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• W2031567798 abstract "The chronic kidney disease–mineral and bone disorder (CKD–MBD) syndrome is an extremely important complication of kidney diseases. Here we tested whether CKD–MBD causes vascular calcification in early kidney failure by developing a mouse model of early CKD in a background of atherosclerosis-stimulated arterial calcification. CKD equivalent in glomerular filtration reduction to human CKD stage 2 stimulated early vascular calcification and inhibited the tissue expression of α-klotho (klotho) in the aorta. In addition, osteoblast transition in the aorta was stimulated by early CKD as shown by the expression of the critical transcription factor Runx2. The ligand associated with the klotho-fibroblast growth factor receptor complex, FGF23, was found to be expressed in the vascular media of sham-operated mice. Its expression was decreased in early CKD. Increased circulating levels of the osteocyte-secreted proteins, FGF23, and sclerostin may have been related to increased circulating klotho levels. Finally, we observed low-turnover bone disease with a reduction in bone formation rates more than bone resorption. Thus, the CKD–MBD, characterized by cardiovascular risk factors, vascular calcification, increased circulating klotho, FGF23 and sclerostin levels, and low-turnover renal osteodystrophy, was established in early CKD. Early CKD caused a reduction of vascular klotho, stimulated vascular osteoblastic transition, increased osteocytic secreted proteins, and inhibited skeletal modeling producing the CKD–MBD. The chronic kidney disease–mineral and bone disorder (CKD–MBD) syndrome is an extremely important complication of kidney diseases. Here we tested whether CKD–MBD causes vascular calcification in early kidney failure by developing a mouse model of early CKD in a background of atherosclerosis-stimulated arterial calcification. CKD equivalent in glomerular filtration reduction to human CKD stage 2 stimulated early vascular calcification and inhibited the tissue expression of α-klotho (klotho) in the aorta. In addition, osteoblast transition in the aorta was stimulated by early CKD as shown by the expression of the critical transcription factor Runx2. The ligand associated with the klotho-fibroblast growth factor receptor complex, FGF23, was found to be expressed in the vascular media of sham-operated mice. Its expression was decreased in early CKD. Increased circulating levels of the osteocyte-secreted proteins, FGF23, and sclerostin may have been related to increased circulating klotho levels. Finally, we observed low-turnover bone disease with a reduction in bone formation rates more than bone resorption. Thus, the CKD–MBD, characterized by cardiovascular risk factors, vascular calcification, increased circulating klotho, FGF23 and sclerostin levels, and low-turnover renal osteodystrophy, was established in early CKD. Early CKD caused a reduction of vascular klotho, stimulated vascular osteoblastic transition, increased osteocytic secreted proteins, and inhibited skeletal modeling producing the CKD–MBD. The chronic kidney disease–mineral and bone disorder (CKD–MBD) syndrome is an extremely important complication of kidney diseases. The CKD–MBD was named in 2006,1.Moe S. Drueke T. Cunningham J. et al.Definition, evaluation, and classification of renal osteodystrophy: a position statement from Kidney Disease: Improving Global Outcomes (KDIGO).Kidney Int. 2006; 69: 1945-1953Abstract Full Text Full Text PDF PubMed Scopus (1457) Google Scholar following the realization that the mineral and skeletal disorders accompanying kidney failure are important contributors to the CKD-associated cardiovascular disease and high mortality rates.2.Go A.S. Chertow G.M. Fan D. et al.Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization.New Engl J Med. 2004; 351: 1296-1305Crossref PubMed Scopus (8983) Google Scholar, 3.Block G.A. Hulbert-Shearon T.E. Levin N.W. et al.Association of serum phosphorus and calcium X phosphate product with mortality risk in chronic hemodialysis patients: a national study.Am J Kidney Dis. 1998; 31: 607-617Abstract Full Text Full Text PDF PubMed Scopus (2110) Google Scholar, 4.Kestenbaum B. Sampson J.N. Rudser K.D. et al.Serum phosphate levels and mortality risk among people with chronic kidney disease.J Am Soc Nephrol. 2005; 16: 520-528Crossref PubMed Scopus (948) Google Scholar, 5.Keith D.S. Nichols G.A. Gullion C.M. et al.Longitudinal follow-up and outcomes among a population with chronic kidney disease in a large managed care organization.Arch Intern Med. 2004; 164: 659-663Crossref PubMed Scopus (1366) Google Scholar Recent studies have suggested that the CKD–MBD, defined as biochemical abnormalities in mineral metabolism, abnormalities in skeletal remodeling, and extraskeletal calcification, is present when the glomerular filtration is reduced by more than 40%.6.Moe S.M. Radcliffe J.S. White K.E. et al.The pathophysiology of early-stage chronic kidney disease–mineral bone disorder (CKD-MBD) and response to phosphate binders in the rat.J Bone Miner Res. 2011; 26: 2672-2681Crossref PubMed Scopus (74) Google Scholar Within the concept of the CKD–MBD, recent progress related to cardiovascular disease risk factors stimulated by kidney disease has uncovered three: vascular calcification, phosphorus, and fibroblast growth factor 23 (FGF23).7.Blacher J. Guerin A.P. Pannier B. et al.Arterial calcifications, arterial stiffness, and cardiovascular risk in end-stage renal disease.Hypertension. 2001; 38: 938-942Crossref PubMed Scopus (1234) Google Scholar, 8.London G.M. Guerin A.P. Marchais S.J. et al.Arterial media calcification in end-stage renal diseases: impact on all-cause and cardiovascular mortality.Nephrol Dial Transplant. 2003; 18: 1731-1740Crossref PubMed Scopus (1509) Google Scholar, 9.Hruska K. Mathew S. Lund R. et al.Cardiovascular risk factors in chronic kidney disease: does phosphate qualify?.Kidney Int. 2011; 79: S9-S13Abstract Full Text Full Text PDF Scopus (39) Google Scholar, 10.Gutierrez O.M. Mannstadt M. Isakova T. et al.Fibroblast growth factor 23 and mortality among patients undergoing hemodialysis.New Engl J Med. 2008; 359: 584-592Crossref PubMed Scopus (1408) Google Scholar, 11.Arnlov J. Carlsson A.C. Sundstrom J. et al.Higher fibroblast growth factor-23 increases the risk of all-cause and cardiovascular mortality in the community.Kidney Int. 2013; 83: 160-166Abstract Full Text Full Text PDF PubMed Scopus (116) Google Scholar Vascular calcification particularly poses an increased risk of cardiovascular and all-cause mortality,7.Blacher J. Guerin A.P. Pannier B. et al.Arterial calcifications, arterial stiffness, and cardiovascular risk in end-stage renal disease.Hypertension. 2001; 38: 938-942Crossref PubMed Scopus (1234) Google Scholar,12.Rennenberg R.J.M.W. Kessels A.G.H. Schurgers L.J. et al.Vascular calcifications as a marker of increased cardiovascular risk: a meta-analysis.Vasc Health Risk Manag. 2009; 5: 185-197Crossref PubMed Google Scholar and of the clinical conditions associated with vascular calcification, the most extensive calcifications occur in CKD.13.Moe S.M. Chen N.X. Pathophysiology of vascular calcification in chronic kidney disease.Circ Res. 2004; 95: 560-567Crossref PubMed Scopus (414) Google Scholar In CKD, vascular calcification is stimulated by hyperphosphatemia and positive calcium balance.14.Mathew S. Lund R. Strebeck F. et al.Reversal of the adynamic bone disorder and decreased vascular calcification in chronic kidney disease by sevelamer carbonate therapy.J Am Soc Nephrol. 