RESUMO
Chronic kidney disease (CKD) is associated with a high incidence of fractures. However, the pathophysiology of this disease is not fully understood, and limited therapeutic interventions are available. This study aimed to determine the impact of type 1 angiotensin II receptor blockade (AT-1RB) on preventing CKD-related fragility fractures and elucidate its pharmacological mechanisms. AT-1RB use was associated with a lower risk of hospitalization due to fractures in 3276 patients undergoing maintenance hemodialysis. In nephrectomized rats, administration of olmesartan suppressed osteocyte apoptosis, skeletal pentosidine accumulation, and apatite disorientation, and partially inhibited the progression of the bone elastic mechanical properties, while the bone mass was unchanged. Olmesartan suppressed angiotensin II-dependent oxidation stress and apoptosis in primary cultured osteocytes in vitro. In conclusion, angiotensin II-dependent intraskeletal oxidation stress deteriorated the bone elastic mechanical properties by promoting osteocyte apoptosis and pentosidine accumulation. Thus, AT-1RB contributes to the underlying pathogenesis of abnormal bone quality in the setting of CKD, possibly by oxidative stress. © 2020 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
Assuntos
Insuficiência Renal Crônica , Uremia , Animais , Densidade Óssea , Osso e Ossos , Humanos , Ratos , Receptores de Angiotensina , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/tratamento farmacológico , Uremia/complicações , Uremia/tratamento farmacológicoRESUMO
INTRODUCTION: High-turnover bone disease is a major consequence of SHPT and may explain the high risk for fracture in patients with advanced chronic kidney disease (CKD). Bisphosphonates suppress bone turnover and improve bone strength, but their effects have not been fully characterized in advanced CKD with severe SHPT. Bisphosphonates also increase 1,25-dihydroxyvitamin D levels in normal and uremic rats, but the underlying mechanism remains to be determined. MATERIALS AND METHODS: We investigated the skeletal and mineral metabolic effects of RIS, a pyridinyl bisphosphonate, in rats with severe SHPT induced by 5/6 nephrectomy plus a high phosphate diet. RESULTS: Nephrectomized rats developed severe SHPT, along with hyperphosphatemia, low 1,25-dihydroxyvitamin D, and markedly increased FGF23. Moreover, these rats exhibited characteristic features of high-turnover renal osteodystrophy, including increased indices of trabecular bone turnover, decreased cortical bone thickness, inferior cortical biomechanical properties, and a prominent increase in peritrabecular fibrosis. RIS treatment increased bone volume and partially attenuated trabecular bone remodeling, cortical bone loss, and mechanical properties, whereas it produced a marked improvement in peritrabecular fibrosis along with a corresponding decrease in osteogenic gene markers. RIS treatment also suppressed the elevation of FGF23, which was associated with increased 1,25-dihydroxyvitamin D. CONCLUSIONS: In a rat model of severe SHPT, treatment with RIS partially attenuated histological manifestations of high-turnover bone disease. RIS treatment also suppressed the elevation of FGF23, which may explain the increased 1,25-dihydroxyvitamin D production during the treatment.
Assuntos
Remodelação Óssea , Osso e Ossos/patologia , Distúrbio Mineral e Ósseo na Doença Renal Crônica/tratamento farmacológico , Distúrbio Mineral e Ósseo na Doença Renal Crônica/fisiopatologia , Minerais/metabolismo , Ácido Risedrônico/uso terapêutico , Animais , Fenômenos Biomecânicos , Nitrogênio da Ureia Sanguínea , Remodelação Óssea/efeitos dos fármacos , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/fisiopatologia , Cálcio/sangue , Distúrbio Mineral e Ósseo na Doença Renal Crônica/sangue , Creatinina/sangue , Modelos Animais de Doenças , Fator de Crescimento de Fibroblastos 23 , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Nefrectomia , Fragmentos de Peptídeos/sangue , Fósforo/sangue , Pró-Colágeno/sangue , Ratos Sprague-Dawley , Ácido Risedrônico/farmacologiaRESUMO
Transforming growth factor (TGF)-ß signaling is not only important in skeletal development, but also essential in bone remodeling in adult bone. The bone remodeling process involves integrated cell activities induced by multiple stimuli to balance bone resorption and bone formation. TGF-ß plays a role in bone remodeling by coordinating cell activities to maintain bone homeostasis. However, mineral metabolism disturbance in chronic kidney disease (CKD) results in abnormal bone remodeling, which leads to ectopic calcification in CKD. High circulating levels of humoral factors such as parathyroid hormone, fibroblast growth factor 23, and Wnt inhibitors modulate bone remodeling in CKD. Several reports have revealed that TGF-ß is involved in the production and functions of these factors in bone. TGF-ß may act as a factor that mediates abnormal bone remodeling in CKD.
