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: Jin Rui Chang, Jun Guo, Yue Wang, Yue Long Hou, Wei Wei Lu, Jin Sheng Zhang, Yan Rong Yu, Ming Jiang Xu, Xiu Ying Liu, Xiu Jie Wang, You Fei Guan, Yi Zhu, Jie Du, Chao Shu Tang, Yong Fen Qi
• Journal: Kidney international (Kidney Int) Vol. 89 Issue 3 Pg. 586-600 (Mar 2016) ISSN: 1523-1755 [Electronic] United States
• PMID: 26880455 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2016 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

Chemical References

• ADM2 protein, human
• Peptide Hormones
• Ramp3 protein, rat
• Receptor Activity-Modifying Protein 3
• Receptors, Calcitonin
• Cholecalciferol
• Cyclic AMP
• Cyclic AMP-Dependent Protein Kinases
• Glucuronidase
• Klotho Proteins

Topics

• Animals
• Aorta, Thoracic (drug effects, metabolism, pathology)
• Cell Transdifferentiation (drug effects)
• Cells, Cultured
• Cholecalciferol
• Cyclic AMP (metabolism)
• Cyclic AMP-Dependent Protein Kinases (metabolism)
• Disease Models, Animal
• Glucuronidase (genetics, metabolism)
• Humans
• Klotho Proteins
• Male
• Muscle, Smooth, Vascular (drug effects, metabolism, pathology)
• Myocytes, Smooth Muscle (drug effects, metabolism, pathology)
• Nephrectomy
• Osteoblasts (drug effects, metabolism, pathology)
• Peptide Hormones (pharmacology)
• Phenotype
• RNA Interference
• Rats, Sprague-Dawley
• Receptor Activity-Modifying Protein 3 (metabolism)
• Receptors, Calcitonin (metabolism)
• Renal Insufficiency, Chronic (drug therapy, genetics, metabolism, pathology)
• Signal Transduction (drug effects)
• Transfection
• Up-Regulation
• Vascular Calcification (genetics, metabolism, pathology, prevention & control)