Urinary Calcium Is Associated with Serum Sclerostin among Stone Formers

Background: Sclerostin plays an important role in bone metabolism and adipose tissue. Animal studies suggest that sclerostin influences urinary calcium (UCa), but this relationship has not been evaluated in stone formers (SFs). We aimed to investigate the association of UCa with serum sclerostin, bone mineral density (BMD), and body composition among SFs.Methods: Clinical and laboratorial data were retrieved from medical records. Determinants of UCa were studied using linear regression.Results: A total of 107 SFs (35.8 ± 9.3 years, 54% male) with eGFR 99.8 ± 14.5 mL/min/1.73 were studied. Subjects were split by sex and grouped into tertiles of UCa levels. Men in the highest UCa tertile had higher body mass index (BMI) and serum sclerostin, lower lean mass, and a trend towards higher fat mass. Women in the highest tertile had higher BMI and a trend towards higher serum sclerostin. Hypertension and metabolic syndrome, but not lower BMD, were more prevalent in the highest UCa tertile for both sexes. Sclerostin was positively correlated with fat mass and inversely correlated with lean mass among men, but not among women. BMD corrected for BMI at lumbar spine was inversely associated with UCa in a univariate analysis, but only serum sclerostin, hypertension, and NaCl intake were independent determinants of UCa in the multivariate model.Conclusion: The present findings disclose that in addition to hypertension and salt intake, serum sclerostin is associated with urinary calcium in stone formers, suggesting that in addition to the hormones traditionally thought to alter calcium reabsorption in the kidney, sclerostin may play a significant additional role, warranting further investigation.</p

Urinary Calcium Is Associated with Serum Sclerostin among Stone Formers

Background: Sclerostin plays an important role in bone metabolism and adipose tissue. Animal studies suggest that sclerostin influences urinary calcium (UCa), but this relationship has not been evaluated in stone formers (SFs). We aimed to investigate the association of UCa with serum sclerostin, bone mineral density (BMD), and body composition among SFs.Methods: Clinical and laboratorial data were retrieved from medical records. Determinants of UCa were studied using linear regression.Results: A total of 107 SFs (35.8 ± 9.3 years, 54% male) with eGFR 99.8 ± 14.5 mL/min/1.73 were studied. Subjects were split by sex and grouped into tertiles of UCa levels. Men in the highest UCa tertile had higher body mass index (BMI) and serum sclerostin, lower lean mass, and a trend towards higher fat mass. Women in the highest tertile had higher BMI and a trend towards higher serum sclerostin. Hypertension and metabolic syndrome, but not lower BMD, were more prevalent in the highest UCa tertile for both sexes. Sclerostin was positively correlated with fat mass and inversely correlated with lean mass among men, but not among women. BMD corrected for BMI at lumbar spine was inversely associated with UCa in a univariate analysis, but only serum sclerostin, hypertension, and NaCl intake were independent determinants of UCa in the multivariate model.Conclusion: The present findings disclose that in addition to hypertension and salt intake, serum sclerostin is associated with urinary calcium in stone formers, suggesting that in addition to the hormones traditionally thought to alter calcium reabsorption in the kidney, sclerostin may play a significant additional role, warranting further investigation.</p

Urinary Calcium Is Associated with Serum Sclerostin among Stone Formers

Background: Sclerostin plays an important role in bone metabolism and adipose tissue. Animal studies suggest that sclerostin influences urinary calcium (UCa), but this relationship has not been evaluated in stone formers (SFs). We aimed to investigate the association of UCa with serum sclerostin, bone mineral density (BMD), and body composition among SFs.Methods: Clinical and laboratorial data were retrieved from medical records. Determinants of UCa were studied using linear regression.Results: A total of 107 SFs (35.8 ± 9.3 years, 54% male) with eGFR 99.8 ± 14.5 mL/min/1.73 were studied. Subjects were split by sex and grouped into tertiles of UCa levels. Men in the highest UCa tertile had higher body mass index (BMI) and serum sclerostin, lower lean mass, and a trend towards higher fat mass. Women in the highest tertile had higher BMI and a trend towards higher serum sclerostin. Hypertension and metabolic syndrome, but not lower BMD, were more prevalent in the highest UCa tertile for both sexes. Sclerostin was positively correlated with fat mass and inversely correlated with lean mass among men, but not among women. BMD corrected for BMI at lumbar spine was inversely associated with UCa in a univariate analysis, but only serum sclerostin, hypertension, and NaCl intake were independent determinants of UCa in the multivariate model.Conclusion: The present findings disclose that in addition to hypertension and salt intake, serum sclerostin is associated with urinary calcium in stone formers, suggesting that in addition to the hormones traditionally thought to alter calcium reabsorption in the kidney, sclerostin may play a significant additional role, warranting further investigation.</p

