Calcimimetic Compound Upregulates Decreased Calcium-Sensing Receptor Expression Level in Parathyroid Glands of Rats with Chronic Renal Insufficiency

Mizobuchi, Masahide; Hatamura, Ikuji; Ogata, Hiroaki; Saji, Fumie; Uda, Susumu; Shiizaki, Kazuhiro; Sakaguchi, Toshifumi; Negi, Shigeo; Kinugasa, Eriko; Koshikawa, Shozo; Akizawa, Tadao

doi:10.1097/01.asn.0000141016.20133.33

Cited by 104 publications

(67 citation statements)

References 34 publications

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“…40 Although in uremia, the CaSR expression is reduced in the parathyroid gland, 41 it was not altered in the myocardium after SNX. Similar to what is seen in the parathyroid glands, 42 the CaSR expression was increased in this study after administration of the calcimimetic.…”

Section: Discussionsupporting

confidence: 73%

Interstitial fibrosis and microvascular disease of the heart in uremia: amelioration by a calcimimetic

Koleganova

Piecha

Ritz

et al. 2009

Laboratory Investigation

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In patients with chronic renal failure, the heart undergoes remodeling, characterized by hypertrophy, fibrosis, and capillary/myocyte mismatch. In this study, we observed the effects of the calcimimetic agent R-568 on microvascular disease and interstitial fibrosis of the heart. Three-month-old male Sprague-Dawley rats were randomized to subtotal nephrectomy (SNX) or sham operation and subsequently received vehicle or R-568 under two experimental protocols, one for 1 month and the other for 3 months. Echocardiography, capillary length density, volume density of interstitial tissue, and immunohistochemistry and western blots (calcium-sensing receptor, collagen I and III, transforming growth factor (TGF)-b, mitogen-activated protein kinases, and nitrotyrosine) were assessed. After SNX, weight and wall thickness of the left and the right ventricle were elevated. The ratio of heart to body weight and interventricular septum thickness were not changed by R-568 treatment. The left ventricle fractional shortening (by echocardiography) was lower in SNX; this was ameliorated by R-568. Reduced capillary length density and increased interstitial fibrosis in SNX were improved by R-568, which also reduced the expression of TGF-b, and collagen I and III. The calcimimetic increased the activation of ERK-1/2, normalized p38 and JNK signaling, and prevented oxidative stress. We conclude that lowering parathyroid hormone with a calcimimetic significantly improves cardiac histology and function but not the left ventricular mass in SNX.

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Section: Discussionsupporting

confidence: 73%

Interstitial fibrosis and microvascular disease of the heart in uremia: amelioration by a calcimimetic

Koleganova

Piecha

Ritz

et al. 2009

Laboratory Investigation

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“…This is not, however, surprising because experimental studies have shown that CaSR signaling to suppress PTH secretion is largely preserved in vitro, even in the setting of reduced CaSR expression (32). Cinacalcet therapy has also been shown to upregulate the expressions of VDR (33) and CaSR (34), which may facilitate the inhibitory effects of vitamin D sterols and cinacalcet on PTH secretion in these patients.…”

Section: Discussionmentioning

confidence: 99%

Cinacalcet Effectively Reduces Parathyroid Hormone Secretion and Gland Volume Regardless of Pretreatment Gland Size in Patients with Secondary Hyperparathyroidism

Komaba¹,

Nakanishi²,

Fujimori³

et al. 2010

Clinical Journal of the American Society of Nephrology

127

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Background and objectives: Cinacalcet is effective in reducing serum parathyroid hormone (PTH) in patients with secondary hyperparathyroidism. However, it has not been proven whether parathyroid gland size predicts response to therapy and whether cinacalcet is capable of inducing a reduction in parathyroid volume.Design, setting, participants, & measurements: This 52-week, multicenter, open-label study enrolled hemodialysis patients with moderate to severe secondary hyperparathyroidism (intact PTH >300 pg/ml). Doses of cinacalcet were adjusted between 25 and 100 mg to achieve intact PTH <180 pg/ml. Ultrasonography was performed to measure the parathyroid gland size at baseline, week 26, and week 52. Findings were also compared with those of historical controls.Results: Of the 81 subjects enrolled, 56 had parathyroid glands smaller than 500 mm 3 (group S) and 25 had at least one enlarged gland larger than 500 mm 3 (group L). Treatment with cinacalcet effectively decreased intact PTH by 55% from baseline in group S and by 58% in group L. A slightly greater proportion of patients in group S versus group L achieved an intact PTH <180 pg/ml (46 versus 32%) and a >30% reduction from baseline (88 versus 78%), but this was not statistically significant. Cinacalcet therapy also resulted in a significant reduction in parathyroid gland volume regardless of pretreatment size, which was in sharp contrast to historical controls (n ‫؍‬ 87) where parathyroid gland volume progressively increased with traditional therapy alone.Conclusions: Cinacalcet effectively decreases serum PTH levels and concomitantly reduces parathyroid gland volume, even in patients with marked parathyroid hyperplasia.

