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Effect of vitamin D supplementation on OPG/RANKL signalling activities in endothelial tissue damage in diet-induced diabetic rat model

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Abstract

Background

Type 2 Diabetes Mellitus is a chronic metabolic disease that causes endothelial damage and is an important risk factor for atherosclerosis. In the present study vitamin D3 supplementation in rats was used to determine the role of Osteoprotegerin (OPG)/Receptor activator kB ligand (RANKL) signalling in endothelial damage and changes in the expression levels of genes involved in this pathway. We hypothesized that vitamin D3 supplementation affects OPG and RANKL activity in the aorta.

Methods

Diabetes was induced in rats via injections of 40 mg/kg of streptozotocin followed by a high fructose (10%) diet. Group 2 (healthy) and 4 (diabetic) received 170 IU/kg of vitamin D3 weekly for 5 weeks, while Group 1 (healthy) and 2 (diabetic) received sterile saline. The aortas of each group were collected to analyse mRNA expression using the real-time PCR method and also to evaluate magnesium and calcium levels using inductively coupled plasma mass spectrometry.

Results

Opg and Il-1b expression levels were significantly associated with both diabetes and vitamin D3 supplementation in the aortas of the study groups (p ≤ 0.05). Opg mRNA expression was also found to correlate with both Icam-1 and Nos3 mRNA expression levels (r = 0.699, p = 0.001 and r = 0.622, p = 0.003, respectively). In addition, when mineral levels in the aortic tissues were compared among all groups, it was found that the interaction of diabetes and vitamin D3 supplementation significantly affected Mg levels and Mg/Ca ratios.

Conclusions

It is concluded that vitamin D3 supplementation has a modulatory effect on OPG/RANKL activity in the vessel wall by ameliorating endothelial damage in diabetes. This effect may contribute to the regulation of cytokine-mediated vascular homeostasis and mineral deposition in the aorta; therefore, further comprehensive studies are proposed to demonstrate this relationship.

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Abbreviations

Bmp2:

Bone morphogenetic protein 2

Ca:

Calcium

CTL:

Healthy control

CTL + VitD:

Control rats supplemented with Vitamin D3

CVD:

Cardiovascular disease

ECs:

Endothelial cells

eNOS:

Endothelial nitric oxide synthase

Gapdh:

Glyceraldehyde 3-phosphate dehydrogenase

Icam-1:

Intercellular adhesion molecule-1

ICP-MS:

Inductively coupled plasma mass spectrometry

Il-1b:

Interleukin 1 β

Mg:

Magnesium

MMPs:

Metalloproteinases

NF kB:

Nuclear factor кB

Nos3:

Nitric oxide synthase 3

OPG:

Osteoprotegerin

Q-PCR:

Quantitative real-time PCR

RANK:

Receptor activator кB

RANKL:

Receptor activator кB Ligand

Runx2:

RUNX family transcription factor 2

STZ:

Streptozotocin

T2DM:

Type 2 diabetes

TNFa:

Tumor necrosis factor α

VDR:

Vitamin D receptor

VSMCs:

Vascular smooth muscle cells

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Funding

This study was supported by the Scientific Research Projects Coordination Unit of Istanbul University (Project numbers: TYL-2019-32715 and TYL-2017-26139).

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Authors and Affiliations

  1. Department of Genetics, Aziz Sancar Institute of Experimental Medicine, Istanbul University, Istanbul, Turkey

    Gizem Celebi & Evrim Komurcu-Bayrak

  2. Graduate School of Health Sciences, Istanbul University, Istanbul, Turkey

    Gizem Celebi

  3. Faculty of Engineering and Natural Sciences, Molecular Biology, Genetics and Bioengineering Program, Sabanci University, 34956, Istanbul, Turkey

    Gizem Celebi

  4. Cerrahpasa Medical Faculty, Medical Biology Department, Istanbul University-Cerrahpasa, Istanbul, Turkey

    Merve Anapali, Fatma Kaya Dagistanli, Ayse Seda Akdemir & Turgut Ulutin

  5. Medical Biology Department, Ataturk University Medical Faculty, Erzurum, Turkey

    Merve Anapali

  6. School of Medicine, Department of Medical Biochemistry, Koç University, 34450, Sariyer, Istanbul, Turkey

    Duygu Aydemir & Nuriye Nuray Ulusu

  7. Koç University Research Center for Translational Medicine (KUTTAM), 34450, Sariyer, Istanbul, Turkey

    Duygu Aydemir & Nuriye Nuray Ulusu

  8. Istanbul Faculty of Medicine, Department of Medical Genetics, Istanbul University, Istanbul, Turkey

    Evrim Komurcu-Bayrak

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  1. Gizem Celebi
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Contributions

GC conducted the experiments, performed the statistical analysis, wrote, and edited the original draft. MA, ASA, DA participated in experiments. MA, FKD, ASA, DA, NNU, TU, and EKB conceived and participated in the study design. EKB reviewed the manuscript. All authors contributed to and have approved the final version of the manuscript.

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Correspondence to Gizem Celebi.

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Celebi, G., Anapali, M., Dagistanli, F.K. et al. Effect of vitamin D supplementation on OPG/RANKL signalling activities in endothelial tissue damage in diet-induced diabetic rat model. Pharmacol. Rep 74, 124–134 (2022). https://doi.org/10.1007/s43440-021-00332-1

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