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Supplementary file 1_Dose-dependent vitamin D3 supplementation attenuates endothelial dysfunction and renal injury in an obstructive sleep apnea rat model.docx Abdulmueen A. Alotaibi (24911983) Syed Shahid Habib (6336014) Hayam Gad (24525758) Tamadar Al Doheyan (24911986) Mubarak Aldosary (24911989) Alanoud T. Aljasham (17630151) Asma F. Alotaibi (24525761) Yasser A. Alshawakir (13730570) Fuzail Ahmad (716427) Abeer A. Al-Masri (18140209) Pharmacology cholecalciferol endothelial dysfunction endothelin-1 E-selectin ICAM-1 intermittent hypoxia nitric oxide obstructive sleep apnea Background<p>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.</p>Methods<p>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).</p>Results<p>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.</p>Conclusion<p>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.</p> 2026-09-15T04:27:52Z Dataset Dataset 10.3389/fphar.2026.1847011.s001 https://figshare.com/articles/dataset/Supplementary_file_1_Dose-dependent_vitamin_D3_supplementation_attenuates_endothelial_dysfunction_and_renal_injury_in_an_obstructive_sleep_apnea_rat_model_docx/33770812 CC BY 4.0