Vascular Calcification Is Associated with Fetuin-A and Cortical Bone Porosity in Stone Formers

Background: Nephrolithiasis has been associated with bone loss and vascular calcification (VC), reflecting abnormal extraosseous calcium deposition. Fetuin-A (Fet-A) acts as a potent inhibitor of ectopic mineralization. The aim of the present study was to evaluate the prevalence of VC in stone formers (SF) and non-stone formers (NSF) and to investigate potential determinants of VC among SF, including circulating levels of Fet-A and bone microarchitecture parameters. Methods: Abdominal aortic calcification (AAC) was assessed using available computed tomography in SF and in age-, sex-, and BMI-matched NSF (potential living kidney donors). Serum Fet-A was measured in stored blood samples from SF. Bone microarchitecture parameters were obtained as a post hoc analysis of a cross-sectional cohort from young SF evaluated by high-resolution peripheral quantitative computed tomography (HR-pQCT). Results: A total of 62 SF (38.0 [28.0-45.3] years old) and 80 NSF (40.0 [37.0-45.8] years old) were included. There was no significant difference in AAC scores between SF and NSF. However, when dividing SF according to mean AAC score, below = 5.8% (n = 29), SF with higher AAC presented significantly higher BMI and tibial cortical porosity (Ct.Po) and significantly lower serum HDL, klotho, Fet-A, and eGFR. Urinary calcium did not differ between groups, but fractional excretion of phosphate was higher in the former. Upon multivariate regression, BMI, serum Fet-A, and tibial Ct.Po remained independently associated with AAC. Conclusions: This study suggests an association between reduced circulating Fet-A levels and increased bone Ct.Po with VC in SF

Transplantation of bone marrow mesenchymal stem cells decreases oxidative stress, apoptosis, and hippocampal damage in brain of a spontaneous stroke model

Stroke is the most common cause of motor disabilities and is a major cause of mortality worldwide. Adult stem cells have been shown to be effective against neuronal degeneration through mechanisms that include both the recovery of neurotransmitter activity and a decrease in apoptosis and oxidative stress. We chose the lineage stroke-prone spontaneously hypertensive rat (SHRSP) as a model for stem cell therapy. SHRSP rats can develop such severe hypertension that they generally suffer a stroke at approximately 1 year of age. the aim of this study was to evaluate whether mesenchymal stem cells (MSCs) decrease apoptotic death and oxidative stress in existing SHRSP brain tissue. the results of qRT-PCR assays showed higher levels of the antiapoptotic BcI-2 gene in the MSC-treated animals, compared with untreated. Our study also showed that superoxide, apoptotic cells, and by-products of lipid peroxidation decreased in MSC-treated SHRSP to levels similar those found in the animal controls, Wistar Kyoto rats. in addition, we saw a repair of morphological damage at the hippocampal region after MSC transplantation. These data suggest that MSCs have neuroprotective and antioxidant potential in stroke-prone spontaneously hypertensive rats. (c) 2014 the Authors. Published by Elsevier Inc.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Universidade Federal de São Paulo, Dept Biofis, BR-04023062 São Paulo, BrazilUniversidade Federal de São Paulo, Ctr Desenvolvimento Modelos Expt Med & Biol, BR-04023062 São Paulo, BrazilUniversidade Federal de São Paulo, Dept Morfol, BR-04023062 São Paulo, BrazilUniversidade Federal de São Paulo, Dept Fisiol, BR-04023062 São Paulo, BrazilUniv Santa Cecilia, Dept Odontol, Santos, SP, BrazilUniversidade Federal de São Paulo, Dept Nefrol, BR-04023062 São Paulo, BrazilUniversidade Federal de São Paulo, Dept Biofis, BR-04023062 São Paulo, BrazilUniversidade Federal de São Paulo, Ctr Desenvolvimento Modelos Expt Med & Biol, BR-04023062 São Paulo, BrazilUniversidade Federal de São Paulo, Dept Morfol, BR-04023062 São Paulo, BrazilUniversidade Federal de São Paulo, Dept Fisiol, BR-04023062 São Paulo, BrazilUniversidade Federal de São Paulo, Dept Nefrol, BR-04023062 São Paulo, BrazilFAPESP: 05/60630-1FAPESP: 10/00106-5Web of Scienc

