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. |
| Authors: |
Obaid, Ahmad A Almasmoum, Hussain Almaimani, Riyad A El-Boshy, Mohamed Aslam, Akhmed Idris, Shakir Ghaith, Mazen M El-Readi, Mahmoud Z Ahmad, Jawwad Farrash, Wesam F Mujalli, Abdulrahman Eid, Safaa Y Elzubier, Mohamed E Refaat, Bassem
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| Citation: |
Obaid AA, etal., J Trace Elem Med Biol. 2023 May 24;79:127221. doi: 10.1016/j.jtemb.2023.127221. |
| RGD ID: |
329853759 |
| Pubmed: |
PMID:37244046 (View Abstract at PubMed) |
| DOI: |
DOI:10.1016/j.jtemb.2023.127221 (Journal Full-text) |
BACKGROUND: Cadmium (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.
AIMS: To 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.
METHODS: Forty 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.
RESULTS: The 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.
CONCLUSIONS: This 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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| Genes (Rattus norvegicus) |
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| Cacna1g (calcium voltage-gated channel subunit alpha1 G) | Cacna1s (calcium voltage-gated channel subunit alpha1 S) | Camk2a (calcium/calmodulin-dependent protein kinase II alpha) | | Cyp24a1 (cytochrome P450, family 24, subfamily a, polypeptide 1) | Cyp27b1 (cytochrome P450, family 27, subfamily b, polypeptide 1) | Gc (GC, vitamin D binding protein) | | Havcr1 (hepatitis A virus cellular receptor 1) | Itpr1 (inositol 1,4,5-trisphosphate receptor, type 1) | Nos2 (nitric oxide synthase 2) | | Ryr1 (ryanodine receptor 1) | S100a1 (S100 calcium binding protein A1) | S100b (S100 calcium binding protein B) | | Tgfb1 (transforming growth factor, beta 1) | Vdr (vitamin D receptor) |
| Genes (Mus musculus) |
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| Cacna1g (calcium channel, voltage-dependent, T type, alpha 1G subunit) | Cacna1s (calcium channel, voltage-dependent, L type, alpha 1S subunit) | Camk2a (calcium/calmodulin-dependent protein kinase II alpha) | | Cyp24a1 (cytochrome P450, family 24, subfamily a, polypeptide 1) | Cyp27b1 (cytochrome P450, family 27, subfamily b, polypeptide 1) | Gc (vitamin D binding protein) | | Havcr1 (hepatitis A virus cellular receptor 1) | Itpr1 (inositol 1,4,5-trisphosphate receptor 1) | Nos2 (nitric oxide synthase 2, inducible) | | Ryr1 (ryanodine receptor 1, skeletal muscle) | S100a1 (S100 calcium binding protein A1) | S100b (S100 protein, beta polypeptide, neural) | | Tgfb1 (transforming growth factor, beta 1) | Vdr (vitamin D (1,25-dihydroxyvitamin D3) receptor) |
| Genes (Homo sapiens) |
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| CACNA1G (calcium voltage-gated channel subunit alpha1 G) | CACNA1S (calcium voltage-gated channel subunit alpha1 S) | CAMK2A (calcium/calmodulin dependent protein kinase II alpha) | | CYP24A1 (cytochrome P450 family 24 subfamily A member 1) | CYP27B1 (cytochrome P450 family 27 subfamily B member 1) | GC (GC vitamin D binding protein) | | HAVCR1 (hepatitis A virus cellular receptor 1) | ITPR1 (inositol 1,4,5-trisphosphate receptor type 1) | NOS2 (nitric oxide synthase 2) | | RYR1 (ryanodine receptor 1) | S100A1 (S100 calcium binding protein A1) | S100B (S100 calcium binding protein B) | | TGFB1 (transforming growth factor beta 1) | VDR (vitamin D receptor) |
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