RESUMO
Abstract Hyperuricemia is common in chronic kidney disease (CKD) and may be present in 50% of patients presenting for dialysis. Hyperuricemia can be secondary to impaired glomerular filtration rate (GFR) that occurs in CKD. However, hyperuricemia can also precede the development of kidney disease and predict incident CKD. Experimental studies of hyperuricemic models have found that both soluble and crystalline uric acid can cause significant kidney damage, characterized by ischemia, tubulointerstitial fibrosis, and inflammation. However, most Mendelian randomization studies failed to demonstrate a causal relationship between uric acid and CKD, and clinical trials have had variable results. Here we suggest potential explanations for the negative clinical and genetic findings, including the role of crystalline uric acid, intracellular uric acid, and xanthine oxidase activity in uric acid-mediated kidney injury. We propose future clinical trials as well as an algorithm for treatment of hyperuricemia in patients with CKD.
Resumo A hiperuricemia é comum na doença renal crônica (DRC) e pode estar presente em até 50% dos pacientes que se apresentam para diálise. A hiperuricemia pode ser secundária ao comprometimento da taxa de filtração glomerular (TFG) que ocorre na DRC. No entanto, ela também pode preceder o desenvolvimento da doença renal e mesmo prever uma DRC incidente. Estudos experimentais de modelos hiperuricêmicos descobriram que tanto o ácido úrico solúvel quanto o cristalino podem causar danos renais significativos, caracterizados por isquemia, fibrose tubulointersticial e inflamação. Entretanto, a maioria dos estudos de randomização Mendeliana falhou em demonstrar uma relação causal entre o ácido úrico e a DRC, e os ensaios clínicos têm apresentado resultados variáveis. Aqui sugerimos explicações potenciais para os achados clínicos e genéticos negativos, incluindo o papel do ácido úrico cristalino, do ácido úrico intracelular e da atividade da xantina oxidase na lesão renal mediada por ácido úrico. Propomos ensaios clínicos futuros, bem como um algoritmo para o tratamento de hiperuricemia em pacientes com DRC.
Assuntos
Humanos , Hiperuricemia/complicações , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/terapia , Ácido Úrico , Diálise Renal , Taxa de Filtração GlomerularRESUMO
Hyperuricemia is common in chronic kidney disease (CKD) and may be present in 50% of patients presenting for dialysis. Hyperuricemia can be secondary to impaired glomerular filtration rate (GFR) that occurs in CKD. However, hyperuricemia can also precede the development of kidney disease and predict incident CKD. Experimental studies of hyperuricemic models have found that both soluble and crystalline uric acid can cause significant kidney damage, characterized by ischemia, tubulointerstitial fibrosis, and inflammation. However, most Mendelian randomization studies failed to demonstrate a causal relationship between uric acid and CKD, and clinical trials have had variable results. Here we suggest potential explanations for the negative clinical and genetic findings, including the role of crystalline uric acid, intracellular uric acid, and xanthine oxidase activity in uric acid-mediated kidney injury. We propose future clinical trials as well as an algorithm for treatment of hyperuricemia in patients with CKD.
Assuntos
Hiperuricemia , Insuficiência Renal Crônica , Taxa de Filtração Glomerular , Humanos , Hiperuricemia/complicações , Diálise Renal , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/terapia , Ácido ÚricoRESUMO
Excessive intake of fructose results in metabolic syndrome (MS) and kidney damage, partly mediated by its metabolism by fructokinase-C or ketohexokinase-C (KHK-C). Osthol has antioxidant properties, is capable of regulating adipogenesis, and inhibits KHK-C activity. Here, we examined the potential protective role of osthol in the development of kidney disease induced by a Western (high-fat/high-sugar) diet. Control rats fed with a high-fat/high-sugar diet were compared with two groups that also received two different doses of osthol (30 mg/kg/d or 40 mg/kg/d body weight BW). A fourth group served as a normal control and received regular chow. At the end of the follow-up, kidney function, metabolic markers, oxidative stress, and lipogenic enzymes were evaluated. The Western diet induced MS (hypertension, hyperglycemia, hypertriglyceridemia, obesity, hyperuricemia), a fall in the glomerular filtration rate, renal tubular damage, and increased oxidative stress in the kidney cortex, with increased expression of lipogenic enzymes and increased kidney KHK expression. Osthol treatment prevented the development of MS and ameliorated kidney damage by inhibiting KHK activity, preventing oxidative stress via nuclear factor erythroid 2-related factor (Nrf2) activation, and reducing renal lipotoxicity. These data suggest that the nutraceutical osthol might be an ancillary therapy to slow the progression of MS and kidney damage induced by a Western diet.