Avaliação das alterações renais e intestinais induzidas pela cirurgia bariátrica em um modelo experimental em ratos

Bariatric surgery is a safe and effective treatment option for those affected by morbid obesity. However, one of the long-term complications after the procedure is an increased risk of developing kidney stones, due to excessive urinary oxalate excretion. The potential underlying mechanisms for hyperoxaluria have not yet been fully clarified, but may comprise increased intestinal oxalate absorption consequent to decreased calcium intake or increased dietary oxalate, fat malabsorption, changes in the gut flora (lower colonization by oxalate-degrading bacterium), and altered intestinal oxalate transport. Slc26a3 is an oxalate transporter responsible for active oxalate uptake along the small intestine, and the phenotype of these transporter knock-out mice is characterized by reduced urinary oxalate. On the other hand, knock-out of Slc26a6, an oxalate transporter responsible for active oxalate secretion along the small intestine results in mice exhibiting hyperoxaluria. The present study aimed to investigate urinary oxalate excretion (and other lithogenic parameters), fecal fat excretion and the expression of the intestinal oxalate transporters Slc26a3 and Slc26a6 in a bariatric surgery model in rats. Male Wistar rats underwent bariatric surgery (BS) or Sham procedure, as control. After recovery, the animals were randomized to different diets. Four (4) groups were fed a high fat diet with 1.0% sodium Ox (BS-F+Ox, n=7 and Sham-F+Ox, n=7) or without it (BS-F, n=t and Sham-F, n=7) for 8 weeks. The remaining 2 groups were maintained under standard chow (BS, n=7 and Sham, n=7) for the same period. One week before surgery (baseline) and at the end of protocol (final period), 24-hour urine and feces collections were obtained for urinary biochemical and fecal fat analysis by steatocrit technique. The urinary supersaturation risk of calcium oxalate [AP(CaOx)] was also calculated. At the end of protocol, the animals were euthanized, and a single fragment was retrieved from the biliopancreatic limb (5 cm before the gastrojejunal anastomosis), alimentary limb (5 cm after the anastomosis) and colon, for quantification of expression of Slc26a3 and Slc26a6 transporters by polymerase chain reaction. At final period, bariatric rats fed with fat presented steatorrhea, irrespective of oxalate supplementation. In bariatric animals fed with fat + oxalate, final urinary oxalate and calcium oxalate supersaturation risk was markedly and significantly increased versus baseline and higher than Sham animals under the same diet and from both bariatric groups under different diets. Slc26a3 was decreased in biliopancreatic limbs of bariatric rats, as a consequence to physiological adaptations imposed by the restriction of food passage through the surgery in this intestinal segment, but Slc26a6 was not altered in any harvested intestinal fragment. In conclusion, the present study suggested that bariatric animals under conditions of a high fat and oxalate diet, induced steatorrhea and a marked and significant increase in urinary oxalate and calcium oxalate supersaturation risk, but Slc26a3 and Slc26a6 oxalate transporters did not contribute to increase urinary oxalate in this rat model. Based on present findings, we speculate that hyperoxaluria after bariatric surgery is a consequence of both fat malabsorption induced by surgery and increased intestinal dietary oxalate absorption, possibly due to enhanced paracellular permeability, suggesting that bariatric patients may benefit from a low-fat and low-oxalate dietA cirurgia bariátrica é um procedimento eficaz e seguro para redução do peso corporal em obesos mórbidos. Entretanto, dentre as suas complicações a longo