Assuntos
Remodelação Óssea , Osso e Ossos/metabolismo , Insuficiência Renal Crônica/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Via de Sinalização Wnt , Animais , Osso e Ossos/patologia , Fator de Crescimento de Fibroblastos 23 , Fatores de Crescimento de Fibroblastos/metabolismo , Humanos , Insuficiência Renal Crônica/patologiaRESUMO
A new adsorbent Cu-Perussian blue@Nanodiamond (Cu-PB@DND) for Cs+ removal was prepared and characterized with IR, SEM, X-ray diffraction, particle size analysis, and zeta-potential. The adsorbent consists of a core of aggregated detonation nanodiamond (DND) particles with the surface treated with Cu-PB. Cesium adsorption was studied in two modes; a co-precipitation mode and a batch mode. In the co-precipitation mode, DND, CuCl2, and K4[Fe(CN)6] were added sequentially to a Cs+ solution in diluted artificial seawater. In the batch mode, adsorbent Cu-PB@DND was dispersed into a Cs+ solution with stirring. The distribution coefficient (Kd) of the co-precipitation mode was 8.8 × 107 (mL/g) at Cs+ 6.6 ppm in 0.07% seawater. The Kd value of the batch mode was 1.3 × 106 (mL/g). Precipitation of Cs+-incorporated particles was complete, and post filtration was not necessary. Excess copper and iron ions were completely removed and were not detected in the supernatant. The adsorption data for Cu-PB@DND were analyzed by assuming Langmuir isotherm and a good fit was obtained with a maximum adsorption capacity Qmax of 759 mg/g. The co-precipitation method was also applied to soil-treated wastewater.
RESUMO
Herein, we measure the Ca isotope ratios (44Ca/42Ca and 43Ca/42Ca) in serum and bone samples collected from rats with chronic kidney disease (CKD) or diabetes mellitus (DM). For the serum samples, the isotope ratios are lower for the CKD (δ44Ca/42Caserum = 0.16 ± 0.11; 2SD, n = 6) and the DM (δ44Ca/42Caserum = -0.11 ± 0.25; 2SD, n = 7) rats than that for the control rats (δ44Ca/42Caserum = 0.25 ± 0.04; 2SD, n = 7). Bone samples from two distinct positions of 20 rats in total, namely, the center and proximal parts of the tibial diaphysis, are subject to Ca isotope analysis. The resulting δ44Ca/42Ca values for the bone of the proximal part are about 0.3 lower than that for the serum samples from the same rats. The larger isotope fractionations between the serum and bone are consistent with previously reported data for vertebrate animals (e.g., Skulan and DePaolo, 1999), which suggests the preferential incorporation of lighter Ca isotopes through bone formation. For the bones from the control and CKD rats, there were no differences in the δ44Ca/42Ca values between the positions of the bone. In contrast, the δ44Ca/42Ca values of the bone for the DM rats were different between the positions of the bone. Due to the lower bone turnover rate for the DM rats, the δ44Ca/42Ca for the middle of the diaphysis can reflect the Ca isotopes in the bone formed prior to the progression of DM states. Thus, the resulting δ44Ca/42Ca values show a clear correlation with bone mineral density (BMD). This can be due to the release of isotopically lighter Ca from the bone to the serum. In the present study, our data demonstrate that the δ44Ca/42Ca value for serum can be used as a new biomarker for evaluating changes in bone turnover rate, followed by changes in bone volume.
