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Objectives
The purpose of this study is to investigate the stage of chronic kidney disease (CKD) in adenine-induced CKD model rats by serum analyses, and to examine bone mineral density (BMD), bone strength, and microstructure of trabecular and cortical bone in these rats.
Methods
Eight-week-old, male Wistar rats (n = 42) were divided into 2 group...
Context in source publication
Citations
... However, 0.75% adenine diet for 6 weeks showed most of the vascular calcification changes expected in cKD animal [236] models [242][243][244]. Additionally, Neven et al. demonstrated bone and mineral disorders for the first time in the adenine-model of induced cKD [245], and subsequently, several studies have utilized the adenine-induced cKD model to assess cKD-related osteoporosis and mineral bone disease [42,43,246,247]. indeed, abnormal mineral metabolism in patients with clinical nephropathy, which leads to secondary hyperparathyroidism, has been replicated in the adenine-induced cKD model [44,223,246]. ...
Chronic kidney disease (CKD) with high morbidity and mortality all over the world is characterized by decreased kidney function, a condition which can result from numerous risk factors, including diabetes, hypertension and obesity. Despite significant advances in our understanding of the pathogenesis of CKD, there are still no treatments that can effectively combat CKD, which underscores the urgent need for further study into the pathological mechanisms underlying this condition. In this regard, animal models of CKD are indispensable. This article reviews a widely used animal model of CKD, which is induced by adenine. While a physiologic dose of adenine is beneficial in terms of biological activity, a high dose of adenine is known to induce renal disease in the organism. Following a brief description of the procedure for disease induction by adenine, major mechanisms of adenine-induced CKD are then reviewed, including inflammation, oxidative stress, programmed cell death, metabolic disorders, and fibrillation. Finally, the application and future perspective of this adenine-induced CKD model as a platform for testing the efficacy of a variety of therapeutic approaches is also discussed. Given the simplicity and reproducibility of this animal model, it remains a valuable tool for studying the pathological mechanisms of CKD and identifying therapeutic targets to fight CKD.
... Eight-week-old, male Wistar rats (N = 9-10) (Charles River Laboratories Inc., Tokyo, Japan) were housed in a controlled environment (temperature 23 ± 2 • C, humidity 40 ± 20%) with a 12-hour light-dark cycle with free access to water and rat food. The details were described in previous studies and followed for the selection of rat species and sex [19]. Rats were treated with a 0.75% adenine diet (Oriental Yeast Co., Ltd., Tokyo Japan) for 4 weeks until 12 weeks of age, followed by a standard rodent chow (CE-7; Clea Japan, Tokyo, Japan) diet to generate CKD model rats (CKD group). ...
... Rats were treated with a 0.75% adenine diet (Oriental Yeast Co., Ltd., Tokyo Japan) for 4 weeks until 12 weeks of age, followed by a standard rodent chow (CE-7; Clea Japan, Tokyo, Japan) diet to generate CKD model rats (CKD group). The 4-week treatment with the adenine diet was decided based on previous studies [19,20], which reported that 4-week treatment with the adenine diet induced non-progressive, irreversible renal failure. ...
... We have previously reported that this CKD model presents with increased serum levels of intact-PTH (I-PTH) and renal fibrosis, as stage IV of CKD and SHPT, and decreased systemic BMD, cortical bone microstructure, and cortical and trabecular bone strength [19]. Similar results were observed in the CKD rats in the present study. ...
Objectives
Chronic kidney disease (CKD) complicated by secondary hyperparathyroidism (SHPT) is associated with an increased risk of fragility fractures. Etelcalcetide (EC) is a treatment for SHPT that reduces serum parathyroid hormone (PTH) levels. However, the effects of combined treatment with osteoporosis drugs such as teriparatide (TPTD) remain unclear. This study investigates the combined effects of EC and TPTD on bone in CKD model rats.
Methods
The CKD model was established in 8-week-old male Wistar rats by feeding them a 0.75% adenine diet for 4 weeks. At 20 weeks of age, the rats were divided into 4 groups (N = 9–10 in each group): CKD group (vehicle administration), TPTD group (30 μg/kg, 3 times/week), EC group (0.6 mg/kg, daily), and Comb group (TPTD and EC combined). EC was injected for 12 weeks starting at 20 weeks of age, and TPTD was injected for 8 weeks starting at 24 weeks of age. After treatment, the followings were evaluated: bone mineral density, bone strength, biochemical tests, bone and fat histomorphometry, and micro-computed tomography.