2007; 18: 122-130Crossref PubMed Scopus (95) Google Scholar, 15.El-Abbadi M.M. Pai A.S. Leaf E.M. et al.Phosphate feeding induces arterial medial calcification in uremic mice: role of serum phosphorus, fibroblast growth factor-23, and osteopontin.Kidney Int. 2009; 75: 1297-1307Abstract Full Text Full Text PDF PubMed Scopus (179) Google Scholar, 16.Chen N.X. O’Neill K.D. Duan D. et al.Phosphorus and uremic serum up-regulate osteopontin expression in vascular smooth muscle cells.Kidney Int. 2002; 62: 1724-1731Abstract Full Text Full Text PDF PubMed Scopus (297) Google Scholar, 17.Shanahan C.M. Crouthamel M.H. Kapustin A. et al.Arterial calcification in chronic kidney disease: key roles for calcium and phosphate.Circ Res. 2011; 109: 697-711Crossref PubMed Scopus (630) Google Scholar, 18.Hill K.M. Martin B.R. Wastney M.E. et al.Oral calcium carbonate affects calcium but not phosphorus balance in stage 3-4 chronic kidney disease.Kidney Int. 2012; 83: 959-966Abstract Full Text Full Text PDF PubMed Scopus (186) Google Scholar Emerging data indicate that the CKD–MBD syndrome may begin early in the course of kidney disease and precede the development of clinically detectable abnormalities in plasma phosphorus (Pi), calcium (Ca), parathyroid hormone (PTH), and calcitriol, which are the hallmarks of the established CKD–MBD. Biomarkers of skeletal osteocyte function have been found to be abnormal early in kidney disease, both clinically and in translational models,6.Moe S.M. Radcliffe J.S. White K.E. et al.The pathophysiology of early-stage chronic kidney disease–mineral bone disorder (CKD-MBD) and response to phosphate binders in the rat.J Bone Miner Res. 2011; 26: 2672-2681Crossref PubMed Scopus (74) Google Scholar,19.Pereira R.C. Juppner H. Azucena-Serrano C.E. et al.Patterns of FGF-23, DMP1 and MEPE expression in patients with chronic kidney disease.Bone. 2009; 45: 1161-1168Abstract Full Text Full Text PDF PubMed Scopus (207) Google Scholar, 20.Fang Y. Zhang Y. Mathew S. et al.Early chronic kidney disease (CKD) stimulates vascular calcification (VC) and decreased bone formation rates prior to positive phosphate balance.J Am Soc Nephrol. 2009; 20: 36AGoogle Scholar, 21.Sabbagh Y. Graciolli F.G. O'Brien S. et al.Repression of osteocyte Wnt/β-catenin signaling is an early event in the progression of renal osteodystrophy.J Bone Miner Res. 2012; 27: 1757-1772Crossref PubMed Scopus (187) Google Scholar, 22.Oliveira R.B. Cancela A.L.E. Graciolli F.G. et al.Early control of PTH and FGF23 in normophosphatemic CKD patients: a new target in CKD-MBD therapy?.Clin J Am Soc Nephrol. 2010; 5: 286-291Crossref PubMed Scopus (306) Google Scholar, 23.Isakova T. Wahl P. Vargas G.S. et al.Fibroblast growth factor 23 is elevated before parathyroid hormone and phosphate in chronic kidney disease.Kidney Int. 2011; 79: 1370-1378Abstract Full Text Full Text PDF PubMed Scopus (920) Google Scholar indicating that kidney injury had affected the skeleton, in other words, the CKD–MBD had begun. Pereira et al.19.Pereira R.C. Juppner H. Azucena-Serrano C.E. et al.Patterns of FGF-23, DMP1 and MEPE expression in patients with chronic kidney disease.Bone. 2009; 45: 1161-1168Abstract Full Text Full Text PDF PubMed Scopus (207) Google Scholar found by skeletal immunocytochemistry and plasma levels that osteocyte production of FGF23 and dentin matrix protein-1 was increased in stage 2 CKD. These results were confirmed by Sabbagh et al.21.Sabbagh Y. Graciolli F.G. O'Brien S. et al.Repression of osteocyte Wnt/β-catenin signaling is an early event in the progression of renal osteodystrophy.J Bone Miner Res. 2012; 27: 1757-1772Crossref PubMed Scopus (187) Google Scholar and Oliveira et al.,22.Oliveira R.B. Cancela A.L.E. Graciolli F.G. et al.Early control of PTH and FGF23 in normophosphatemic CKD patients: a new target in CKD-MBD therapy?.Clin J Am Soc Nephrol. 