Assuntos
Densidade Óssea , Isótopos de Cálcio/metabolismo , Diabetes Mellitus Experimental/diagnóstico , Insuficiência Renal Crônica/diagnóstico , Animais , Diabetes Mellitus Experimental/metabolismo , Masculino , Ratos , Ratos Sprague-Dawley , Insuficiência Renal Crônica/metabolismoRESUMO
We investigated the possible linkage between the crystallinity and elemental ratios (Mg/Ca and Sr/Ca) of the femoral cortical bones of rats with chronic kidney disease (CKD) or diabetes mellitus (DM). The Mg/Ca and Sr/Ca ratios were measured by using the laser ablation-inductively coupled plasma mass spectrometry (LA-ICPMS) technique and the crystallinity was evaluated by Raman spectroscopy on the same sample slice. The measured crystallinity varied significantly along the radial direction, reflecting the heterogeneities in the Mg/Ca ratio for the bone samples. For the endosteal cortical bone of CKD rats, the Mg/Ca ratio became higher. This is explained by the increase of the abundance of Mg in the bone, possibly due to the higher absorption efficiency of Mg in the intestine or due to the lower excretion efficiency of Mg from the kidney. For areas with a higher Mg/Ca ratio, the crystallinity of the bone was significantly more degraded than that for areas with a lower Mg/Ca ratio, suggesting that the substitution of Ca by Mg induced the deterioration of the crystallinity of hydroxyapatite (HAp). In addition, the measured Mg/Ca and Sr/Ca ratios of the bone were positively correlated with those found in serum samples. The data obtained here demonstrated that the metabolic alterations for inorganic elements caused the ionic substitutions of Ca by foreign cationic ions, and that the contents of foreign ions in the bone greatly affected the crystallinity of HAp.
Assuntos
Densidade Óssea , Osso e Ossos/patologia , Magnésio/análise , Estrôncio/análise , Animais , Cálcio/análise , Diabetes Mellitus/patologia , Durapatita/química , Lasers , Masculino , Ratos , Ratos Sprague-Dawley , Insuficiência Renal Crônica/patologia , Espectrofotometria Atômica , Análise Espectral RamanRESUMO
Chronic kidney disease (CKD) is associated with an increased risk of fragility fractures, but the underlying pathophysiological mechanism remains obscure. We performed an in vivo experimental study to examine the roles of uremia and abnormal mineral/parathyroid metabolism in the development of bone metabolic abnormalities in uremic rats. Male Sprague-Dawley rats were divided into four groups, comprising sham operation (high turnover bone control=HTB-Cont), 5/6-nephrectomy (high turnover bone nephrectomized=HTB-Nx), thyroparathyroidectomy (low turnover bone control=LTB-Cont), and thyroparathyroidectomy plus 5/6 nephrectomy (low turnover bone nephrectomized=LTB-Nx), and maintained for 16 weeks. Uremia was successfully created in the LTB-Nx and HTB-Nx groups, while hyperparathyroidism was only found in the HTB-Nx group. Cancellous bone histomorphometry revealed significantly higher bone turnover in the HTB-Nx group than in the LTB-Nx group. Storage modulus at 1 Hz and tan delta in cortical bone of the femur, which represent the viscoelastic mechanical properties, were significantly lower in both Nx groups than in the Cont groups regardless of bone metabolism. Pentosidine-to-matrix ratio was increased and crystallinity was decreased in both Nx groups regardless of bone turnover. Mineral-to-matrix ratio was significantly decreased in the HTB-Nx group, but increased in the LTB-Nx group. Enzymatic collagen crosslinks were decreased in the HTB-Nx group. The degree of orientation of the c-axis in carbonated hydroxyapatite (biological apatite=BAp) crystallites was decreased in both Nx groups regardless of bone metabolism. Stepwise multivariate regression revealed that pentosodine-to-matrix ratio and BAp preferential c-axis orientation were significantly associated with storage modulus and tan delta. In conclusion, bone elastic mechanical properties deteriorated regardless of bone metabolism or bone mass in rats with chronic kidney injury. Various changes in bone mineral properties were associated with CKD, including abnormal parathyroid function, impaired bone turnover, and uremia associated with the accumulation of uremic toxins, were responsible for these changes. Pentosidine-to-matrix ratio and BAp orientation at position 5 were the two meaningful determinants of elastic bone mechanical strength, and both factors were associated with the severity of uremia, but not parathyroid function or bone metabolism. These two factors may account for the increased bone fragility among CKD patients.