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“…The same was seen in the tubulointerstitium by immunohistochemistry. The changes in glomerular CaSR expression correspond to changes observed by others in the parathyroid glands (9,14).…”

Section: Discussionmentioning

confidence: 99%

Calcimimetic R-568 or calcitriol: equally beneficial on progression of renal damage in subtotally nephrectomized rats

Piecha¹,

Kökény²,

Nakagawa³

et al. 2008

American Journal of Physiology-Renal Physiology

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Patients with renal insufficiency develop secondary hyperparathyroidism. Monotherapy with active vitamin D or calcimimetics ameliorates secondary hyperparathyroidism. We compared kidney damage in subtotally nephrectomized (SNX) rats treated with active vitamin D (calcitriol) or the calcimimetic R-568. Male Sprague-Dawley SNX and sham-operated (sham-op) rats were randomized into the following treatment groups: SNX ϩ R-568, SNX ϩ calcitriol, SNX ϩ vehicle, sham-op ϩ R-568, sham-op ϩ calcitriol, and sham-op ϩ vehicle. Albuminuria and blood pressure were monitored and kidneys were examined using morphometry, immunohistochemistry, quantitative RT-PCR, and in situ hybridization. Parathyroid hormone concentrations were lowered to the same extent by the two interventions, although phosphorus and the calcium-phosphorus product were reduced only by R-568 treatment. SNX rats developed marked albuminuria, which was significantly reduced in ad libitum-and pair-fed animals treated with R-568 and animals treated with calcitriol. Mean glomerular volume (6.05 Ϯ 1.46 vs. 2.70 Ϯ 0.91 mm 3 ), podocyte volume (831 Ϯ 127 vs. 397 Ϯ 67 m 3 ), the degree of foot process fusion (mean width of foot processes ϭ 958 Ϯ 364 vs. 272 Ϯ 35 nm), and glomerular basement membrane thickness (244 Ϯ 6 vs. 267 Ϯ 23 nm), as well as desmin staining, were significantly higher in vehicletreated SNX than sham-operated animals. These changes were ameliorated with R-568 and calcitriol. In SNX, as well as sham-operated, animals, expression of the calcium-sensing receptor (protein and mRNA) was upregulated by treatment with the calcimimetic, but not calcitriol. Calcitriol and R-568 were similarly effective in ameliorating kidney damage. secondary hyperparathyroidism; chronic renal failure; nephroprotection; calcimimetics; calcitriol SECONDARY HYPERPARATHYROIDISM (sHPT) is a common feature of chronic kidney disease. Parathyroid hormone (PTH) concentrations increase progressively with diminishing glomerular filtration rate, but it is unclear whether PTH per se modifies progression.Active metabolites of vitamin D are widely used to control sHPT. Moreover, beneficial effects of active vitamin D on progression of chronic kidney disease have been documented (13,19).A therapeutic alternative is the use of calcimimetics (R-568 and, in humans, cinacalcet HCl), allosteric activators of the calcium-sensing receptor (CaSR), which reduce PTH secretion and interfere with parathyroid hyperplasia (4,20,22). In addition, however, Ogata et al. (17) showed that short-term treatment with R-568 reduces albuminuria and attenuates glomerular and tubulointerstitial lesions in subtotally nephrectomized (SNX) rats.The present study was designed to compare the effect of the two interventions on albuminuria and morphological lesions of the kidney in the SNX rat. The readouts were morphology and ultrastructure of podocytes, glomerulosclerosis index (GSI), and tubulointerstitial damage index, as well as expression profile of TGF-␤1, endothelin-1 (ET-1), and VEGF using immunohistochemistry a...

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Calcimimetic Compound Upregulates Decreased Calcium-Sensing Receptor Expression Level in Parathyroid Glands of Rats with Chronic Renal Insufficiency

Cited by 104 publications

References 34 publications

Interstitial fibrosis and microvascular disease of the heart in uremia: amelioration by a calcimimetic

Interstitial fibrosis and microvascular disease of the heart in uremia: amelioration by a calcimimetic

Cinacalcet Effectively Reduces Parathyroid Hormone Secretion and Gland Volume Regardless of Pretreatment Gland Size in Patients with Secondary Hyperparathyroidism

Calcimimetic R-568 or calcitriol: equally beneficial on progression of renal damage in subtotally nephrectomized rats

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