prazo, figuram o aumento do risco de nefrolitíase, devido principalmente à elevação do oxalato urinário, cuja fisiopatogenia não está completamente esclarecida. Dentre os mecanismos propostos para a ocorrência de hiperoxalúria em pacientes bariátricos, destacam-se a hiperabsorção intestinal de oxalato decorrente do aumento da ingestão de oxalato ou da redução da ingestão de cálcio, má absorção de gorduras, alterações na flora intestinal (menor colonização intestinal por bactérias degradadoras de oxalato), e/ou alterações no transporte intestinal de oxalato. Estudos experimentais em camundongos nocautes para Slc26a3, transportador intestinal responsável pela absorção de oxalato, revelaram redução do oxalato urinário. Por outro lado, camundongos nocautes para Slc26a6, transportador intestinal responsável pela secreção de oxalato, apresentaram hiperoxalúria. Os objetivos do presente estudo foram avaliar a excreção urinária de oxalato (e de outros parâmetros litogênicos), excreção fecal de gorduras e expressão dos transportadores intestinais de oxalato Slc26a3 e Slc26a6 em um modelo de cirurgia bariátrica em ratos. Ratos Wistar machos foram submetidos à cirurgia bariátrica (CB) ou a procedimento Sham, como controle. Após a recuperação, os animais foram divididos em grupos, de acordo com a dieta administrada: 4 grupos receberam dieta rica em gordura, suplementada com oxalato de sódio a 1% (CB-G+Ox, n=7 e Sham-G+Ox, n=7) ou não (CB-G, n=7 e Sham-G, n=7) e 2 grupos receberam dieta padrão (CB, n=7 e Sham, n=7) por 8 semanas. Foram coletadas urina e fezes de 24 horas no período basal (1 semana antes da cirurgia) e ao fim do experimento (final) para análises bioquímicas urinárias e pesquisa de gordura fecal pela técnica de esteatócrito. O risco de cristalização de oxalato de cálcio [AP(CaOx)] também foi calculado. Ao final do protocolo, os animais foram eutanasiados e fragmentos da alça biliopancreática (5 cm antes da anastomose gastrojejunal), alça alimentar (5 cm após a anastomose) e cólon foram coletados para quantificação da expressão dos transportadores intestinais de oxalato Slc26a3 e Slc26a6 por reação de polimerase em cadeia. No período final, os animais bariátricos que receberam dieta rica em gordura apresentaram esteatorreia, independente da suplementação com oxalato. Os animais bariátricos que receberam dieta rica em gordura e oxalato, apresentaram um aumento marcado e significante no oxalato urinário e no risco de cristalização de oxalato de cálcio, comparado ao período basal, aos controles Sham que receberam a mesma dieta e também a ambos os grupos de animais bariátricos sob diferentes dietas. A expressão de Slc26a3 foi significantemente menor somente na alça biliopancreática de animais bariátricos, sugerindo um mecanismo de adaptação à restrição da passagem de alimentos imposta pela cirurgia bariátrica. Não houve alterações na expressão de Slc26a6 em nenhum dos segmentos intestinais analisados. Em conclusão, o presente estudo sugere que, sob condições dietéticas rica em gordura e oxalato, os animais submetidos à cirurgia bariátrica apresentaram um aumento marcante e significante do oxalato urinário e do risco de cristalização de oxalato de cálcio, além de má-absorção de gorduras. Os presentes achados não sugeriram participação dos transportadores Slc26a3 e Slc26a6 no aumento do oxalato urinário neste modelo. Os resultados indicam que a hiperoxalúria pós cirurgia bariátrica é provavelmente uma consequência da má absorção induzida pela cirurgia juntamente com o aumento da absorção de oxalato dietético, possivelmente devido ao aumento do transporte paracelular de oxalato e não via transportador, sugerindo que uma dieta pobre em gordura e oxalato deva ser benéfica aos pacientes bariátricos.Dados abertos - Sucupira - Teses e dissertações (2013 a 2016