Assuntos
Doenças Ósseas/diagnóstico por imagem , Doenças Ósseas/metabolismo , Fêmur/diagnóstico por imagem , Fêmur/metabolismo , Insuficiência Renal Crônica/diagnóstico por imagem , Insuficiência Renal Crônica/metabolismo , Animais , Fenômenos Biomecânicos/fisiologia , Densidade Óssea/fisiologia , Remodelação Óssea/fisiologia , Masculino , Radiografia , Ratos , Ratos Sprague-Dawley , Difração de Raios XRESUMO
Low-turnover bone disease is one of the bone abnormalities observed in patients with chronic kidney disease (CKD) and is recognized to be associated with low serum parathyroid hormone (PTH) level and skeletal resistance to PTH. Indoxyl sulfate (IS) is a representative uremic toxin that accumulates in the blood as renal dysfunction progresses in CKD patients. A recent in vitro study using an osteoblastic cell culture system suggests that IS has an important role in the pathogenesis of low bone turnover through induction of skeletal resistance to PTH. However, the effects of IS on the progression of low bone turnover have not been elucidated. In the present study, we produced rats with low bone turnover by performing parathyroidectomy (PTX) and fed these rats a diet containing indole, a precursor of IS, to elevate blood IS level from indole metabolism. Bone metabolism was evaluated by measuring histomorphometric parameters of secondary spongiosa of the femur. Histomorphometric analyses revealed significant decreases in both bone formation-related parameters and bone resorption-related parameters in PTX rats. In indole-treated PTX rats, further decreases in bone formation-related parameters were observed. In addition, serum alkaline phosphatase activity, a bone formation marker, and bone mineral density of the tibia tended to decrease in indole-treated PTX rats. These findings strongly suggest that IS exacerbates low bone turnover through inhibition of bone formation by mechanisms unrelated to skeletal resistance to PTH.
Assuntos
Remodelação Óssea/fisiologia , Indicã/metabolismo , Paratireoidectomia/efeitos adversos , Insuficiência Renal Crônica/complicações , Animais , Densidade Óssea , Modelos Animais de Doenças , Masculino , Hormônio Paratireóideo/metabolismo , Ratos , Ratos Sprague-Dawley , Insuficiência Renal Crônica/fisiopatologiaRESUMO
Chronic kidney disease (CKD) patients have an extremely increased risk of fragility fractures, but the underling pathophysiological mechanisms remain obscure. Recently, the progresses of analysis technology have revealed the changes of bone quality in CKD condition. In particular, we can observe the characteristic changes of bone microarchitecture and bone chemical compositions in both human bone biopsy samples and experimental animal bones. Here, I will provide a short review on these bone quality factors and discuss on the relationship between bone quality and fracture in CKD patients.
Assuntos
Densidade Óssea , Doenças Ósseas Metabólicas/fisiopatologia , Fraturas Ósseas/fisiopatologia , Insuficiência Renal Crônica/complicações , Animais , Doenças Ósseas Metabólicas/etiologia , Durapatita/metabolismo , Fraturas Ósseas/etiologia , Humanos , Diálise RenalRESUMO
Chronic kidney disease (CKD) is associated with increased risks of cardiovascular morbidity and mortality. Cardiac remodeling including myocardial fibrosis and hypertrophy is frequently observed in CKD patients. In this study, we investigate the mechanism involved in cardiac hypertrophy associated with CKD using a rat model, by morphological and chemical component changes of the hypertrophic and non-hypertrophic hearts. Sprague-Dawley rats were 4/5 nephrectomized (Nx) at 11 weeks of age and assigned to no treatment and treatment with AST-120, which was reported to affect the cardiac damage, at 18 weeks of age. At 26 weeks of age, the rats were euthanized under anesthesia, and biochemical tests as well as analysis of cardiac condition were performed by histological and spectrophotometric methods. Cardiac hypertrophy and CKD were observed in 4/5 Nx rats even though vascular calcification and myocardial fibrosis were not detected. The increasing myocardial protein was confirmed in hypertrophic hearts by infrared spectroscopy. The absorption of amide I and other protein bands in hypertrophic hearts increased at the same position as in normal cardiac absorption. Infrared spectra also showed that lipid accumulation was also detected in hypertrophic heart. Conversely, the absorptions of protein were obviously reduced in the myocardium of non-hypertrophic heart with CKD compared to that of hypertrophic heart. The lipid associated absorption was also decreased in non-hypertrophic heart. Our results suggest that cardiac remodeling associated with relatively early-stage CKD may be suppressed by reducing increased myocardial protein and ameliorating cardiac lipid load.
