title: Intermedin1-53 attenuates vascular calcification in rats with chronic kidney disease by upregulation of α-Klotho.
abstract: Deficiency in α-Klotho is involved in the pathogenesis of vascular calcification. Since intermedin (IMD)1-53 (a calcitonin/calcitonin gene-related peptide) protects against vascular calcification, we studied whether IMD1-53 inhibits vascular calcification by upregulating α-Klotho. A rat model of chronic kidney disease (CKD) with vascular calcification induced by the 5/6 nephrectomy plus vitamin D3 was used for study. The aortas of rats with CKD showed reduced IMD content but an increase of its receptor, calcitonin receptor-like receptor, and its receptor modifier, receptor activity-modifying protein 3. IMD1-53 treatment reduced vascular calcification. The expression of α-Klotho was greatly decreased in the aortas of rats with CKD but increased in the aortas of IMD1-53-treated rats with CKD. In vitro, IMD1-53 increased α-Klotho protein level in calcified vascular smooth muscle cells. α-Klotho knockdown blocked the inhibitory effect of IMD1-53 on vascular smooth muscle cell calcification and their transformation into osteoblast-like cells. The effect of IMD1-53 to upregulate α-Klotho and inhibit vascular smooth muscle cell calcification was abolished by knockdown of its receptor or its modifier protein, or treatment with the protein kinase A inhibitor H89. Thus, IMD1-53 may attenuate vascular calcification by upregulating α-Klotho via the calcitonin receptor/modifying protein complex and protein kinase A signaling.
authors.affiliation: The Key Laboratory of Remodeling-related Cardiovascular Diseases, Capital Medical University, Ministry of Education, Beijing, China; Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing Anzhen Hospital Affiliated with the Capital Medical University, Beijing, China; Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Peking University Health Science Center, Beijing, China; Insititute of Basic Medicine Science, Xi'an Medical University, Xi'an, China.
authors.forename: Jin Rui
authors.initials: JR
authors.lastname: Chang
authors.affiliation: The Key Laboratory of Remodeling-related Cardiovascular Diseases, Capital Medical University, Ministry of Education, Beijing, China; Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing Anzhen Hospital Affiliated with the Capital Medical University, Beijing, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Guo
authors.affiliation: Renal Department, Peking University Third Hospital, Beijing, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Wang
authors.affiliation: The Key Laboratory of Remodeling-related Cardiovascular Diseases, Capital Medical University, Ministry of Education, Beijing, China; Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing Anzhen Hospital Affiliated with the Capital Medical University, Beijing, China; Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Peking University Health Science Center, Beijing, China.
authors.forename: Yue Long
authors.initials: YL
authors.lastname: Hou
authors.affiliation: The Key Laboratory of Remodeling-related Cardiovascular Diseases, Capital Medical University, Ministry of Education, Beijing, China; Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing Anzhen Hospital Affiliated with the Capital Medical University, Beijing, China; Department of Pathogen Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.
authors.forename: Wei Wei
authors.initials: WW
authors.lastname: Lu
authors.affiliation: The Key Laboratory of Remodeling-related Cardiovascular Diseases, Capital Medical University, Ministry of Education, Beijing, China; Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing Anzhen Hospital Affiliated with the Capital Medical University, Beijing, China; Department of Pathogen Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.
authors.forename: Jin Sheng
authors.initials: JS
authors.lastname: Zhang
authors.affiliation: Department of Pathogen Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.
authors.forename: Yan Rong
authors.initials: YR
authors.lastname: Yu
authors.affiliation: Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Peking University Health Science Center, Beijing, China.
authors.forename: Ming Jiang
authors.initials: MJ
authors.lastname: Xu
authors.affiliation: Key Laboratory of Genetic Network Biology, Collaborative Innovation Center of Genetics and Development, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China.
authors.forename: Xiu Ying
authors.initials: XY
authors.lastname: Liu
authors.affiliation: Key Laboratory of Genetic Network Biology, Collaborative Innovation Center of Genetics and Development, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China.
authors.forename: Xiu Jie
authors.initials: XJ
authors.lastname: Wang
authors.affiliation: Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Peking University Health Science Center, Beijing, China.
authors.forename: You Fei
authors.initials: YF
authors.lastname: Guan
authors.affiliation: Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Peking University Health Science Center, Beijing, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: The Key Laboratory of Remodeling-related Cardiovascular Diseases, Capital Medical University, Ministry of Education, Beijing, China; Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing Anzhen Hospital Affiliated with the Capital Medical University, Beijing, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Du
authors.affiliation: The Key Laboratory of Remodeling-related Cardiovascular Diseases, Capital Medical University, Ministry of Education, Beijing, China; Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing Anzhen Hospital Affiliated with the Capital Medical University, Beijing, China; Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Peking University Health Science Center, Beijing, China.
authors.forename: Chao Shu
authors.initials: CS
authors.lastname: Tang
authors.affiliation: The Key Laboratory of Remodeling-related Cardiovascular Diseases, Capital Medical University, Ministry of Education, Beijing, China; Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing Anzhen Hospital Affiliated with the Capital Medical University, Beijing, China; Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Peking University Health Science Center, Beijing, China; Department of Pathogen Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China. Electronic address: yongfenqi@163.com.
authors.forename: Yong Fen
authors.initials: YF
authors.lastname: Qi
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D054338:Cell Transdifferentiation / Q000187:drug effects*; D002478:Cells, Cultured; D002762:Cholecalciferol; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004195:Disease Models, Animal; D005966:Glucuronidase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D000090265:Klotho Proteins; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009392:Nephrectomy; D010006:Osteoblasts / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D036361:Peptide Hormones / Q000494:pharmacology*; D010641:Phenotype; D034622:RNA Interference; D017207:Rats, Sprague-Dawley; D058264:Receptor Activity-Modifying Protein 3 / Q000378:metabolism; D018003:Receptors, Calcitonin / Q000378:metabolism; D051436:Renal Insufficiency, Chronic / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D014162:Transfection; D015854:Up-Regulation; D061205:Vascular Calcification / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*
chemical_list: C484330:ADM2 protein, human; D036361:Peptide Hormones; C545510:Ramp3 protein, rat; D058264:Receptor Activity-Modifying Protein 3; D018003:Receptors, Calcitonin; D002762:Cholecalciferol; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D005966:Glucuronidase; D000090265:Klotho Proteins
keywords: calcitonin receptor-like receptor; chronic kidney disease; intermedin(1-53); vascular calcification; α-Klotho