Magnesium Modifies the Impact of Calcitriol Treatment on Vascular Calcification in Experimental Chronic Kidney Disease.
Chronic kidney disease (CKD) patients are commonly treated with vitamin D analogs, such as calcitriol. Recent epidemiologic evidence revealed a significant interaction between vitamin D and magnesium, since an inverse relationship between vitamin D levels and mortality mainly occurs in patients with a high magnesium intake. The aim of the study was to assess the mechanisms involved by determining whether magnesium alone or combined with calcitriol treatments differentially impacts vascular calcification (VC) in male Sprague-Dawley rats with adenine-induced CKD. Treatment with moderate doses of calcitriol (80 μg/kg) suppressed parathyroid hormone to near or slightly below control levels. Given alone, this dose of calcitriol increased the prevalence of VC; however, when magnesium was given in combination, the severity of calcification was attenuated in the abdominal aorta (51% reduction), iliac (44%), and carotid arteries (46%) compared with CKD controls. The decreases in vascular calcium content were associated with a 20-50% increase in vascular magnesium. Calcitriol treatment alone significantly decreased TRPM7 protein (↓ to ∼11%), whereas the combination treatment increased both mRNA (1.7×) and protein (6.8×) expression compared with calcitriol alone. In summary, calcitriol increased VC in certain conditions, but magnesium prevented the reduction in TRPM7 and reduced the severity of VC, thereby increasing the bioavailable magnesium in the vascular microenvironment. These findings suggest that modifying the adverse effect profile of calcitriol with magnesium may be a plausible approach to benefiting the increasing number of CKD patients being prescribed calcitriol.
Department of Biomedical and Molecular Sciences (J.G.E.Z., K.M.M., B.S., H.B., K.L., M.A.A.) and Department of Medicine (R.M.H.), Queen's University, Kingston, Ontario, Canada.
Jason G E
JG
Zelt
Department of Biomedical and Molecular Sciences (J.G.E.Z., K.M.M., B.S., H.B., K.L., M.A.A.) and Department of Medicine (R.M.H.), Queen's University, Kingston, Ontario, Canada.
Kristin M
KM
McCabe
Department of Biomedical and Molecular Sciences (J.G.E.Z., K.M.M., B.S., H.B., K.L., M.A.A.) and Department of Medicine (R.M.H.), Queen's University, Kingston, Ontario, Canada.
Bruno
B
Svajger
Department of Biomedical and Molecular Sciences (J.G.E.Z., K.M.M., B.S., H.B., K.L., M.A.A.) and Department of Medicine (R.M.H.), Queen's University, Kingston, Ontario, Canada.
Henry
H
Barron
Department of Biomedical and Molecular Sciences (J.G.E.Z., K.M.M., B.S., H.B., K.L., M.A.A.) and Department of Medicine (R.M.H.), Queen's University, Kingston, Ontario, Canada.
Kim
K
Laverty
Department of Biomedical and Molecular Sciences (J.G.E.Z., K.M.M., B.S., H.B., K.L., M.A.A.) and Department of Medicine (R.M.H.), Queen's University, Kingston, Ontario, Canada adams@queensu.ca holdenr@kgh.kari.net.
Rachel M
RM
Holden
Department of Biomedical and Molecular Sciences (J.G.E.Z., K.M.M., B.S., H.B., K.L., M.A.A.) and Department of Medicine (R.M.H.), Queen's University, Kingston, Ontario, Canada adams@queensu.ca holdenr@kgh.kari.net.
Michael A
MA
Adams
D000225:Adenine / Q000494:pharmacology; D000818:Animals; D001012:Aorta, Abdominal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002117:Calcitriol / Q000627:therapeutic use*; D002118:Calcium / Q000378:metabolism; D002120:Calcium Channel Agonists / Q000627:therapeutic use*; D002339:Carotid Arteries / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004032:Diet; D004305:Dose-Response Relationship, Drug; D006439:Hemodynamics / Q000187:drug effects; D007083:Iliac Artery / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008274:Magnesium / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D010281:Parathyroid Hormone / Q000037:antagonists & inhibitors / Q000097:blood; D051381:Rats; D017207:Rats, Sprague-Dawley; D051436:Renal Insufficiency, Chronic / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D050053:TRPM Cation Channels / Q000378:metabolism; D061205:Vascular Calcification / Q000188:drug therapy* / Q000209:etiology
D002120:Calcium Channel Agonists; D010281:Parathyroid Hormone; D050053:TRPM Cation Channels; C486584:Trpm7 protein, rat; D002117:Calcitriol; D008274:Magnesium; D000225:Adenine; D002118:Calcium