Assuntos
Cardiomegalia/patologia , Fibrose/patologia , Lipídeos/química , Proteínas/metabolismo , Insuficiência Renal Crônica/patologia , Animais , Determinação da Pressão Arterial , Cardiomegalia/etiologia , Fibrose/etiologia , Masculino , Nefrectomia , Ratos , Ratos Sprague-Dawley , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/cirurgia , Toxinas Biológicas/metabolismo , Uremia/metabolismoRESUMO
The pathogenesis of bone disorders in young male athletes has not been well understood. We hypothesized that bone fragility is caused by low energy availability, due to insufficient food intake and excessive exercise energy expenditure in young male athletes. To examine this hypothesis, we investigated the influence of food restriction on bone strength and bone morphology in exercised growing male rats, using three-point bending test, dual-energy X-ray absormetry, and micro-computed tomography. Four-week-old male Sprague-Dawley rats were divided randomly into the following groups: the control (Con) group, exercise (Ex) group, food restriction (R) group, and food restriction plus exercise (REx) group after a 1-wk acclimatization period. Thirty-percent food restriction in the R and REx groups was carried out in comparison with that in the Con group. Voluntary running exercise was performed in the Ex and REx groups. The experimental period lasted 13 wk. At the endpoint of this experiment, the bone strength of the femurs and tibial BMD in the REx group were significantly lower than those in the Con group. Moreover, trabecular bone volume and cortical bone volume in the REx group were also significantly lower than those in the Con group. These findings indicate that food restriction causes low bone strength and microarchitectural deterioration in exercised growing male rats.
Assuntos
Densidade Óssea , Dieta Redutora/efeitos adversos , Fêmur/crescimento & desenvolvimento , Tíbia/crescimento & desenvolvimento , Animais , Peso Corporal , Doenças Ósseas Metabólicas/etiologia , Doenças Ósseas Metabólicas/patologia , Ingestão de Energia , Metabolismo Energético , Hormônios/sangue , Masculino , Condicionamento Físico Animal , Ratos , Ratos Sprague-Dawley , Corrida , Microtomografia por Raio-XRESUMO
Athletes, in particular endurance athletes and dancers, are chronically exposed to a state of low energy availability due to insufficient dietary energy intake and massive exercise energy expenditure. Low energy availability sometimes causes bone fragility, thereby increasing the risk of bone disorders. Although the decrease in energy availability shows no sexual dimorphism, epidemiological studies have reported that bone disorders are less frequent in male athletes than in female athletes. We hypothesized that bone tissue was not affected by low energy availability in males. The purpose of this study was to examine the influence of food restriction combined with voluntary running training on bone morphology and strength in adult male rats. Fourteen-week-old male Sprague-Dawley rats were divided randomly into four groups: control (C) group, food restriction (R) group, exercise (Ex) group, and food restriction plus exercise (REx) group. For the R and REx groups, 30 % food restriction was carried out in comparison with the C group. Bone strength, bone mineral density (BMD), bone architecture, and bone turnover rate were measured after a 13-week experimental period. Bone strength was not significantly lower in the REx group compared with the C group. BMD and trabecular bone volume showed no difference among groups. These findings indicate that bone morphology and strength were little affected by food restriction combined with exercise training in adult male rats.
Assuntos
Densidade Óssea , Remodelação Óssea , Osso e Ossos/patologia , Privação de Alimentos , Condicionamento Físico Animal , Animais , Peso Corporal , Osso e Ossos/metabolismo , Dieta , Metabolismo Energético , Fêmur/patologia , Masculino , Ratos , Ratos Sprague-Dawley , Corrida , Tíbia/patologia , Fatores de Tempo , Microtomografia por Raio-XRESUMO
The prevalence of hip fracture is very high among patients with chronic kidney disease (CKD); however, the reason for this is unclear. We examined the effects of accumulated uremic toxins on bone chemical composition and elastic mechanical properties. Rats underwent thyroparathyroidectomy and progressive partial nephrectomy (TPTx-Nx), and were administered with vehicle or AST-120 to reduce serum indoxyl sulfate (IS) levels. Bone mechanical properties, bone mineral density (BMD), cortical bone chemical composition, and histomorphometry were determined. Storage modulus was reduced in TPTx-Nx rats compared with rats that underwent TPTx alone. BMD and histomorphometric parameters did not differ between the groups. In terms of cortical bone chemical composition, the mineral/matrix ratio and carbonate substitution was increased, whereas crystallinity was decreased in TPTx-Nx rats. The enzymatic crosslink ratio and pentosidine:matrix ratio were increased in TPTx-Nx rats. AST-120 abolished the effects of TPTx-Nx and decreased the serum IS concentration. Stepwise multiple regression analysis revealed that the pentosidine:matrix and mineral:matrix ratios were independent contributors to the storage modulus. In conclusion, the accumulated uremic toxins, including IS, seem to play an important role in deteriorating bone mechanical properties by altering the chemical composition of bone. This mechanism may account for the increased prevalence of hip fracture among patients with CKD.
