剂量依赖性维生素D3补充可减轻阻塞性睡眠呼吸暂停大鼠模型中的内皮功能障碍和肾损伤

文献信息

中文摘要

背景： 间歇性缺氧（IH）诱导的氧化应激、一氧化氮耗竭和黏附分子上调所驱动的内皮功能障碍是阻塞性睡眠呼吸暂停（OSA）相关心血管并发症的基础。常与OSA共存的维生素D缺乏可能通过损害内皮型一氧化氮合酶（eNOS）调节和增强肾素-血管紧张素-醛固酮系统（RAAS）活性进一步放大这种内皮损伤；然而，维生素D3对IH模型中内皮和肾脏联合结局的剂量依赖性治疗潜力尚未被表征。
方法： 将56只成年雄性Sprague-Dawley大鼠分配至七组：对照组、维生素D缺乏（VDD）组、VDD伴重度IH（SIH-VDD）组，以及四个补充亚组，在重度或中度IH下接受高剂量（37.5 μg/kg/天）或低剂量（25 μg/kg/天）胆钙化醇，持续14天。通过ELISA定量血清E-选择素、ICAM-1、ET-1、NO和PCSK9。由盲法病理学家在H&E切片上评估肾脏组织病理学。数据采用单因素MANOVA、单变量ANOVA和LSD事后检验进行分析（p < 0.05）。
结果： SIH-VDD组显示最严重的内皮激活：E-选择素峰值（4.92 ± 0.90 ng/mL）、ICAM-1（201.50 ± 21.55 ng/mL）、ET-1（5.31 ± 0.81 pg/mL）和PCSK9（213.50 ± 14.71 ng/mL），同时NO最低（14.88 ± 2.16 μmol/L；与对照组相比均p < 0.001）。高剂量补充在所有标志物上产生显著恢复；在重度IH下PCSK9恢复至接近对照水平（162.50 ng/mL）。低剂量补充产生不完全的正常化。肾脏组织病理学显示IH暴露组有轻度间质淋巴细胞浸润，近端肾小管空泡化仅见于SIH-VDD组，在所有补充组中完全缺失。肾小球结构始终保持完好。
结论： 在实验性OSA模型中，维生素D缺乏联合IH上调内皮功能障碍标志物并诱导肾小管损伤。高剂量维生素D3以剂量和严重程度依赖的方式减轻这些变化，支持其作为OSA相关内皮和肾脏并发症的药理学辅助治疗的作用。

英文摘要

BACKGROUND: Endothelial dysfunction driven by intermittent hypoxia (IH)-induced oxidative stress, nitric oxide depletion, and adhesion molecule upregulation underlies obstructive sleep apnea (OSA)-related cardiovascular complications. Vitamin D deficiency, which frequently coexists with OSA, may further amplify this endothelial injury through impaired endothelial nitric oxide synthase (eNOS) regulation and heightened renin-angiotensin-aldosterone system (RAAS) activity; however, the dose-dependent therapeutic potential of vitamin D3 on combined endothelial and renal outcomes in an IH model remains uncharacterized.
METHODS: Fifty-six adult male Sprague-Dawley rats were allocated to seven groups: control, vitamin D-deficient (VDD), VDD with severe IH (SIH-VDD), and four supplementation subgroups receiving high-dose (37.5 μg/kg/day) or low-dose (25 μg/kg/day) cholecalciferol under severe or moderate IH for 14 days. Serum E-selectin, ICAM-1, ET-1, NO, and PCSK9 were quantified by ELISA. Renal histopathology was assessed on H&E sections by a blinded pathologist. Data were analyzed by one-way MANOVA, univariate ANOVA, and LSD post hoc tests (p < 0.05).
RESULTS: The SIH-VDD group showed the most severe endothelial activation: peak E-selectin (4.92 ± 0.90 ng/mL), ICAM-1 (201.50 ± 21.55 ng/mL), ET-1 (5.31 ± 0.81 pg/mL), and PCSK9 (213.50 ± 14.71 ng/mL), with the lowest NO (14.88 ± 2.16 μmol/L; all p < 0.001 vs. control). High-dose supplementation produced substantial recovery across all markers; PCSK9 normalized to near-control (162.50 ng/mL) under severe IH. Low-dose supplementation yielded incomplete normalization. Renal histopathology revealed mild interstitial lymphocytic infiltration in IH-exposed groups, with proximal tubular vacuolisation exclusively in the SIH-VDD group and entirely absent in all supplemented groups. Glomerular architecture remained preserved throughout.
CONCLUSION: Vitamin D deficiency combined with IH upregulates endothelial dysfunction markers and induces renal tubular injury in an experimental OSA model. High-dose vitamin D3 attenuates these changes dose- and severity-dependently, supporting its role as a pharmacological adjunct for OSA-associated endothelial and renal complications.