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Dose-dependent vitamin D3 supplementation attenuates endothelial dysfunction and renal injury in an obstructive sleep
Abdulmueen A Alotaibi1,2, Syed Shahid Habib1, Hayam Gad1
1Department of Physiology, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
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.