Assuntos
Osso e Ossos/fisiopatologia , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/fisiopatologia , Uremia/complicações , Uremia/fisiopatologia , Animais , Fenômenos Biomecânicos , Densidade Óssea , Osso e Ossos/patologia , Creatinina/metabolismo , Módulo de Elasticidade , Fêmur/patologia , Fêmur/fisiopatologia , Testes de Função Renal , Modelos Lineares , Masculino , Ratos , Ratos Sprague-Dawley , Insuficiência Renal Crônica/sangue , Análise Espectral Raman , Uremia/sangueRESUMO
Recent data suggest that several uremic toxins may contribute to the development of bone abnormalities in chronic kidney disease. p-Cresyl sulfate (PCS), the sulfate conjugate of p-cresol, is a protein-bound uremic toxin associated with the progression of chronic kidney disease, cardiovascular risk, and mortality. However, the effects of PCS on bone metabolism remain unclear. In the present study, we evaluated the toxic effects of PCS on primary mouse osteoblasts, compared with an extensively studied uremic toxin indoxyl sulfate (IS). Pre-treatment of osteoblasts with PCS at 0.125 mM and above significantly decreased parathyroid hormone (PTH)-induced cAMP production in a dose-dependent manner. PCS also induced a significant increase in intracellular production of reactive oxygen species (ROS) at 0.25 mM and above, but not at lower concentrations. PCS at 0.125 mM (a concentration that did not induce significant ROS increase) decreased cell viability by augmenting DNA fragmentation and reducing cell proliferation. Inhibition of JNK and p38 mitogen-activated protein kinase (MAPK) abolished the PCS-induced increase in DNA fragmentation and decrease in cAMP production in osteoblastic cells. Compared with PCS, IS induced ROS production at 0.05 mM but did not reduce cAMP production from 0.05 to 0.5 mM. IS induced decrease in cell viability and increase in DNA fragmentation at 0.5mM only. These results suggest that PCS damages osteoblastic cells through not only increasing ROS production but also activating JNK/p38 MAPKs, which is different from the mechanism of injury by IS. These damages of osteoblasts induced by PCS may play a critical role in impairing bone metabolism in patients with chronic kidney disease in whom PCS accumulates.
Assuntos
Cresóis/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Osteoblastos/efeitos dos fármacos , Osteoblastos/metabolismo , Animais , Western Blotting , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , AMP Cíclico/metabolismo , Fragmentação do DNA/efeitos dos fármacos , Camundongos , Camundongos Transgênicos , Hormônio Paratireóideo/farmacologia , Espécies Reativas de Oxigênio/metabolismoRESUMO
Accelerated cardiovascular disease is a frequent complication of CKD. Monocyte-mediated inflammation and adhesion of monocytes to vascular endothelium are key events in atherogenesis. An oral adsorbent, AST-120, retards renal function deterioration by lowering IS, which is known to accumulate in CKD patients. However, the effect of AST-120 on CKD-related monocyte activation is unknown. We aimed to determine whether AST-120 improves monocyte-mediated inflammation through IS reduction. Flow cytometric analysis showed that Mac-1 expression and ROS production were significantly higher in peripheral blood monocytes of subtotal Nx CKD mice than in sham-operated mice. AST-120 treatment significantly decreased Mac-1 expression and ROS production in CKD model mice. Furthermore, administration of IS induced monocyte-mediated inflammation and ROS generation. In vitro studies indicated that IS dose-dependently increased THP-1 monocytic cell adhesion to IL-1ß-activated HUVECs under physiological flow conditions. IS also induced monocyte-mediated inflammation and ROS production in THP-1 cells. Phosphorylation of p38 MAPK and membrane translocation of NAD(P)H oxidase subunit p47phox in THP-1 cells were induced by IS. Both SB203580 (p38 MAPK inhibitor) and apocynin [NAD(P)H oxidase inhibitor] reduced THP-1 cell adhesion to HUVECs. Apocynin also inhibited IS-induced ROS production in THP-1 cells. IS induced monocyte-driven inflammation through NAD(P)H oxidase- and p38 MAPK-dependent pathways in monocytes. The main finding of this study was that AST-120 inhibited monocyte activation by reducing IS in vivo. This provides new insights on how AST-120 attenuates the progression of atherosclerosis in CKD.
