title: Sustained activation of renal N-methyl-D-aspartate receptors decreases vitamin D synthesis: a possible role for glutamate on the onset of secondary HPT.
abstract: N-methyl-D-aspartate (NMDA) receptors (NMDAR) are tetrameric amino acid receptors that act as membrane calcium channels. The presence of the receptor has been detected in the principal organs responsible for calcium homeostasis (kidney, bone, and parathyroid gland), pointing to a possible role in mineral metabolism. The aim of this study was to test the effect of NMDAR activation in the kidney and on 1,25(OH)₂D₃ synthesis. We determined the presence of NMDAR subunits in HK-2 (human kidney cells) cells and proved its functionality. NMDA treatment for 4 days induced a decrease in 1α-hydroxylase levels and 1,25(OH)₂D₃ synthesis through the activation of the MAPK/ERK pathway in HK-2 cells. In vivo administration of NMDA for 4 days also caused a decrease in blood 1,25(OH)₂D₃ levels in healthy animals and an increase in blood PTH levels. This increase in PTH induced a decrease in the urinary excretion of calcium and an increase in urinary excretion of phosphorous and sodium as well as in diuresis. Bone turnover markers also increased. Animals with 5/6 nephrectomy showed low levels of renal 1α-hydroxylase as well as high levels of renal glutamate compared with healthy animals. In conclusion, NMDAR activation in the kidney causes a decrease in 1,25(OH)₂D₃ synthesis, which induces an increase on PTH synthesis and release. In animals with chronic kidney disease, high renal levels of glutamate could be involved in the downregulation of 1α-hydroxylase expression.
authors.affiliation: Institut de Recerca Biomèdica de Lleida, Spain.
authors.forename: Eva
authors.initials: E
authors.lastname: Parisi
authors.forename: Milica
authors.initials: M
authors.lastname: Bozic
authors.forename: Mercé
authors.initials: M
authors.lastname: Ibarz
authors.forename: Sara
authors.initials: S
authors.lastname: Panizo
authors.forename: Petya
authors.initials: P
authors.lastname: Valcheva
authors.forename: Blai
authors.initials: B
authors.lastname: Coll
authors.forename: Elvira
authors.initials: E
authors.lastname: Fernández
authors.forename: José M
authors.initials: JM
authors.lastname: Valdivielso
mesh_terms: D000818:Animals; D002118:Calcium / Q000097:blood / Q000652:urine; D002460:Cell Line; D003404:Creatinine / Q000097:blood / Q000652:urine; D005260:Female; D018698:Glutamic Acid / Q000378:metabolism*; D006801:Humans; D006962:Hyperparathyroidism, Secondary / Q000209:etiology*; D007668:Kidney / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D015675:Osteocalcin / Q000097:blood / Q000652:urine; D010281:Parathyroid Hormone / Q000097:blood; D010710:Phosphates / Q000097:blood / Q000652:urine; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000737:chemistry / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism*; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000096:biosynthesis / Q000378:metabolism
chemical_list: D010281:Parathyroid Hormone; D010710:Phosphates; D012333:RNA, Messenger; D016194:Receptors, N-Methyl-D-Aspartate; D015675:Osteocalcin; D014807:Vitamin D; D018698:Glutamic Acid; C097949:1,25-dihydroxyvitamin D; D003404:Creatinine; D006899:Mixed Function Oxygenases; D002118:Calcium
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