Results
In CKD model rats, the combination of EC and TPTD was more effective in increasing cortical bone thickness and bone strength and inhibiting porosity. In addition, the combined treatment decreased bone marrow adiposity and fibrosis, and it increased bone mass and improved bone microstructure in trabecular bone.
Conclusions
With the observed benefits such as improved bone mass, bone strength, structural properties, and bone marrow adiposity, combination therapy may be a potential way to improve bone fragility in CKD.
... Eight-week-old, male Wistar rats (n = 9 -11) (Charles River Laboratories Inc., Tokyo, Japan) were housed in a controlled environment (temperature 23˚C ± 2˚C, humidity 40% ± 20%) with a 12-hour light-dark cycle with free access to water and rat food. The details were described in our previous study [14]. Rats were treated with a 0.75% adenine diet (Oriental Yeast Co., Ltd., Tokyo, Japan) for 4 weeks until 12 weeks of age and then fed a standard rodent chow (CE-7; ...
The increasing prevalence of osteoporosis and chronic kidney disease (CKD) due to the aging of society has highlighted the need for development of effective treatments for elderly patients. This study examined whether the combination of treadmill exercise therapy and alendronate (ALN) can improve bone mineral density (BMD) and bone strength without worsening renal function in adenine-induced CKD model rats.
8-week-old male Wistar rats (n = 70) were divided into experimental groups based on the treatment protocol, i.e., non-CKD (control), vehicle only (CKD), ALN only, exercise only, and combined ALN plus exercise. A 0.75% adenine diet was used to induce CKD. Groups were killed at either 20 or 30 weeks of age. Comprehensive assessments included serum and urine biochemistry tests, renal histology, bone histomorphometry, BMD measurement, micro-computed tomography examinations, and biomechanical testing.
Blood biochemistry tests, urine analyses and histological evaluations of the kidney demonstrated that ALN treatment did not worsen renal function or kidney fibrosis in moderate-stage CKD model rats. Both ALN and treadmill exercise significantly suppressed bone resorption (p < 0.05–p < 0.01). Moreover, ALN monotherapy and combined ALN and treadmill exercise significantly improved BMD of the lumbar spine and femur, bone microstructure, and trabecular bone strength (p < 0.05–p < 0.01). Treadmill exercise was also shown to decrease cortical porosity at the mid-diaphysis of the femur and improve kidney fibrosis.
The combination of ALN and treadmill exercise is effective in improving BMD, the microstructure of trabecular and cortical bone, and bone strength, without compromising renal function in adenine-induced CKD model rats.
Secondary hyperparathyroidism (SHPT) is a major comorbidity of chronic kidney disease (CKD). Chronic elevation of PTH levels is associated with cortical bone deterioration and increase in the risk of fractures in CKD patients. Here, we evaluated the effect of repeated administration of upacicalcet, a novel positive allosteric modulator of the calcium-sensing receptor, in a rat model of adenine-induced renal failure, by determining serum levels of intact PTH (iPTH), calcium, phosphorus, creatinine, and urea nitrogen. Furthermore, parathyroid hyperplasia (parathyroid gland weight and Ki-67-positive cell density), ectopic calcification (calcium content in the thoracic aorta, kidney and heart and positive von Kossa staining in the thoracic aorta), and bone morphometry parameters (cortical porosity and fibrosis volume) were evaluated. Rats treated with either 0.2 mg/kg or 1 mg/kg upacicalcet exhibited significantly lower serum iPTH levels than CKD-control rats, as early as 7 days after the first dose. Repeated administration of upacicalcet reduced serum iPTH levels and inhibited parathyroid hyperplasia in rats with adenine-induced severe renal failure. Moreover, it suppressed ectopic calcification and cortical pore formation. In contrast, serum calcium and phosphorus levels were not significantly affected, suggesting a low risk of hypocalcemia, which often occurs with SHPT treatment. In conclusion, repeated administration of upacicalcet decreased serum iPTH levels and suppressed parathyroid hyperplasia in the adenine-induced CKD rat model of SHPT. Furthermore, ectopic calcification and cortical pore formation were suppressed without significant changes in blood mineral parameters. Upacicalcet safely inhibited the progression of SHPT in an adenine-induced CKD rat model.