Assuntos
Carbono/farmacologia , Fármacos Gastrointestinais/farmacologia , Indicã/metabolismo , Inflamação/metabolismo , Monócitos/metabolismo , Óxidos/farmacologia , Insuficiência Renal Crônica/metabolismo , Animais , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/imunologia , Doenças Cardiovasculares/metabolismo , Linhagem Celular , Modelos Animais de Doenças , Citometria de Fluxo , Humanos , Immunoblotting , Inflamação/etiologia , Inflamação/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Monócitos/efeitos dos fármacos , Monócitos/imunologia , Espécies Reativas de Oxigênio/imunologia , Espécies Reativas de Oxigênio/metabolismo , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/imunologiaRESUMO
BACKGROUND: Both organic and inorganic phosphorus (Pi) are present in regularly consumed foods, such as meats, eggs, and dairy products. Pi is often included in foods as an additive (as hidden phosphorus). The intestinal peptide transporter PepT1 mediates protein absorption, which is disturbed in renal insufficiency. Our aim was to determine the effects of dietary Pi content on the peptide transport activity and expression of PepT1. METHODS: The following animal models were used: (1) 7-week-old male Wistar rats; and (2) rats that underwent 3/4 nephrectomy to induce chronic kidney disease (CKD). The rats were fed a normal-protein (20%) diet containing low (0.02%), normal (0.6%), or high (1.2%) Pi levels. They were also fed diets containing varying amounts of protein and either low or normal Pi levels as follows: (1) low Pi/normal protein, (2) low Pi/high (50%) protein, (3) normal Pi/normal protein, and (4) normal Pi/high protein. RESULTS: Intestinal peptide transport activity and PepT1 expression levels were significantly higher in the CKD rats than in sham-operated control ones. Compared with the normal-protein diet, the high-protein diet increased PepT1 expression in the CKD rats. Intestinal dipeptide transport activity and PepT1 protein levels did not increase in the rats fed the low-Pi/high-protein diet. In contrast, intestinal dipeptide transport activity and PepT1 protein expression were markedly increased in the rats fed the normal-Pi/high-protein diet. CONCLUSION: Dietary Pi levels regulate intestinal peptide transport activity through PepT1.
Assuntos
Regulação da Expressão Gênica , Fósforo na Dieta/administração & dosagem , Simportadores/genética , Animais , Transporte Biológico/efeitos dos fármacos , Doença Crônica , Dieta , Absorção Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Intestinos/efeitos dos fármacos , Rim/efeitos dos fármacos , Rim/patologia , Masculino , Nefrectomia/métodos , Transportador 1 de Peptídeos , Fósforo na Dieta/farmacocinética , Ratos , Ratos Wistar , Insuficiência Renal/tratamento farmacológico , Insuficiência Renal/patologia , Simportadores/metabolismoRESUMO
BACKGROUND: Diabetic bone disease is a major complication in diabetes mellitus and is characterized by low-turnover bone formation. Recent studies have demonstrated that oxidative stress could be associated with diabetic bone disease and that ß-adrenergic antagonists could increase bone formation. Our study investigated the effect of carvedilol (ß-blocker), possessing an antioxidant effect, on diabetic bone disease. METHODS: We used the non-obese, type 2 diabetes model Spontaneously Diabetic Torii (SDT) rats in this study. Sprague-Dawley rats were used as controls (control, n = 6). SDT rats were divided into four groups: diabetic (DM, n = 8), DM+insulin (DM+I, n = 7), DM+carvedilol (DM+C, n = 8), and DM+N-acetylcysteine (DM+N, n = 10) at 20 weeks. The rats were sacrificed at 30 weeks, after which blood and urine samples, bone mineral density, histomorphometry, and oxidative stress were evaluated. RESULTS: The number of 8-hydroxydeoxyguanosine-positive cells in bone tissue was significantly lower in the DM+C and DM+N groups than in the DM group. Mineral apposition rate and bone formation rate per bone surface in the DM+C and DM+N groups were significantly higher than those in the DM group, and these parameters were better in the DM+C group than in the DM+N group. CONCLUSION: Our data suggest that carvedilol has stronger effects on diabetic low-turnover bone disease beyond that which can be attributed to its antioxidative stress mechanism.