The Relationship between bone mineral metabolism and autonomic nervous system in a diet induced obese model in rats with normal renal function

Introdução: A interação entre a obesidade e o metabolismo mineral ósseo é bastante complexa. Embora tradicionalmente o aumento de peso corporal tenha sido considerado protetor contra a osteoporose devido à ação benéfica imposta pela maior carga mecânica, estudos recentes têm sugerido efeitos deletérios. O tecido adiposo secreta hormônios e citocinas, como a leptina, que possui ações estimulatórias diretas sobre as células ósseas, ou inibitórias via sinalização hipotalâmica e hiperativação do sistema nervoso simpático. Outro modulador importante da massa óssea é o neuropeptídeo Y (NPY), produzido principalmente no hipotálamo e associado negativamente com a formação óssea. Objetivos: Avaliar os parâmetros de remodelação e metabolismo mineral ósseo em um modelo experimental de obesidade induzida por dieta hiperlipídica em ratos, bem como avaliar os efeitos promovidos pela denervação total bilateral do tecido adiposo branco retroperitoneal (TABr). Métodos: Ratos Wistar machos foram alimentados com dieta hiperlipídica contendo 59% de gorduras (DHL) ou dieta controle (Ctl) durante 18 semanas. Na semana 14, foi realizada a cirurgia de denervação (Dn) do TABr ou cirurgia Sham, originando 4 grupos experimentais: Ctl, DHL, Ctl+Dn e DHL+Dn. O peso corporal foi aferido semanalmente e amostras de soro foram coletadas na semana 18 para determinação da função renal, perfis glicêmico e lipídico, leptina, NPY e outros hormônios calciotrópicos. Ao final do protocolo, os animais foram eutanasiados e depósitos de tecido adiposo, hipotálamo e tíbias foram coletados para análises moleculares. A tíbia direita foi processada para análise histomorfométrica de microarquitetura óssea e de parâmetros dinâmicos através da leitura da marcação por oxitetraciclina administrada previamente aos animais. Resultados: Os grupos DHL e DHL+Dn apresentaram aumento significante do peso corporal, circunferência abdominal e dos depósitos de tecidos adiposos, inclusive na medula óssea. A análise histomorfométrica do grupo DHL revelou redução significante da formação e retardo na mineralização óssea, acompanhada de redução do marcador sérico de formação óssea P1NP, porém sem alterações nos parâmetros de reabsorção óssea. O grupo DHL também apresentou elevação significante dos níveis séricos e ósseos de leptina e FGF23, e dos níveis sérico e hipotalâmico de NPY, além de redução de 1,25-dihidroxivitamina D3, PTH, osteoprotegerina e ACTH. A denervação do TABr restabeleceu as alterações ósseas encontradas e normalizou os níveis séricos e hipotalâmicos de NPY. Conclusões: O presente estudo demonstrou efeitos deletérios da obesidade sobre o tecido ósseo, comprometendo basicamente a formação e mineralização, efeitos esses possivelmente mediados pelas ações centrais da leptina e do NPY. A denervação do TABr restaurou a formação óssea e o aumento da expressão hipotalâmica de NPY, sugerindo uma mediação central do processo de remodelação óssea na obesidade.Introduction: The interaction between obesity and bone metabolism is complex. Although increased body weight had been traditionally considered as protective against osteoporosis due to the mechanical loading, recent studies suggest a negative effect of obesity upon bone metabolism. Adipose tissue releases hormones and cytokines, such as leptin, which plays a role in the regulation of bone metabolism by a direct action on bone cells (stimulatory) or through inhibitory effects via a central nervous system (CNS) relay resulting in activation of the sympathetic nervous system. Neuropeptide Y (NPY) is another important regulator of bone metabolism, mainly produced in the hypothalamus and is negatively correlated with bone formation. Objectives: To evaluate parameters of bone mineral metabolism and remodeling in an experimental model of diet-induced obesity in rats as well as to evaluate the effects evoked by bilateral retroperitoneal white adipose tissue (rWAT) denervation. Methods: Male Wistar rats were fed with high-fat diet containing 59% of fat (HFD) or standard diet as controls (Ctrl) for 18 weeks and rWAT denervation (Dnx) or Sham surgery was performed at the 14th week providing 4 experimental groups: Ctrl, HFD, Ctrl+Dnx and HFD+Dnx. Body weight was weekly assessed, and serum samples were collected at 18th week for determination of renal function, glucose and lipid profiles, leptin, NPY and calciotropic hormones. At the end of protocol, animals were euthanized and adipose tissue pads, hypothalamus and tibias were collected for molecular analyses. The right tibia was harvested to assess bone microarchitecture by histomorphometric analysis including double-labeled oxytetracycline previously administered for measurement of dynamic parameters. Results: Both HFD group and HFD+Dnx groups presented significantly increased body weight, abdominal circumference and adipose tissue pad including bone marrow adipose tissue. In HFD group, histomorphometry disclosed reduction of bone formation and delayed mineralization associated to decreased serum bone formation marker P1NP, without alterations in bone resorption. Higher serum and bone tissue levels of leptin and FGF23 were observed in HFD group, in addition to a higher serum and hypothalamic levels of NPY and lower serum 1,25-dihidroxivitamin D3, PTH, osteoprotegerin and ACTH. The rWAT denervation restored bone formation and normalized serum and hypothalamic NPY levels. Conclusions: Present findings suggest that obesity negatively affects bone remodeling probably due to central actions of leptin and NPY. The rWAT denervation restored both bone formation and increased hypothalamic NPY levels, suggesting a CNS mediation of bone remodeling in obesity

