Cinacalcet suppresses calcification of the aorta and heart in uremic rats

Kawata, Takehisa; Nagano, Nobuo; Obi, Masaki; Miyata, Sonoe; Koyama, Chika; Kobayashi, Nobuhiko; Wakita, Sachiko; Wada, Michihito

doi:10.1038/ki.2008.407

Cited by 102 publications

(73 citation statements)

References 28 publications

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“…Findings in tissues different from kidney may support this hypothesis because a decreased CASR expression was observed in human calcified arteries and CASR activation may prevent calcium phosphate precipitation in arterial walls of uremic rats (24,25). Therefore, the loss of CASR expression might expose the hypertonic interstitium of the kidney papillae to the risk of calcification as Randall's plaque (23).…”

Section: Discussionsupporting

confidence: 58%

Polymorphisms at the regulatory regions of the CASR gene influence stone risk in primary hyperparathyroidism

Vezzoli¹,

Scillitani²,

Corbetta³

et al. 2011

European Journal of Endocrinology

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Background and objective: Single nucleotide polymorphisms (SNPs) of the calcium-sensing receptor (CASR) gene at the regulatory region were associated with idiopathic calcium nephrolithiasis. To confirm their association with nephrolithiasis, we tested patients with primary hyperparathyroidism (PHPT). Design: A genotype-phenotype association study. Methods: In all, 332 PHPT patients and 453 healthy controls were genotyped for the rs7652589 (GOA) and rs1501899 (GOA) SNPs sited in the noncoding regulatory region of the CASR gene. Allele, haplotype, and diplotype distribution were compared between PHPT patients and controls, and in stone forming and stone-free PHPT patients. Results: The allele frequency at rs7652589 and rs1501899 SNPs was similar in PHPT patients and controls. The A minor alleles at these two SNPs were more frequent in stone forming (nZ157) than in stone-free (nZ175) PHPT patients (rs7652589: 36.9 vs 27.1%, PZ0.007; rs1501899: 37.1 vs 26.4%, PZ0.003). Accordingly, homozygous or heterozygous PHPT patients for the AA haplotype (nZ174, AA/AA or AA/GG diplotype) had an increased stone risk (odds ratio 1.83, 95% confidence interval 1.2-2.9, PZ0.008). Furthermore, these PHPT patients had higher serum concentrations of ionized calcium and parathyroid hormone (1.50G0.015 mmol/l and 183G12.2 pg/ml) than patients with the GG/GG diplotype (nZ145, 1.47G0.011 mmol/l (PZ0.04) and 150G11.4 pg/ml (PZ0.049)). Using a logistic regression model, the increase in stone risk in PHPT patients was predicted by AA/AA or AA/GG diplotype, the highest tertile of serum ionized calcium values and the lowest tertile of age. Conclusions: Polymorphisms located in the regulatory region of the CASR gene may increase susceptibility of the PHPT patients to kidney stone production.

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Section: Discussionsupporting

confidence: 58%

Polymorphisms at the regulatory regions of the CASR gene influence stone risk in primary hyperparathyroidism

Vezzoli¹,

Scillitani²,

Corbetta³

et al. 2011

European Journal of Endocrinology

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“…We measured the calcium content in the tissues according to the modified method described by Kawata et al [22]. Tissue samples from the aorta were collected and frozen at -20°C until analysis.…”

Section: Methodsmentioning

confidence: 99%

Ferric Citrate Hydrate, a New Phosphate Binder, Prevents the Complications of Secondary Hyperparathyroidism and Vascular Calcification

et al. 2013

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Background/Aims: Ferric citrate hydrate (JTT-751) is being developed as a treatment for hyperphosphatemia in chronic kidney disease patients, and shows serum phosphorus-reducing effects on hyperphosphatemia in hemodialysis patients. We examined whether JTT-751 could reduce phosphorus absorption in normal rats and prevent the progression of ectopic calcification, secondary hyperparathyroidism and bone abnormalities in chronic renal failure (CRF) rats. Methods: Normal rats were fed a diet containing 0.3, 1 or 3% JTT-751 for 7 days. The effects of JTT-751 on phosphorus absorption were evaluated with fecal and urinary phosphorus excretion. Next, a CRF model simulating hyperphosphatemia was induced by feeding rats a 0.75% adenine diet. After 21 days of starting the adenine diet feeding, 1 or 3% JTT-751 was administered for 35 days by dietary admixture. The serum phosphorus levels and mineral parameters were measured. Calcification in the aorta was examined biochemically and histopathologically. Hyperparathyroidism and bone abnormalities were evaluated by histopathological analysis of the parathyroid and femur, respectively. Results: In normal rats, JTT-751 increased fecal phosphorus excretion and reduced phosphorus absorption and urinary phosphorus excretion. In CRF rats, JTT-751 reduced serum phosphorus levels, the calcium-phosphorus product and calcium content in the aorta. Serum intact parathyroid hormone levels and the incidence and severity of parathyroid hyperplasia were also decreased. JTT-751 reduced femoral bone fibrosis, porosity and osteoid formation. Conclusions: JTT-751 could bind with phosphate in the gastrointestinal tract, increase fecal phosphorus excretion and reduce phosphorus absorption. JTT-751 could prevent the progression of ectopic calcification, secondary hyperparathyroidism and bone abnormalities in rats.