Assuntos
Antagonistas Adrenérgicos beta/uso terapêutico , Doenças Ósseas/etiologia , Doenças Ósseas/prevenção & controle , Carbazóis/uso terapêutico , Complicações do Diabetes/etiologia , Complicações do Diabetes/prevenção & controle , Diabetes Mellitus Tipo 2/complicações , Propanolaminas/uso terapêutico , Animais , Doenças Ósseas/metabolismo , Carvedilol , Complicações do Diabetes/metabolismo , Masculino , Ratos , Ratos Sprague-DawleyRESUMO
Chronic kidney disease has a high level of oxidative stress, a phenomenon that is induced, at least in part, by the accumulation of uremic toxins. Several reports have revealed that indoxyl sulfate, one of the uremic toxins, accelerates oxidative stress in chronic kidney disease. On the other hand, it is also well known that statins have pleiotropic effects; however, it still remains unclear whether statins suppress osteoblastic cell dysfunction or cytotoxicity induced by uremic toxins. To elucidate whether statins ameliorate osteoblast dysfunction induced by uremic toxins, we conducted an in vitro study using primary cultured osteoblastic cells from mouse calvariae. Indoxyl sulfate induced reactive oxygen species production and reduced cell viability in osteoblastic cells in a dose dependent manner. The addition of pravastatin suppressed reactive oxygen species production and ameliorated cell viability. These data suggest that pravastatin attenuates oxidative stress and protects osteoblastic cell viability from indoxyl sulfate.
Assuntos
Indicã/metabolismo , Osteoblastos/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Pravastatina/farmacologia , Animais , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Indicã/administração & dosagem , Camundongos , Osteoblastos/metabolismo , Pravastatina/administração & dosagemRESUMO
The bone histomorphometry is well-known as the histological evaluation method for the investigation of the efficacy of various kinds of medicine on bone metabolism disorder. Recently, in addition, it is indispensable for bone researchers to clarify characteristic of bone metabolism in genetically-modified mice by means of bone histomorphometry. Thus, bone histomorphometry has broad utility. However, it would not be an exaggeration to say that researchers are interested in only numerical value of various kinds of parameters without understanding lots of information obtained from morphological observation. Especially, we have to pay attention to measurement and interpretation of parameters of bone histomorphometry in case of growing bone, because growing bone is changing its size of longitudinal and width. In this review, we would like to explain how to measure with bone histomorphometry for modeling bone in growing animals.
Assuntos
Animais de Laboratório , Doenças Ósseas Metabólicas/diagnóstico , Doenças Ósseas Metabólicas/patologia , Osso e Ossos/patologia , Animais , Animais Geneticamente Modificados , Doenças Ósseas Metabólicas/metabolismo , Doenças Ósseas Metabólicas/fisiopatologia , Remodelação Óssea , Osso e Ossos/anatomia & histologia , Osso e Ossos/metabolismo , Osso e Ossos/fisiologia , Modelos Animais de Doenças , Feminino , Masculino , Camundongos , Ratos , Ratos Sprague-DawleyRESUMO
Bone fragility is a complication of chronic kidney disease (CKD). Patients on dialysis have higher risk of fracture than the general population, but the reason remains obscure. Bone strength is determined by bone mass and bone quality. Although factors affecting bone quality include microarchitecture, remodeling activity, mineral content, and collagen composition, it remains unclear which factor is critically important for bone strength in CKD. We conducted an in vivo study to elucidate the factors that reduce bone mechanical property in CKD. Rats underwent thyroparathyroidectomy and progressive partial nephrectomy (TPTx-Nx). Bone mechanical property, bone mineral density (BMD), and cortical bone chemical composition (all in femur) as well as histomorphometry (in tibia) were determined. The storage modulus, which is a mechanical factor, was reduced in CKD model rats compared with controls that underwent thyroparathyroidectomy alone (TPTx). There were no differences in BMD and histomorphometric parameters between groups. However, cortical bone chemical composition differed: mineral to matrix ratio and carbonate substitution increased whereas crystallinity decreased in TPTx-Nx. In addition, enzymatic crosslinks ratio and pentosidine to matrix ratio also increased. These changes were significant in TPTx-Nx rats with most impaired renal function. Stepwise multiple regression analysis identified mature to immature crosslink ratio and crystallinity as independent contributors to storage modulus. Deteriorated bone mechanical properties in CKD may be caused by changes in chemical composition of the cortical bone, and is independent of BMD or cancellous bone microarchitecture.