maxacalcitol and Disease-Models--Animal

Left ventricular hypertrophy (LVH) is a cardiovascular complication highly prevalent in patients with chronic kidney disease (CKD). Previous studies analyzing 1α-hydroxylase or vitamin D receptor (Vdr) knockout mice revealed active vitamin D as a promising agent inhibiting LVH progression. Paricalcitol, an active vitamin D analog, failed to suppress the progression of LV mass index (LVMI) in pre-dialysis patients with CKD. As target genes of activated VDR differ depending on its agonists, we examined the effects of maxacalcitol (22-oxacalcitriol: OCT), a less calcemic active vitamin D analog, on LVH in hemodialysis patients and animal LVH models with renal insufficiency.. In retrospective cohort study, patients treated with OCT who underwent hemodialysis were enrolled. Using cardiac echocardiography, LV mass was evaluated by the area-length method. In animal study, angiotensin II (Ang II)-infused Wister rats with heminephrectomy or Ang II-stimulated neonatal rat ventricular myocytes (NRVM) were treated with OCT.. OCT significantly inhibited the progression of LVMI in hemodialysis patients. In Ang II-infused heminephrectomized rats, OCT suppressed the progression of LVH in a blood pressure-independent manner. OCT also suppressed the activity of calcineurin in the left ventricle of model rats. Specifically, OCT reduced the protein levels of calcineurin A, but not the mRNA levels of Ppp3ca (calcineurin Aα). Luciferase assays showed that OCT increased the promoter activity of Fbxo32 (atrogin1), an E3 ubiquitin ligase targeting calcineurin A. Finally, OCT promoted ubiquitination and degradation of calcineurin A.. Our works indicated that OCT retards progression of LVH through calcineurin-NFAT pathway, which reveal a novel aspect of OCT in attenuating pathological LVH.

Topics: Aged; Animals; Calcineurin; Calcitriol; Cell Culture Techniques; Disease Models, Animal; Female; Humans; Hypertrophy, Left Ventricular; Male; Middle Aged; Myocytes, Cardiac; NFATC Transcription Factors; Pregnancy; Rats; Rats, Wistar; Renal Insufficiency; Retrospective Studies

The aim of this study was to explore whether 22-oxacalcitriol could protect inflammatory response induced by ischemia-reperfusion injury (IRI) in rats, and to investigate its underlying mechanism.. 24 male Sprague Dawley rats were randomly assigned into the sham group, the IRI group and the 22-oxacalcitriol group, with 8 rats in each group. Serum and heart samples of each rat were collected 10 days after the animal procedure. The serum levels of creatine kinase-MB (CK-MB) and lactate dehydrogenase (LDH) in each rat were detected by relative commercial kits. Pathological lesions in rat myocardium were observed by hematoxylin and eosin (HE) staining. Cardiomyocyte apoptosis in rat heart was accessed by TUNEL staining. Meanwhile, the serum levels of tumor necrosis factor-α (TNF-α), interleukin 1 beta (IL-1β), interleukin-6 (IL-6), and KC-GRO were detected by Real Time-quantitative Polymerase Chain Reaction (RT-qPCR). Also, the protein expression levels of NF-κB, TNF-α, VCAM-1, ICAM-1, and MCP-1 in rat myocardium were detected by Western blot and immunohistochemistry.. The serum levels of CK-MB and LDH in rats of the IRI group were significantly higher than those of the sham group. 22-oxacalcitriol treatment remarkably decreased the serum levels of CK-MB and LDH when compared with the IRI group. However, cardiomyocyte apoptosis of the 22-oxacalcitriol group was markedly less than the IRI group. The activities of SOD, GSH, CAT and T-AOC in the cardiac homogenate of the 22-oxacalcitriol group were significantly elevated than those of the IRI group. Meanwhile, malondialdehyde (MDA) and reactive oxygen species (ROS) levels were remarkably decreased by 22-oxacalcitriol treatment. Furthermore, the serum levels of TNF-α, IL-1β, IL-6 and KC-GRO were significantly downregulated in the 22-oxacalcitriol group. Western blot results showed that the protein expression levels of NF-κB, TNF-α, VCAM-1, ICAM-1 and MCP-1 in the 22-oxacalcitriol group were significantly lower than those of the IRI group.. 22-oxacalcitriol inhibits the inflammatory response in the myocardium by suppressing NF-kB/TNF-α pathway, thereby protecting myocardial ischemia-reperfusion injury in rats.

