title: The role of calbindin-D28k on renal calcium and magnesium handling during treatment with loop and thiazide diuretics.
abstract: Calbindin-D28k (CBD-28k) is a calcium binding protein located in the distal convoluted tubule (DCT) and plays an important role in active calcium transport in the kidney. Loop and thiazide diuretics affect renal Ca and Mg handling: both cause Mg wasting, but have opposite effects on Ca excretion as loop diuretics increase, but thiazides decrease, Ca excretion. To understand the role of CBD-28k in renal Ca and Mg handling in response to diuretics treatment, we investigated renal Ca and Mg excretion and gene expression of DCT Ca and Mg transport molecules in wild-type (WT) and CBD-28k knockout (KO) mice. Mice were treated with chlorothiazide (CTZ; 50 mg · kg(-1) · day(-1)) or furosemide (FSM; 30 mg · kg(-1) · day(-1)) for 3 days. To avoid volume depletion, salt was supplemented in the drinking water. Urine Ca excretion was reduced in WT, but not in KO mice, by CTZ. FSM induced similar hypercalciuria in both groups. DCT Ca transport molecules, including transient receptor potential vanilloid 5 (TRPV5), TRPV6, and CBD-9k, were upregulated by CTZ and FSM in WT, but not in KO mice. Urine Mg excretion was increased and transient receptor potential subfamily M, member 6 (TRPM6) was upregulated by both CTZ and FSM in WT and KO mice. In conclusion, CBD-28k plays an important role in gene expression of DCT Ca, but not Mg, transport molecules, which may be related to its being a Ca, but not a Mg, intracellular sensor. The lack of upregulation of DCT Ca transport molecules by thiazides in the KO mice indicates that the DCT Ca transport system is critical for Ca conservation by thiazides.
authors.affiliation: Division of Nephrology, Department of Internal Medicine, Kaohsiung Chang-Gung Memorial Hospital, Kaohsiung, Taiwan, and Chang-Gung University, College of Medicine, Taoyuan, Taiwan; Kidney Research Center, Chang Gung Memorial Hospital, Chang-Gung University, College of Medicine, Taoyuan, Taiwan;
authors.forename: Chien-Te
authors.initials: CT
authors.lastname: Lee
authors.affiliation: Division of Nephrology, Department of Internal Medicine, Kaohsiung Chang-Gung Memorial Hospital, Kaohsiung, Taiwan, and Chang-Gung University, College of Medicine, Taoyuan, Taiwan;
authors.forename: Hwee-Yeong
authors.initials: HY
authors.lastname: Ng
authors.affiliation: Division of Nephrology, Department of Internal Medicine, Kaohsiung Chang-Gung Memorial Hospital, Kaohsiung, Taiwan, and Chang-Gung University, College of Medicine, Taoyuan, Taiwan;
authors.forename: Yueh-Ting
authors.initials: YT
authors.lastname: Lee
authors.affiliation: Departments of Chemistry and Biochemistry, University of Arizona, Tucson, Arizona;
authors.forename: Li-Wen
authors.initials: LW
authors.lastname: Lai
authors.affiliation: Arizona Kidney Disease and Heart Center, Tucson, Arizona; and Department of Medicine, University of Arizona, Tucson, Arizona lienhoward@gmail.com.
authors.forename: Yeong-Hau H
authors.identifier: http://orcid.org/0000-0001-7338-5210
authors.initials: YH
authors.lastname: Lien
mesh_terms: D000818:Animals; D015153:Blotting, Western; D064092:Calbindin 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism* / Q000652:urine; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism; D002740:Chlorothiazide / Q000494:pharmacology*; D005455:Fluorescent Antibody Technique; D005665:Furosemide / Q000494:pharmacology*; D005786:Gene Expression Regulation; D005838:Genotype; D007686:Kidney Tubules, Distal / Q000187:drug effects* / Q000378:metabolism; D008274:Magnesium / Q000378:metabolism* / Q000652:urine; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D060888:Real-Time Polymerase Chain Reaction; D065667:Renal Elimination / Q000187:drug effects*; D064030:S100 Calcium Binding Protein G / Q000235:genetics / Q000378:metabolism; D049993:Sodium Chloride Symporter Inhibitors / Q000494:pharmacology*; D049994:Sodium Potassium Chloride Symporter Inhibitors / Q000494:pharmacology*; D050916:TRPV Cation Channels / Q000235:genetics / Q000378:metabolism
chemical_list: C576499:Calb1 protein, mouse; D064092:Calbindin 1; D015220:Calcium Channels; D064030:S100 Calcium Binding Protein G; C576507:S100g protein, mouse; D049993:Sodium Chloride Symporter Inhibitors; D049994:Sodium Potassium Chloride Symporter Inhibitors; D050916:TRPV Cation Channels; C492240:Trpv5 protein, mouse; C446923:Trpv6 protein, mouse; D002740:Chlorothiazide; D005665:Furosemide; D008274:Magnesium; D002118:Calcium
keywords: TRPM6; TRPV5; TRPV6; calbindin-D28k; calbindin-D9k; furosemide; thiazides