RESUMO
Humans are predisposed to gout because they lack uricase that converts uric acid to allantoin. Rodents have uricase, resulting in low basal serum uric acid. A uricase inhibitor raises serum uric acid in rodents. There were two aims of the study in polycystic kidney disease (PKD): 1) to determine whether increasing serum uric acid with the uricase inhibitor, oxonic acid, resulted in faster cyst growth and 2) to determine whether treatment with the xanthine oxidase inhibitor, oxypurinol, reduced the cyst growth caused by oxonic acid. Orthologous models of human PKD were used: PCK rats, a polycystic kidney and hepatic disease 1 (Pkhd1) gene model of autosomal recessive PKD (ARPKD) and Pkd1RC/RC mice, a hypomorphic Pkd1 gene model. In PCK rats and Pkd1RC/RC mice, oxonic acid resulted in a significant increase in serum uric acid, kidney weight, and cyst index. Mechanisms of increased cyst growth that were investigated were proinflammatory cytokines, the inflammasome, and crystal deposition in the kidney. Oxonic acid resulted in an increase in proinflammatory cytokines in the serum and kidney in Pkd1RC/RC mice. Oxonic acid did not cause activation of the inflammasome or uric acid crystal deposition in the kidney. In Pkd1RC/RC male and female mice analyzed together, oxypurinol decreased the oxonic acid-induced increase in cyst index. In summary, increasing serum uric acid by inhibiting uricase with oxonic acid results in an increase in kidney weight and cyst index in PCK rats and Pkd1RC/RC mice. The effect is independent of inflammasome activation or crystal deposition in the kidney.NEW & NOTEWORTHY This is the first reported study of uric acid measurements and xanthine oxidase inhibition in polycystic kidney disease (PKD) rodents. Raising serum uric acid with a uricase inhibitor resulted in increased kidney weight and cyst index in Pkd1RC/RC mice and PCK rats, elevated levels of proinflammatory cytokines in the serum and kidney in Pkd1RC/RC mice, and no uric acid crystal deposition or activation of the caspase-1 inflammasome in the kidney.
Assuntos
Modelos Animais de Doenças , Rim , Doenças Renais Policísticas , Urato Oxidase , Ácido Úrico , Animais , Ácido Úrico/sangue , Doenças Renais Policísticas/patologia , Doenças Renais Policísticas/metabolismo , Doenças Renais Policísticas/tratamento farmacológico , Rim/patologia , Rim/efeitos dos fármacos , Rim/metabolismo , Masculino , Oxipurinol/farmacologia , Ácido Oxônico/farmacologia , Inibidores Enzimáticos/farmacologia , Ratos , Feminino , Inflamassomos/metabolismo , Citocinas/metabolismo , Citocinas/sangue , Camundongos , Canais de Cátion TRPP/genética , Canais de Cátion TRPP/metabolismo , Xantina Oxidase/antagonistas & inibidores , Xantina Oxidase/metabolismo , Ratos Sprague-Dawley , Camundongos Endogâmicos C57BLRESUMO
Childhood obesity is a global public health concern with significant implications for long-term health. This study addresses the rising rates of obesity among school-age children (10-12 years) and investigates the effectiveness of aerobic exercise interventions in improving anthropometric parameters, specifically focusing on BMI and mid-arm circumference (MAC). The study emphasizes the role of schools in shaping children's behaviors and aims to contribute empirical evidence to inform health promotion strategies for this demographic. The research employs a quasi-experimental design, involving 60 school-age children in Visnagar, Gujarat, India. The 12-week aerobic exercise intervention, conducted three times a week, comprises activities like running, jumping jacks, and dance routines. Data collection includes sociodemographic information, BMI, and MAC measurements. The study design, participant criteria, and intervention details are carefully outlined. Socio-demographic variables such as age and monthly family income significantly influence BMI, highlighting the importance of considering these factors in interventions. Pretest results show 80% of children classified as overweight, reducing to 58.3% post-intervention. The mean BMI significantly decreases from 24.41 to 22.84 (p < 0.05), indicating the positive impact of aerobic exercise. The study also explores the association between BMI, MAC, and socio-demographic variables through chi-square tests. Data shows the prevalence of overweight and obesity among school-age children and demonstrates the effectiveness of a 12-week aerobic exercise program in improving BMI. Findings align with existing literature on the positive impact of physical activity on weight management in children.
RESUMO
Metformin (MET) has the potential to activate p-AMPK and block mTORC1-induced proliferation of tubular cells in PKD kidneys. The aim of this study was to determine the effects of MET on cyst growth, kidney function, AMPK and mTOR signaling, and lactate levels in male PCK rats, a Pkhd1 gene mutation model of human autosomal recessive polycystic kidney disease (ARPKD). MET 300 mg/kg/day IP from days 28 to 84 of age resulted in a mean serum metformin level that was 10 times the upper limit of therapeutic, no effect on cyst indices, nephrotoxicity, and increased serum lactate. MET 150 mg/kg resulted in a therapeutic serum metformin level but had no effect on kidney weight, cyst indices, kidney function, or mTOR and autophagy proteins. In summary, a standard dose of MET was ineffective in reducing PKD, did not activate p-AMPK or suppress mTOR and the higher dose resulted in increased lactate levels and nephrotoxicity. In conclusion, the study dampens enthusiasm for human studies of MET in PKD. Doubling the metformin dose resulted in a 10-fold increase in mean blood levels and toxicity suggesting that the dosage range between therapeutic and toxic is narrow.