2010; 5: 286-291Crossref PubMed Scopus (306) Google Scholar who also found that osteocyte sclerostin was increased in early CKD, and that osteocyte nuclear β-catenin was decreased, indicating decreased osteocyte Wnt activity in early CKD. As Wnt activity is the major skeletal anabolic principle of the postnatal skeleton,24.Babij P. Zhao W. Small C. et al.High bone mass in mice expressing a mutant LRP5 gene.J Bone Miner Res. 2003; 18: 960-974Crossref PubMed Scopus (442) Google Scholar,25.Little R.D. Carulli J.P. DelMastro R.G. et al.A mutation in the LDL receptor-related protein 5 gene results in the autosomal dominant high-bone-mass trait.Am J Hum Genet. 2002; 70: 11-19Abstract Full Text Full Text PDF PubMed Scopus (1084) Google Scholar these results indicate that kidney disease signals a decrease in bone formation. Fang et al.20.Fang Y. Zhang Y. Mathew S. et al.Early chronic kidney disease (CKD) stimulates vascular calcification (VC) and decreased bone formation rates prior to positive phosphate balance.J Am Soc Nephrol. 2009; 20: 36AGoogle Scholar showed, in a translational model of early CKD, elevated FGF23 levels in the presence of normal plasma Ca, Pi, PTH, and calcitriol, and a decrease in bone formation rates. These results confirmed earlier reports before FGF23 studies from our laboratory that when Ca, Pi, calcitriol, and PTH were maintained normal in CKD, decreased bone formation rates and the adynamic bone disorder were observed.26.Lund R.J. Davies M.R. Brown A.J. et al.Successful treatment of an adynamic bone disorder with bone morphogenetic protein-7 in a renal ablation model.J Am Soc Nephrol. 2004; 15: 359-369Crossref PubMed Scopus (87) Google Scholar However, it is unknown whether vascular calcification and renal osteodystrophy produced by kidney disease27.Mahmoodi B.K. Matsushita K. Woodward M. et al.Associations of kidney disease measures with mortality and end-stage renal disease in individuals with and without hypertension: a meta-analysis.Lancet. 2012; 380: 1649-1661Abstract Full Text Full Text PDF PubMed Scopus (329) Google Scholar,28.Fox C.S. Matsushita K. Woodward M. et al.Associations of kidney disease measures with mortality and end-stage renal disease in individuals with and without diabetes: a meta-analysis.Lancet. 2012; 380: 1662-1673Abstract Full Text Full Text PDF PubMed Scopus (737) Google Scholar are present in the early stages of the CKD–MBD. These studies were conducted to test the hypothesis that the CKD–MBD begins early in kidney disease, including the onset of heightened cardiovascular risk related to vascular calcification. We developed an animal model of early CKD using the atherosclerosis-bearing low-density lipoprotein–deficient mouse (ldlr-/-) fed high-fat, Western-type diets (40% of calories from fat). The phenotype of these mice is further characterized by insulin resistance progressing to type 2 diabetes over time. The mice respond as humans to atherosclerosis with neointimal plaque calcification that is stimulated by advanced CKD.29.Davies M.R. Lund R.J. Hruska K.A. BMP-7 is an efficacious treatment of vascular calcification in a murine model of atherosclerosis and chronic renal failure.J Am Soc Nephrol. 