Topics: Animals; Apoptosis; Calcitriol; Cardiotonic Agents; Disease Models, Animal; Down-Regulation; Heart; Humans; Male; Myocardial Reperfusion Injury; Myocardium; Myocytes, Cardiac; NF-kappa B; Rats; Signal Transduction; Tumor Necrosis Factor-alpha

In this study, we investigated the effects of direct injection (DI) of calcitriol or maxacalcitol into the hyperplastic parathyroid gland (PTG) on altered gene expression related to the advanced status of secondary hyperparathyroidism (SHPT).. Sprague-Dawley rats were 5/6-nephrectomized (uremic) or sham-operated (normal). In each uremic rat, one of the bilateral PTG was treated by DI of calcitriol (PTG(CAL)) or maxacalcitol (PTG(OCT)), and the other gland was treated with control solution (PTG(CONT)). The PTG were evaluated for levels of expression of various mRNA and immunohistochemical staining of proliferating cell nuclear antigen (PCNA).. Significant differences in levels of expression of mRNA and PCNA were confirmed between the uremic and normal groups. In PTG(CAL) and PTG(OCT), expressions of almost all mRNA and PCNA were significantly improved; both agents were able to normalize the abnormalities of the uremic PTG, in contrast to the baseline and individual PTG(CONT). However, the difference in effect between PTG(CAL) and PTG(OCT) was only small.. Our results suggest that very high concentrations of calcitriol or maxacalcitol in the PTG improve abnormal gene expression and proliferation activity of parathyroid cells, and might explain the better control of SHPT using the DI technique.

Topics: Animals; Calcitriol; Disease Models, Animal; Dose-Response Relationship, Drug; Gene Expression; Hyperparathyroidism, Secondary; Hyperplasia; Male; Nephrectomy; Parathyroid Glands; Parathyroid Hormone; Rats; Rats, Sprague-Dawley; Uremia; Vitamins

Injection of maxacalcitol (OCT) directly into the parathyroid gland (PTG) is a clinically safe and effective treatment for advanced secondary hyperparathyroidism (A-SHPT) resistant to conventional medical treatment. In the present study, the degree of nuclear localization of directly injected OCT in parathyroid cells (PTC) was investigated by microautoradiography (mARG) in a model of A-SHPT.. The 5/6 nephrectomized Sprague-Dawley rats were fed a high-phosphate and low-calcium diet for 8 weeks and consequently the level of vitamin D receptor (VDR) in their PTC severely decreased. The bilateral PTG were surgically exposed and only the left gland were directly injected with 3H-OCT (DI-3H-OCT). The time course of the changes in both radioactivity and localization of 3H-OCT in the bilateral glands was analysed using a bioimaging analyser system and mARG, respectively. A very high dose of unlabelled calcitriol was administered intravenously (IV-1,25D3) prior to DI-3H-OCT, as a competitive study.. Peak radioactivity levels in the directly injected and intact PTG occured immediately and 1 h, respectively, after DI-3H-OCT, and the difference was about 50-fold higher in the treated gland. The of mARG showed a marked concentration of silver grains in the nuclei of PTC in the gland treated with DI-3H-OCT and that concentration was significantly suppressed by IV-1,25D3.. Direct injection of OCT into the PTG enables the administration of the highly concentrated drug for specific binding to nuclear vitamin D binding sites, including VDR of PTC, which markedly suppresses the parathyroid hormone, improves the response to calcium and vitamin D and induces apoptosis in PTC.

Topics: Animals; Antineoplastic Agents; Apoptosis; Calcitriol; Calcium; Disease Models, Animal; Hyperparathyroidism, Secondary; Injections; Male; Parathyroid Glands; Parathyroid Hormone; Protein Binding; Rats; Rats, Sprague-Dawley; Receptors, Calcitriol; Uremia; Vitamin D

1,25-Dihydroxy-22-oxavitamin D(3) (22-oxacalcitriol, OCT) is an analogue of 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3), calcitriol) with less calcaemic activity, thus more suitable than 1,25(OH)(2)D(3) for the control of parathyroid hormone (PTH) secretion in chronic dialysis patients. As the low-calcaemic action of OCT has been mainly attributed to its short half-life in the blood stream, the number of doses per week is the key factor to effective OCT therapy toward suppression of PTH secretion and hypercalcaemia. Thus, we investigated a comparison between daily and thrice-weekly i.v. administration of OCT regarding suppression of PTH secretion and calcaemic action in 5/6 nephrectomized rats as a model for chronic renal failure.. Model rats of chronic renal failure were made by 5/6 nephrectomy. At 3 months after surgery, they were administered either vehicle or OCT intravenously, daily (0.125 or 0.625 microg/kg) or thrice-weekly (0.6 or 3.0 microg/kg) for 2 weeks.. The data show that 0.625 microg/kg/day (=4.375 microg/kg/week) suppresses PTH secretion with significant increase in calcium levels at 24 h after the final administration, on the other hand, 3.0 microg/kg/ thrice-weekly (=9.0 microg/kg/week) suppresses PTH secretion, although moderate compared with 0.625 microg/kg/day, with a slight (not significant) increase in calcium.. The current clinical mode of OCT therapy, i.v. thrice-weekly administration, is a practically recommendable protocol.

