Vitamin D and calcium co-therapy mitigates pre-established cadmium nephropathy by regulating renal calcium homeostatic molecules and improving anti-oxidative and anti-inflammatory activities in rat |
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| Affiliation: | 1. Laboratory Medicine Department, Faculty of Applied Medical Sciences, Umm Al-Qura University, Al Abdeyah, PO Box 7607, Makkah, Saudi Arabia;2. Biochemistry Department, Faculty of Medicine, Umm Al-Qura University, Al Abdeyah, PO Box 7607, Makkah, Saudi Arabia;3. Clinical Pathology Department, Faculty of Veterinary Medicine, Mansoura University, Mansoura, Egypt;4. Biochemistry Department, Faculty of Pharmacy, Al-Azhar University, Assuit 71524, Egypt;1. Department of Biomedical Engineering, Iskenderun Technical University, Hatay 31200, Turkey;2. Department of Genetics, Inonu University School of Medicine, Malatya 44280, Turkey;3. Department of Molecular Biology and Genetics, Izmir Institute of Technology, Izmir 35430, Turkey;1. Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran;2. Department of Genetic, Faculty of Advanced Science and Technology, Tehran Medical Science, Islamic Azad University, Tehran, Iran;3. Department of Genetic, Hormozgan University of Medical Science, Hormozegan, Iran;4. Department of Molecular Genetics, Tehran Medical Science, Islamic Azad University, Tehran, Iran;5. Department of Microbiology, East Branch of Payamnoor University, Tehran, Iran;6. Cellular and Molecular Research Center, Sabzevar University of Medical Sciences, Sabzevar, Iran;7. Department of Pharmacognosy, Faculty of Pharmacy, Tehran, University of Medical Sciences, Tehran, Iran;8. School of Advanced Sciences and Technology, Islamic Azad University of Tehran Medical Branch, Tehran, Iran;9. Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi 110062, India;10. Department of Pharmacology, Saveetha Dental College, Saveetha Institute of Medical and Technical Science, Chennai, India;11. Herbal and Traditional Medicines Research Center, Kerman University of Medical Sciences, Kerman, Iran;12. Gastroenterology and Hepatology Research Center, Institute of Basic and Clinical hysiology Sciences, Kerman University of Medical Sciences, Kerman, Iran;13. Department of Biochemistry, Faculty of Medicine, Kerman University of Medical Sciences, Kerman, Iran;14. Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran;15. Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran;p. Department of Biotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran;1. Department of Occupational and Environmental Health, Xiangya School of Public Health, Central South University, Changsha 410078, China;2. Center of Clinical Pharmacology, the Third Xiangya Hospital, Central South University, Changsha 410013, China;3. Environmental Science and Engineering, College of Resource and Environment, Hunan Agricultural University, Changsha 410128, China;1. Department of Critical Care Medicine, Shaoxing People''s Hospital, No.568 Zhong Xing Road, Shaoxing, Zhejiang, 312000, China;2. Department of Cardiology, Kunshan Hospital of Traditional Chinese Medicine, Suzhou, Jiangsu, 215300, China;3. Department of Cardiology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu 221000, China;4. Department of Cardiology, Wuxi No.2 People''s Hospital, Wuxi Clinical College of Nanjing Medical University, Wuxi, Jiangsu, 214000, China;5. Department of Cardiology, Jiangnan University Medical Center, No.68 Zhongshan Road, Wuxi, Jiangsu, 214001, China;1. Department of Restorative Dentistry, School of Dentistry, Tehran University of Medical Sciences, Tehran, Iran;2. Department of Radiopharmacy, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran;3. Iranian National Center for Addiction Studies (INCAS), Tehran University of Medical Sciences, Tehran, Iran;4. School of Dentistry, Tehran University of Medical Sciences, Tehran, Iran;5. Department of Community Oral Health, School of Dentistry, Tehran University of Medical Sciences, Tehran, Iran;6. Research Center for Caries Prevention, Dentistry Research Institute, Tehran University of Medical Sciences, Tehran, Iran;7. Department of Cariology, Operative Dentistry and Dental Public Health, Oral Health Research Institute, Indiana University School of Dentistry, Indianapolis, IN, USA |
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| Abstract: | BackgroundCadmium (Cd) is a major environmental pollutant and chronic toxicity could induce nephropathy by increasing renal oxidative stress and inflammation. Although vitamin D (VD) and calcium (Ca) prophylactic treatments attenuated Cd-induced cell injury, none of the prior studies measure their renoprotective effects against pre-established Cd-nephropathy.AimsTo measure the alleviating effects of VD and/or Ca single and dual therapies against pre-established nephrotoxicity induced by chronic Cd toxicity prior to treatment initiation.MethodsForty male adult rats were allocated into: negative controls (NC), positive controls (PC), Ca, VD and VC groups. The study lasted for eight weeks and all animals, except the NC, received CdCl2 in drinking water (44 mg/L) throughout the study. Ca (100 mg/kg) and/or VD (350 IU/kg) were given (five times/week) during the last four weeks to the designated groups. Subsequently, the expression of transforming growth factor-β (TGF-β1), inducible nitric oxide synthase (iNOS), neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), VD synthesising (Cyp27b1) and catabolizing (Cyp24a1) enzymes with VD receptor (VDR) and binding protein (VDBP) was measured in renal tissues. Similarly, renal expression of Ca voltage-dependent channels (CaV1.1/CaV3.1), store-operated channels (RyR1/ITPR1), and binding proteins (CAM/CAMKIIA/S100A1/S100B) were measured. Serum markers of renal function alongside several markers of oxidative stress (MDA/H2O2/GSH/GPx/CAT) and inflammation (IL-6/TNF-α/IL-10) together with renal cell apoptosis and expression of caspase-3 were also measured.ResultsThe PC group exhibited hypovitaminosis D, hypocalcaemia, hypercalciuria, proteinuria, reduced creatinine clearance, and increased renal apoptosis/necrosis with higher caspase-3 expression. Markers of renal tissue damage (TGF-β1/iNOS/NGAL/KIM-1), oxidative stress (MDA/H2O2), and inflammation (TNF-α/IL-1β/IL-6) increased, whilst the antioxidants (GSH/GPx/CAT) and IL-10 decreased, in the PC group. The PC renal tissues also showed abnormal expression of Cyp27b1, Cyp24a1, VDR, and VDBP, alongside Ca-membranous (CaV1.1/CaV3.1) and store-operated channels (RyR1/ITPR1) and cytosolic Ca-binding proteins (CAM/CAMKIIA/S100A1/S100B). Although VD was superior to Ca monotherapy, their combination revealed the best mitigation effects by attenuating serum and renal tissue Cd concentrations, inflammation and oxidative stress, alongside modulating the expression of VD/Ca-molecules.ConclusionsThis study is the first to show improved alleviations against Cd-nephropathy by co-supplementing VD and Ca, possibly by better regulation of Ca-dependent anti-oxidative and anti-inflammatory actions. |
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| Keywords: | Vitamin D receptor Endoplasmic reticulum stress Voltage-dependent calcium channel Ryanodine receptor Inositol triphosphate receptor Calmodulin |
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