2003; 14: 1559-1567Crossref PubMed Scopus (178) Google Scholar Using inulin clearances to determine glomerular filtration rate (GFR), we staged CKD in mice and developed a model of CKD equivalent in GFR to stage 2 human CKD using unilateral renal injury and contralateral nephrectomy. This model mimics acute kidney injury (AKI) and incomplete recovery in humans with atherosclerosis and insulin resistance/diabetes. The peak GFR (representing a 25–40% decrease from normal GFR) established after recovery from AKI slowly diminished over weeks related to interstitial inflammation and fibrosis, allowing the development of the CKD–MBD. By using this model, we characterized the early CKD–MBD discovering stimulated vascular calcification in early CKD before hyperphosphatemia. The discovery of vascular calcification early in CKD produced a requisite search for mechanisms, and we discovered mesenchymal transition in vascular cells and newly recognized abnormalities in the arterial tree that cause vascular calcification, reduction of vascular klotho,30.Hu M.C. Shi M. Zhang J. et al.Klotho deficiency causes vascular calcification in chronic kidney disease.J Am Soc Nephrol. 2011; 22: 124-136Crossref PubMed Scopus (702) Google Scholar, 31.Voigt M. Fischer D-C. Rimpau M. et al.Fibroblast growth factor (FGF)-23 and fetuin-A in calcified carotid atheroma.Histopathology. 2010; 56: 775-788Crossref PubMed Scopus (33) Google Scholar, 32.Lim K. Lu T-S. Molostvov G. et al.Vascular klotho deficiency potentiates the development of human artery calcification and mediates resistance to fibroblast growth factor 23.Circulation. 2012; 125: 2243-2255Crossref PubMed Scopus (342) Google Scholar expression of FGF23, and increased circulating klotho (c-klotho). The elevations in c-klotho explain the early stimulation of skeletal osteocytes and FGF23 secretion independent of changes in the serum phosphorus. The overall experimental design is shown in Figure 1. The serum/plasma chemistries (blood urea nitrogen (BUN), Ca, Pi, and PTH) determined in the experimental groups are shown in Table 1. The BUN of wild-type and sham-operated mice ranged from 20 to 23mg/dl (Table 1). In mice with mild renal ablation, referred to in this paper as CKD-2, the mean BUN of the group was not elevated at 22 weeks and only increased to 24–30mg/dl at 28 weeks (CKD-2–28). Inulin clearances confirmed a 33% reduction in GFR in the 22-week ldlr-/- CKD-2 group (Figure 2). A 40% reduction from normal GFR is the low end of the GFR range in human stage 2 CKD. The CKD-2 animals were normocalcemic and normophosphatemic at 22 weeks (Table 1). In the 28-week CKD-2–28 animals, compatible with the slight progression of the kidney insufficiency, hyperphosphatemia had developed (12.7±3.9mg/dl). These findings are compatible with our previous findings of hyperphosphatemia in mice with more severe ablation and GFR in the human stage 3 CKD range.14.Mathew S. Lund R. Strebeck F. et al.Reversal of the adynamic bone disorder and decreased vascular calcification in chronic kidney disease by sevelamer carbonate therapy.J Am Soc Nephrol. 2007; 18: 122-130Crossref PubMed Scopus (95) Google Scholar,33.Davies M.R. Lund R.J. Mathew S. et al.Low turnover osteodystrophy and vascular calcification are amenable to skeletal anabolism in an animal model of chronic kidney disease and the metabolic syndrome.J Am Soc Nephrol. 2005; 16: 917-928Crossref PubMed Scopus (136) Google Scholar PTH levels were elevated to 120±48pg/ml in the CKD-2 animals at 22 weeks, but were only 90.8±20pg/ml at 28 weeks (not significantly different from the normal levels of the sham-operated animals). The elevation of PTH at 22 weeks in the CKD-2/3 groups following mild renal injury suggests that the elevation may have been related to changes associated with the AKI phase of the model. As shown in Figure 3a, longitudinal analysis of PTH levels demonstrated threefold elevations of PTH during the AKI phase (15 weeks, 1 week