Topics: Animals; Blood Urea Nitrogen; Body Weight; Calcitriol; Calcium; Creatinine; Disease Models, Animal; Drug Administration Schedule; Injections, Intravenous; Male; Nephrectomy; Parathyroid Hormone; Phosphates; Rats; Rats, Sprague-Dawley; Uremia

Calcitriol, 1,25(OH)(2)D(3), has been reported to have a beneficial effect on bone histology in patients with predialysis chronic renal failure; however, such treatment involves a risk of hypercalcemia. To investigate the effects of 1,25(OH)(2)D(3) and 22-oxacalcitriol (OCT) on the progression of histologic deterioration, we administered intraperitoneal 1,25(OH)(2)D(3) or OCT, three times a week, to rats with adriamycin-induced progressive renal failure, from the 10th week after the induction of ADR-induced nephropathy. The rats were divided into the following groups: (1) high-dose 1,25(OH)(2)D(3), 0.2 microg/kg (group D(3)-0.2); (2) low-dose 1,25(OH)(2)D(3), 0.04 microg/kg (group D(3)-0.04); (3) high-dose OCT, 0.2 microg/kg (group OCT-0.2); (4) low-dose OCT, 0.04 microg/kg (group OCT-0.04); and (5) ADR-induced nephropathy (group ADR). The death rate at week 20 in group D(3)-0.2 was 50%, significantly higher than the death rates in the other groups, except for group D(3)-0.04 (P <.05). The serum creatinine and blood urea nitrogen levels were the highest in group D(3)-0.2, although the difference was not significant. In contrast, in groups OCT-0.2 and OCT-0.04, tubular changes and interstitial volume were smaller than in groups D(3)-0.2 and D(3)-0.04 (P <.05). Although calcium deposits increased in group D(3)-0.2, the difference was not significant. Glomerular expression of transforming growth factor-beta1 (TGF-beta1) expression was less in groups OCT-0.2 and OCT-0.04 than in groups D(3)-0.2 and D(3)-0.04 (P <.05). Glomerular fibronectin expression was less in group OCT-0.2 than in groups D(3)-0.2 and ADR (P <.05). Tubulointerstitial expression of TGF-beta1 was greater in group D(3)-0.2 than in group ADR and greater in group D(3)-0.04 than in group OCT-0.04 (P <.05). We conclude that a high dose of 1,25(OH)(2)D(3) accelerated the progressive renal deterioration of ADR-induced nephropathy, and, as a result, OCT was able to attenuate renal histologic lesions.

Topics: Animals; Bone Density; Calcitriol; Disease Models, Animal; Doxorubicin; Glomerulosclerosis, Focal Segmental; Kidney; Kidney Failure, Chronic; Male; Rats; Rats, Sprague-Dawley

Calcitriol therapy suppresses serum levels of parathyroid hormone (PTH) in patients with renal failure but has several drawbacks, including hypercalcemia and/or marked suppression of bone turnover, which may lead to adynamic bone disease. A new vitamin D analogue, 22-oxacalcitriol (OCT), has been shown to have promising characteristics. This study was undertaken to determine the effects of OCT on serum PTH levels and bone turnover in states of normal or impaired renal function.. Sixty dogs were either nephrectomized (Nx, N = 38) or sham-operated (Sham, N = 22). The animals received supplemental phosphate to enhance PTH secretion. Fourteen weeks after the start of phosphate supplementation, half of the Nx and Sham dogs received doses of OCT (three times per week); the other half were given vehicle for 60 weeks. Thereafter, the treatment modalities for a subset of animals were crossed over for an additional eight months. Biochemical and hormonal indices of calcium and bone metabolism were measured throughout the study, and bone biopsies were done at baseline, 60 weeks after OCT or vehicle treatment, and at the end of the crossover period.. In Nx dogs, OCT significantly decreased serum PTH levels soon after the induction of renal insufficiency. In long-standing secondary hyperparathyroidism, OCT (0.03 microg/kg) stabilized serum PTH levels during the first months. Serum PTH levels rose thereafter, but the rise was less pronounced compared with baseline than the rise seen in Nx control. These effects were accompanied by episodes of hypercalcemia and hyperphosphatemia. In animals with normal renal function, OCT induced a transient decrease in serum PTH levels at a dose of 0.1 microg/kg, which was not sustained with lowering of the doses. In Nx dogs, OCT reversed abnormal bone formation, such as woven osteoid and fibrosis, but did not significantly alter the level of bone turnover. In addition, OCT improved mineralization lag time, (that is, the rate at which osteoid mineralizes) in both Nx and Sham dogs.. These results indicate that even though OCT does not completely prevent the occurrence of hypercalcemia in experimental dogs with renal insufficiency, it may be of use in the management of secondary hyperparathyroidism because it does not induce low bone turnover and, therefore, does not increase the risk of adynamic bone disease.