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“…77 Lactose has been shown to increase calcium and phosphorus absorption in the intestine. 78,79 Se-vere medial calcifications were reported with aortic calcium concentrations of approximately 25 mg/g dry tissue.…”

Section: Remnant Kidney Ratmentioning

confidence: 99%

“…In accordance with medial calcification in human vessels, 101,102 no local vascular inflammation is detected, the media thickness is increased and osteochondrogenic cells around calcified foci are observed in uremic rat models. 70,77,102 Experiments aiming to investigate the efficiency of therapies on medial calcification should optimally use rodent models that develop consistent, robust medial calcification in all animals within a relative short time period as seen in the adenine-induced CRF rat model either on a low protein diet or treated with low dose vitamin D 3 , or 5/6th nephrectomized rats administered high doses of vitamin D 3 . Alternatively, experimental models showing a high biological variability with respect to the severity of arterial calcification might be applied to define and analyze determinants of vascular calcification and to get a better insight into the molecular evolution of the calcification process.…”

Section: The Adenine-induced Chronic Renal Failure Ratmentioning

confidence: 99%

Vascular Calcification in Chronic Renal Failure

Neven

D’Haese

2011

Circulation Research

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Accelerated atherosclerotic plaque calcification and extensive medial calcifications are common and highly detrimental complications of chronic kidney disease. Valid murine models have been developed to investigate both pathologically distinguishable complications, which allow for better insight into the cellular mechanisms underlying these vascular pathologies and evaluation of compounds that might prevent or retard the onset or progression of vascular calcification. This review describes various experimental models that have been used for the study of arterial intimal and/or medial calcification and discusses the extent to which this experimental research has contributed to our current understanding of vascular calcification, particularly in the setting of chronic renal failure. (Circ Res. 2011;108:249-264.) Key Words: animal models Ⅲ vascular calcification Ⅲ chronic renal failure C ardiovascular disease is the main cause of morbidity and mortality in patients with chronic kidney disease (CKD), accounting for approximately 50% of all deaths in patients on dialysis and in recipients of renal transplants. 1 A large-scale prospective population-based study showed that renal function was inversely associated with cardiovascular and allcause mortality. 2 Vascular calcification is the major cause of cardiovascular disease in patients with CKD as it contributes to myocardial ischemia, impaired myocardial function, valvular insufficiency, arrhythmias and stroke and is shown to be a strong independent predictor of mortality in the general 3,4 as well as in the dialysis population. [5][6][7] In patients with endstage renal disease, the risk of death increases with the number of vascular sites affected by calcification in the aorta and the carotid and femoral arteries. 5 The high prevalence of vascular calcification is already reported in early stages of CKD 8,9 and in young dialysis patients. 10,11 Atherosclerotic plaque burden in the intimal layer is higher and these lesions are also more heavily calcified in CKD patients compared to the normal population. 12-14 Although intimal calcification is associated with cardiovascular mortality, 6 it remains controversial whether calcification of advanced atherosclerotic lesions stabilizes plaque vulnerability [15][16][17] or rather contributes to rupture of the fibrous cap, 18,19 leading to thrombotic events and myocardial infarction. Interestingly, Ehara et al 20 nicely showed that the pattern of calcification in the intimal plaque is of importance: small, frequent, spotty calcifications are more often found in patients with an acute myocardial infarction or with unstable angina pectoris, whereas the presence of extensive calcifications was highest in those with stable angina pectoris. Recent investigations add new insights to this observation and indicate that, in contrast to spacious calcified areas, sparse microcalcifications produce local stress, 21 activate macrophages to secrete inflammatory mediators 22 and induce apoptosis of vascular smooth muscle cells, 23...

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Cinacalcet suppresses calcification of the aorta and heart in uremic rats

Cited by 102 publications

References 28 publications

Polymorphisms at the regulatory regions of the CASR gene influence stone risk in primary hyperparathyroidism

Polymorphisms at the regulatory regions of the CASR gene influence stone risk in primary hyperparathyroidism

Ferric Citrate Hydrate, a New Phosphate Binder, Prevents the Complications of Secondary Hyperparathyroidism and Vascular Calcification

Vascular Calcification in Chronic Renal Failure

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