after surgery) that progressively diminished to levels insignificantly elevated from normal at 28 weeks.Table 1Serum and plasma chemistries and PTH levelsExperiment groupsBUN (mg/dl)Ca (mg/dl)Pi (mg/dl)PTH (pg/ml)WT, wild-type C57BL622.4±4.68.28±1.88.85±0.270.2±10.9Sham, ldlr-/- high fat20.6±3.78.96±0.87.92±2.374.5±35.4CKD-2, ldlr-/- high fat (22 weeks)21.1±2.87.94±1.28.8 ± 3.5120±48CKD-2–28 ldlr-/- high fat (28 weeks)27.5±4*#8.8±1.412.7±3.9*#90.8±20CKD-3 ldlr-/- high fat (22 weeks)43.7±7.5*#10.8±0.7*#11.78±1.9*#NACKD-3–28 ldlr-/- high fat (28 weeks)53.3±13.4*#11.13±1.5*#13±2.7*#467±125*#Abbreviations: BUN, blood urea nitrogen; Ca, calcium; CKD, chronic kidney disease; ldlr-/- low-density lipoprotein–deficient; NA, not available; Pi, phosphorus; PTH, parathyroid hormone; WT, wild type.*P<0.01 compared with sham.#P<0.01 compared with CKD-2.Number of animals per group ‘N=8–21.’ Open table in a new tab Figure 2Inulin clearances in low-density lipoprotein–deficient(ldlr-/-) high fat–fed mice. Sham-operated mice had inulin clearances of 0.006ml/min/g. The mild renal injury group (chronic kidney disease (CKD)-2) had reductions in inulin clearance (glomerular filtration rate (GFR)) up to 40% (mean 33%) of the sham-operated control levels. The blood urea nitrogen (BUN) levels were not different between sham-operated and CKD-2 mice. More severe renal injury (CKD-3) produced inulin clearance reductions of 75% in CKD-3 mice and elevations in BUN levels to the 45mg/dl range. Inulin clearances and BUN levels were determined at 22 weeks of age.View Large Image Figure ViewerDownload (PPT)Figure 3Longitudinal analysis of parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23) levels in low-density lipoprotein–deficient(ldlr-/-) high fat–fed mice with chronic kidney disease (CKD)-2 and CKD-2–28, and FGF23 levels in ldlr-/-high fat–fed mice with CKD-2–28 and CKD-3–28. (a, b) CKD was established at 14 weeks of age as described in methods and Figure 1. Plasma was obtained at 15, 22, and 28 weeks. FGF23 was measured using an intact hormone assay (Kainos). (c, d) Two different enzyme-linked immunosorbent assays (ELISAs) for FGF23, an intact hormone assay and a C-terminal assay, as described in Materials and Methods, were used to determine the effects of CKD on FGF23 levels in the circulation. FGF23 levels in C57Bl6J wild-type (WT) mice were measured to establish the reference range. FGF23 levels measured using the intact hormone assay were increased in CKD-3–28 mice compared with CKD-2–28, but not when the C-terminal assay was used.View Large Image Figure ViewerDownload (PPT) Abbreviations: BUN, blood urea nitrogen; Ca, calcium; CKD, chronic kidney disease; ldlr-/- low-density lipoprotein–deficient; NA, not available; Pi, phosphorus; PTH, parathyroid hormone; WT, wild type. *P<0.01 compared with sham. #P<0.01 compared with CKD-2. Number of animals per group ‘N=8–21.’ Plasma FGF23 levels measured by the Kainos intact hormone assay were elevated by CKD-2 (Figure 3b). FGF23 levels progressively increased from 15 to 22 weeks in the face of normophosphatemia, and continued to rise with the development of hyperphosphatemia in CKD-2–28 instead of diminishing, similar to PTH levels, which was compatible with FGF23 being the basis for the decrease in PTH levels.34.Ben-Dov I.Z. Galitzer H. Lavi-Moshayoff V. et al.The parathyroid is a target organ for FGF23 in rats.J Clin Invest. 2007; 117: 4003-4008PubMed Google Scholar The use of a domestic FGF23 assay detecting the C-terminus of FGF23 (Immunotopics, Stillwater, MN) demonstrated elevated levels similar to the intact hormone assay at 28 weeks in the CKD-2–28 group (Figure 3c and d). These results suggest the role of FGF23 in maintaining phosphate homeostasis in early CKD. Aortic and large artery calcification is a critical component of the CKD–MBD, producing vascular stiffness and increased cardiovascular disease in CKD.35.London G.M. Cardiovascular calcifications in uremic patients: clinical impact on cardiovascular function.J Am Soc Nephrol. 