Comparison of the Effects of Mesenchymal Stem Cells with Their Extracellular Vesicles on the Treatment of Kidney Damage Induced by Chronic Renal Artery Stenosis

Background. Chronic renal artery stenosis is considered one of the most common causes of renovascular hypertension (RH). Chronic hypoxia can lead to irreversible damage to renal tissue and to a progressive deterioration of renal function. We have previously shown that bone marrow-derived mesenchymal stem cells (BMSCs) improved renal parenchyma and function in a model of RH (2 kidneys, 1 clip model (2K-1C) in rats. Microvesicles (MVs) and exosomes (EXs) released by MSCs have been shown to induce effects similar to those induced by whole cells but with fewer side effects. In this study, we compared the effects of adipose-derived MSCs (ASCs) with those of the MVs and EXs released by ASCs on tissue inflammation and renal function in 2 K-1C rats. Results. Flow cytometry analysis showed that even after 15 days, ASCs were still detected in both kidneys. The expression of a stem cell homing marker (SDF1-α) was increased in ASC-treated animals in both the stenotic and contralateral kidneys. Interestingly, SDF1-α expression was also increased in MV- and EX-treated animals. A hypoxia marker (HIF1-α) was upregulated in the stenotic kidney, and treatments with ASCs, MVs, and EXs were effective in reducing the expression of this marker. Stenotic animals showed a progressive increase in systolic blood pressure (SBP), while animals treated with ASCs, MVs, and EXs showed a stabilization of SBP, and this stabilization was similar among the different treatments. Stenotic animals developed significant proteinuria, which was reduced by ASCs and MVs but not by EXs. The increased expression of Col I and TGFβ in both kidneys was reduced by all the treatments, and these treatments also effectively increased the expression of the anti-inflammatory cytokine IL-10 in both kidneys; however, only ASCs were able to reduce the overexpression of the proinflammatory cytokine IL-1β in both kidneys of 2K-1C animals. Conclusion. The results of this study demonstrated that the EVs released by ASCs produced beneficial results but with lower efficacy than whole cells. ASCs produced stronger effects in this model of renal chronic hypoxia, and the use of EVs instead of whole cells should be evaluated depending on the parameter to be corrected