫组织化学进行评估，电镜观察肾脏切片线粒体超微结构变化。
CB1R在4w和6wCIH组中的表达显著升高，并随着长期缺氧而进一步增加；然而，Ri阻止了CIH诱导的CB1R表达的增加。Fis1和p66Shc在CIH组的表达增加，但Mfn1表达下降。Ri降低Fis1和p66Shc表达并增加Mfn1表达。与4w或6wCIH组相比，4w或6wCIH组的肾脏损伤明显改善。CB1R表达与Fis1、p66Shc呈正相关,与Mfn1呈负相关。同时,电镜显示各组肾小管细胞中片段化线粒体百分比与CB1R表达趋势一致。
CIH引起内源性大麻素紊乱并诱导线粒体动力学异常，导致肾损伤。用CB1R拮抗剂治疗可通过抑制肾脏线粒体动力学失调来减轻CIH诱导的肾损伤。