2003; 14: S305-S309Crossref PubMed Google Scholar Vascular calcification in the CKD-2 mice was studied by histology and determination of the aortic Ca content in mg/g dry weight. The CKD-2–28 mice had aortic medial narrowing and advential hyperplasia, but there was no clear evidence of Ca deposition in the media by Alizarin red (Figure 4) or the less sensitive von Kossa (not shown) staining. Aortic Ca content was significantly increased in the CKD-2–28 mice compared with the sham-operated control mice (Figure 4b), and we observed detectable increases in the neointimal atherosclerotic plaque Ca deposits as shown below for the CKD-3–28 mice similar to that previously reported in stage 4 CKD.29.Davies M.R. Lund R.J. Hruska K.A. BMP-7 is an efficacious treatment of vascular calcification in a murine model of atherosclerosis and chronic renal failure.J Am Soc Nephrol. 2003; 14: 1559-1567Crossref PubMed Scopus (178) Google Scholar Osteoblastic transition of neointimal cells in atherosclerotic lesions has been shown to be critical in the pathogenesis of vascular calcification stimulated by CKD-3–28 in the ldlr-/- high fat–fed mouse model,36.Mathew S. Tustison K.S. Sugatani T. et al.The mechanism of phosphorus as a cardiovascular risk factor in chronic kidney disease.J Am Soc Nephrol. 2008; 19: 1092-1105Crossref PubMed Scopus (203) Google Scholar and other studies using different models have shown that osteoblastic transition is involved in medial calcification.13.Moe S.M. Chen N.X. Pathophysiology of vascular calcification in chronic kidney disease.Circ Res. 2004; 95: 560-567Crossref PubMed Scopus (414) Google Scholar,37.Speer M.Y. Yang H.Y. Brabb T. et al.Smooth muscle cells give rise to osteochondrogenic precursors and chondrocytes in calcifying arteries.Circ Res. 2009; 104: 733-741Crossref PubMed Scopus (431) Google Scholar,38.Shanahan C.M. Cary N.R.B. Salisbury J.R. et al.Medial localization of mineralization-regulating proteins in association with Monckeberg’s sclerosis: evidence for smooth muscle cell-mediated vascular calcification.Circulation. 1999; 100: 2168-2176Crossref PubMed Scopus (572) Google Scholar Therefore, we examined whether cells in the aortas of our mice with early CKD expressed evidence of osteoblastic transition. The critical osteoblast transcription factor Runx2 has been shown to be expressed in calcifying vessels, and it serves as the hallmark of osteoblastic transition of cells in the vasculature. We found Runx2 to be strongly expressed in the aortas of our CKD-2–28 mice (Figure 5a). Furthermore, as osteocytes differentiate from osteoblasts, and osteocytes are the main source of FGF23, we examined aortas for FGF23 expression. As shown in Figure 5b, there was significant expression of FGF23 in the aortas of our sham-operated ldlr-/- high fat–fed mice, which was reduced by CKD-2 induction. Immunohistochemical analysis of aortic FGF23 expression (Figure 5c) revealed occasional cells in the aortic media of sham-operated mice positive for FGF23. This was lost in the media of CKD-2 mice, replaced by increased advential staining of unknown nature. An advential reaction was also detected when a nonspecific IgG (Total IgG) was used in place of the primary antibody (Figure 5c), but it was clearly distinct from the strong reactivity induced by CKD. As the advential reaction exactly matched the immunolocalization of FGFR1 (not shown), one possibility is that this reaction