Shanxi Medical University, No. 56, Xijian South Road, Taiyuan, 030001, Shanxi, People's Republic of China.
The Second Hospital of Shanxi Medical University, No. 382, Wuyi Road, Taiyuan, 030001, Shanxi Province, People's Republic of China.
BMC Nephrol. 2021 Apr 26;22(1):153. doi: 10.1186/s12882-021-02362-6.
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.
阻塞性睡眠呼吸暂停（OSA）引起的慢性肾脏病主要是由慢性间歇性低氧（CIH）引起的。我们的研究旨在探讨 CIH 诱导的肾损伤的机制，以及大麻素受体 1（CB1R）拮抗剂利莫那班（Ri）是否缓解 CIH 诱导的肾损伤。
雄性 Sprague-Dawley 大鼠随机分为五组：一组正常对照组（NC），两组慢性间歇性低氧（CIH）组，两组 CIH+Ri 组。NC 组大鼠暴露于室内空气，而 CIH 组大鼠分别暴露于 CIH 环境 4 周（4w CIH 组）和 6 周（6w CIH 组）。此外，CIH+Ri 组大鼠分别给予 1.5mg/kg/天 Ri 4 周（4w CIH+Ri 组）和 6 周（6w CIH+Ri 组）。然后处死大鼠，取出肾脏进行下游分析。在肾组织中，通过苏木精-伊红（HE）染色和过碘酸希夫（PAS）染色观察形态改变，通过 Western blot 和免疫组织化学检测 CB1R、Fis1、Mfn1 和 p66Shc 的表达，通过电子显微镜观察肾组织切片中线粒体的超微结构变化。
4w 和 6w CIH 组 CB1R 表达明显升高，随着低氧时间的延长进一步增加，而 Ri 可防止 CIH 诱导的 CB1R 表达增加。CIH 组 Fis1 和 p66Shc 表达增加，而 Mfn1 表达减少。Ri 降低了 Fis1 和 p66Shc 的表达，增加了 Mfn1 的表达。与 4w 或 6w CIH 组相比，4w 或 6w CIH+Ri 组的肾脏损伤明显改善。CB1R 表达与 Fis1 和 p66Shc 呈正相关，与 Mfn1 呈负相关。同时，电子显微镜显示各组肾小管细胞中片段化线粒体的百分比与 CB1R 表达趋势一致。
CIH 导致内源性大麻素紊乱，并诱导异常的线粒体动力学，导致肾脏损伤。CB1R 拮抗剂的治疗通过抑制失调的肾线粒体动力学减轻 CIH 诱导的肾损伤。