Topics: Animals; Bone Diseases, Metabolic; Bone Remodeling; Calcitriol; Calcium; Disease Models, Animal; Dogs; Female; Humans; Hypercalcemia; Hyperparathyroidism, Secondary; Kidney Failure, Chronic; Nephrectomy; Parathyroid Hormone; Phosphorus; Time Factors

The effects of a new derivative of vitamin D3, 22-oxa-1 alpha,25-dihydroxyvitamin D3 (OCT), on rheumatoid arthritis was investigated using collagen-induced arthritis in rat, as an experimental model of the disease. Peroral administration of OCT significantly suppressed the incidence of arthritis and inhibited hind-paw-swelling. The levels of IgM and IgG antibodies against Type II collagen in sera were found to decrease in the OCT treated-group. The production of immunoglobulin against Type II collagen from rat spleen cells was also decreased in this group. These immunological effects of OCT on collagen-induced arthritis were more remarkable than those of 1 alpha-hydroxyvitamin D3. These findings indicated that OCT may have a therapeutic value as an immunoregulatory agent for patients with rheumatoid arthritis through inhibition of the autoimmune response to Type II collagen.

Topics: Administration, Oral; Animals; Antibody Formation; Arthritis, Rheumatoid; Autoantibodies; Body Weight; Calcitriol; Collagen; Disease Models, Animal; Male; Rats; Rats, Inbred Lew

The purpose of the present study was to examine the effect of a two day and a five day administration of 22-oxa-calcitriol (OCT) on calcium metabolism in rats with advanced chronic renal failure and severe secondary hyperparathyroidism. A first series of 27 uremic rats received either placebo, OCT or calcitriol (0.3 microgram i.p./rat) 48 and 24 hours before sacrifice. A second series of 18 uremic rats received either placebo, OCT (0.3 microgram i.p./rat) or calcitriol (0.05 microgram i.p./rat) for five days. We found that after 48 hours (series 1) both calcitriol and OCT increased blood ionized calcium (Ca2+) as compared to vehicle (1.23 +/- 0.04 and 1.10 +/- 0.02 mM, P < 0.01 and P < 0.05, respectively vs. control, 1.02 +/- 0.03 mM). Duodenal Ca transport (S/M) using the everted gut sac technique was not stimulated by OCT, even though it increased from 2.8 +/- 0.4 to 7.0 +/- 0.6 (P < 0.01) with calcitriol. In contrast, duodenal calbindin-D9k mRNA expression and protein content increased to a similar extent with OCT and calcitriol. Calcitriol was more potent in reducing plasma iPTH1-34 levels than OCT: 344 +/- 75 pg/ml (calcitriol) versus 632 +/- 46 pg/ml (OCT) compared with 897 +/- 74 pg/ml (control), P < 0.01. In the second series of rats, the injection of OCT (0.3 microgram i.p./rat) over five days was less effective than the lower dose of calcitriol (0.05 microgram i.p./rat) in reducing circulating iPTH: 110 +/- 26 (calcitriol) and 281 +/- 64 (OCT) versus 624 +/- 135 pg/ml (control), P < 0.01.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Calbindins; Calcitriol; Calcium; Disease Models, Animal; Drug Evaluation, Preclinical; Duodenum; Hyperparathyroidism, Secondary; Ion Transport; Male; Parathyroid Hormone; Peptide Fragments; Rats; Rats, Wistar; RNA, Messenger; S100 Calcium Binding Protein G; Teriparatide; Uremia