represented FGF23 from the circulation bound to its receptor. The expression of the FGF23/klotho hormonal axis in the aorta was further examined by analysis of klotho expression in the aorta. As shown in Figure 5a, there was significant expression of klotho in the sham-operated control mice, and induction of CKD-2 markedly decreased klotho expression. These results are in agreement with the recent findings of klotho expression in human vascular media by Lim et al.32.Lim K. Lu T-S. Molostvov G. et al.Vascular klotho deficiency potentiates the development of human artery calcification and mediates resistance to fibroblast growth factor 23.Circulation. 2012; 125: 2243-2255Crossref PubMed Scopus (342) Google Scholar As shown in Figure 5c, compared with FGF23, which was expressed in occasional cells and decreased by CKD stage 2, α-klotho was strongly expressed in the media of aortas of wild-type and sham-operated ldlr-/- high fat–fed mice, and severely depressed in the media of mice with CKD stage 2. In contrast to the reduction in α-klotho in the vasculature, the circulating hormonal form of klotho, cut klotho or c-klotho, which derives from proteolytic cleavage of renal distal tubular α-klotho,39.Smith R.C. O’Bryan L.M. Farrow E.G. et al.Circulating αKlotho influences phosphate handling by controlling FGF23 production.J Clin Invest. 2012; 122: 4710-4715Crossref PubMed Scopus (121) Google Scholar was elevated several fold in the CKD-2 mice (Figure 5d). The skeletons of the CKD-2–28 mice were analyzed by micro-computed tomography scanning and histomorphometry of trabecular bone. Significant trabecular osteodystrophy was discovered in the ldlr-/- high fat–fed sham-operated mice that produced a decrease in trabecular bone volume and trabecular number and thickness (Supplementary Figure S1 online). The osteodystrophy was affected by CKD-2–28 through a decrease in total area. Histomorphometric analysis confirmed the osteodystrophy of the sham-operated ldlr-/- high fat–fed mice, and demonstrated the effects of CKD-2–28. Bone formation rates/bone surface were 2.29±1.49mm3/cm2 per year in 28-week-old wild-type C57Bl6J mice used as the normal reference. They were 1.64±0.67mm3/cm2 per year in the sham-operated ldlr-/- high fat–fed control mice and 0.87mm3/cm2 per year in the CKD-2–28 mice (P<0.05 compared with the sham). Download .jpg (.05 MB) Help with files Supplementary Figure 1 A cortical bone osteodystrophy was also observed by micro-computed tomography in the ldlr-/- high fat–fed sham-operated mice. The osteodystrophy was worsened by the induction of stage 2 CKD characterized by cortical bone thinning (loss of total volume) and porosity (decrease in BMD; Figure 6). In mice undergoing more severe renal ablation and reduction of GFR to levels equal to human stage 3 CKD (CKD-3, and CKD-3–28), the BUN levels were increased to between 35 and 55mg/dl (Table 1), and the animals were hypercalcemic. PTH levels in the CKD-3–28 mice were very high compared with the near-normal levels observed in CKD-2–28 mice (Table 1). FGF23 levels were significantly more elevated in the CKD-3–28 mice than in the CKD-2–28 mice using the intact hormone assay, whereas the C-terminal assay results were similar to CKD-2–28 values (Figure 3c and d). CKD-3–28 significantly increased the number and size of aortic neointimal plaque calcifications without p" @default.
• W2031567798 created "2016-06-24" @default.
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• W2031567798 date "2014-01-01" @default.
• W2031567798 modified "2023-10-02" @default.
• W2031567798 title "Early chronic kidney disease–mineral bone disorder stimulates vascular calcification" @default.
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