AIMS: Vascular calcification (VC) contributes to morbidity and mortality in patients with chronic kidney disease (CKD). Allosteric modulators of the calcium (Ca)-sensing receptor (CaSR) may slow the progression of VC in CKD patients either by reducing serum parathyroid hormone (PTH), Ca, and phosphate levels or by a direct effect on the vessel wall. The aim of this study was to examine the effects of calcimimetics on CaSR expression, cell phenotype, and mineral deposition in human vascular smooth muscle cells (h-VSMCs). METHODS AND RESULTS: Primary h-VSMCs were exposed for 14 days to increasing concentrations of Ca(2+) (from 1.8 to 5 mmol/L) in the presence or absence of calcimimetics R-568 or AMG 641 (0.1 μmol/L). Mineralization was detected by Alizarin red staining, and the cell phenotype was assessed using immunocytochemistry and qRT-PCR. CaSR expression was evaluated using flow cytometry. Short- and long-term exposure (1 day to 14 days) of h-VSMCs to calcimimetics promoted CaSR protein transport from the endoplasmic reticulum to the plasma membrane with enhanced CaSR expression on the cell surface, together with an increase in total cell CaSR expression due to enhanced biosynthesis. In pro-mineralizing conditions, exposure to calcimimetics counteracted the Ca(2+)-dependent reduction of CaSR expression, decreased matrix collagen secretion, and mineral deposition by ~90%. These effects involved CaSR activation since it could be inhibited by CaSR siRNA, but not scrambled siRNA. CONCLUSIONS: The calcimimetic-dependent increase in biosynthesis and activation of the CaSR in h-VSMCs probably play a key role in the protection against calcium-induced VC.
AIMS: Vascular calcification (VC) contributes to morbidity and mortality in patients with chronic kidney disease (CKD). Allosteric modulators of the calcium (Ca)-sensing receptor (CaSR) may slow the progression of VC in CKDpatients either by reducing serum parathyroid hormone (PTH), Ca, and phosphate levels or by a direct effect on the vessel wall. The aim of this study was to examine the effects of calcimimetics on CaSR expression, cell phenotype, and mineral deposition in human vascular smooth muscle cells (h-VSMCs). METHODS AND RESULTS: Primary h-VSMCs were exposed for 14 days to increasing concentrations of Ca(2+) (from 1.8 to 5 mmol/L) in the presence or absence of calcimimetics R-568 or AMG 641 (0.1 μmol/L). Mineralization was detected by Alizarin red staining, and the cell phenotype was assessed using immunocytochemistry and qRT-PCR. CaSR expression was evaluated using flow cytometry. Short- and long-term exposure (1 day to 14 days) of h-VSMCs to calcimimetics promoted CaSR protein transport from the endoplasmic reticulum to the plasma membrane with enhanced CaSR expression on the cell surface, together with an increase in total cell CaSR expression due to enhanced biosynthesis. In pro-mineralizing conditions, exposure to calcimimetics counteracted the Ca(2+)-dependent reduction of CaSR expression, decreased matrix collagen secretion, and mineral deposition by ~90%. These effects involved CaSR activation since it could be inhibited by CaSR siRNA, but not scrambled siRNA. CONCLUSIONS: The calcimimetic-dependent increase in biosynthesis and activation of the CaSR in h-VSMCs probably play a key role in the protection against calcium-induced VC.
Authors: T I Chang; S Abdalla; G M London; G A Block; R Correa-Rotter; T B Drüeke; J Floege; C A Herzog; K W Mahaffey; S M Moe; P S Parfrey; D C Wheeler; B Dehmel; W G Goodman; G M Chertow Journal: J Hum Hypertens Date: 2015-06-04 Impact factor: 3.012
Authors: Patrick S Parfrey; Tilman B Drüeke; Geoffrey A Block; Ricardo Correa-Rotter; Jürgen Floege; Charles A Herzog; Gerard M London; Kenneth W Mahaffey; Sharon M Moe; David C Wheeler; Yumi Kubo; Bastian Dehmel; William G Goodman; Glenn M Chertow Journal: Clin J Am Soc Nephrol Date: 2015-02-20 Impact factor: 8.237
Authors: Martin Schepelmann; Marianna Ranieri; Irene Lopez-Fernandez; Thomas S Webberley; Sarah C Brennan; Polina L Yarova; Joao Graca; Umar-Khetaab Hanif; Christian Müller; Teresa Manhardt; Martina Salzmann; Helen Quasnichka; Sally A Price; Donald T Ward; Thierry Gilbert; Vladimir V Matchkov; Robert A Fenton; Amanda Herberger; Jenna Hwong; Christian Santa Maria; Chia-Ling Tu; Enikö Kallay; Giovanna Valenti; Wenhan Chang; Daniela Riccardi Journal: J Am Soc Nephrol Date: 2022-05-17 Impact factor: 14.978