Assuntos
Cumarínicos/farmacologia , Dieta Ocidental/efeitos adversos , Frutoquinases/antagonistas & inibidores , Nefropatias/prevenção & controle , Síndrome Metabólica/prevenção & controle , Animais , Cumarínicos/uso terapêutico , Dieta da Carga de Carboidratos/efeitos adversos , Dieta Hiperlipídica/efeitos adversos , Frutoquinases/metabolismo , Frutose/metabolismo , Nefropatias/etiologia , Nefropatias/metabolismo , Masculino , Síndrome Metabólica/etiologia , Síndrome Metabólica/metabolismo , Fator 2 Relacionado a NF-E2 , Estresse Oxidativo , Substâncias Protetoras/farmacologia , Substâncias Protetoras/uso terapêutico , Ratos , Ratos WistarRESUMO
Currently, there is the paradox of low water intake but increased intake of sugar-sweetened beverages (SB) in several populations; those habits are associated with an increased prevalence of metabolic derangements and greater chronic disease mortality. Persistent heat dehydration and increased SB intake stimulate the continued release of vasopressin and overactivation of the polyol-fructokinase pathway, synergizing each other, an effect partially mediated by oxidative stress. The objective of the present study was to evaluate whether water restriction concurrent with SB hydration can cause renal damage by stimulating similar pathways as heat dehydration. Three groups of male Wistar rats (n = 6) were fluid restricted; from 10 am to 12 pm animals could rehydrate with tap water (W), or sweetened beverages, one prepared with 11% of a fructose-glucose combination (SB), or with the noncaloric edulcorant stevia (ST). A normal control group of healthy rats was also studied. The animals were followed for 4 weeks. Markers of dehydration and renal damage were evaluated at the end of the study. Fluid restriction and water hydration mildly increased urine osmolality and induced a 15% fall in CrCl while increased the markers of tubular damage by NAG and KIM-1. Such changes were in association with a mild overexpression of V1a and V2 renal receptors, polyol fructokinase pathway overactivation, and increased renal oxidative stress with reduced expression of antioxidant enzymes. Hydration with SB significantly amplified those alterations, while in stevia hydrated rats, the changes were similar to the ones observed in water hydrated rats. These data suggest that current habits of hydration could be a risk factor in developing kidney damage.
Assuntos
Nefropatias , Rim/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Bebidas Adoçadas com Açúcar/efeitos adversos , Animais , Desidratação/metabolismo , Desidratação/patologia , Frutoquinases/metabolismo , Frutose/efeitos adversos , Frutose/farmacologia , Glucose/efeitos adversos , Glucose/farmacologia , Rim/patologia , Nefropatias/induzido quimicamente , Nefropatias/metabolismo , Nefropatias/patologia , Masculino , Ratos , Ratos Wistar , Receptores de Vasopressinas/metabolismoRESUMO
Chronic vasopressin secretion induced by recurrent mild heat stress exposure is significantly enhanced by limited rehydration with a fructose-containing beverage both in rodents and in humans. Moreover, this effect has been associated with upregulation of the polyol-fructokinase pathway and increased renal oxidative stress. Previously, we have shown that pharmacological inhibition of both V1a and V2 vasopressin receptors with conivaptan improved such renal alterations. The aim of this study was to evaluate the independent contributions of V1a and V2 receptors to the renal damage caused by mild heat stress and limited rehydration with a fructose-containing beverage. Osmotic minipumps were used to deliver either relcovaptan (0.64 mg/day) or tolvaptan (0.25 mg/day) in male Wistar rats for two weeks. Corresponding dilution vehicles were used as controls. To induce dehydration, rats were exposed to mild heat stress (37 °C for 1 h, Monday to Friday). All groups received a 10% fructose solution as a rehydration fluid for 2 h after mild heat stress. For the remainder of the day and on weekends, rats received tap water. The independent blockade of either the V1a or the V2 receptor prevented renal damage, reduced oxidative stress, and decreased plasma cortisol and systemic inflammation. However, the beneficial effects were regulated by different mechanisms. Tolvaptan inhibited polyol-fructokinase pathway overactivation, while relcovaptan prevented upregulation of the renin-angiotensin system and SGK1 expression. These data suggest that both V1a and V2 receptors participate in renal damage caused by heat stress-induced dehydration when fructose-containing beverages are used as rehydration fluids.
Assuntos
Bebidas/análise , Frutose/metabolismo , Resposta ao Choque Térmico , Receptores de Vasopressinas/metabolismo , Animais , Hidratação , Resposta ao Choque Térmico/efeitos dos fármacos , Hidrocortisona/sangue , Proteínas Imediatamente Precoces/genética , Proteínas Imediatamente Precoces/metabolismo , Indóis/farmacologia , Córtex Renal/metabolismo , Masculino , Estresse Oxidativo/efeitos dos fármacos , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Pirrolidinas/farmacologia , Ratos , Ratos Wistar , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/patologia , Sistema Renina-Angiotensina/efeitos dos fármacos , Temperatura , Tolvaptan/farmacologia , Regulação para Cima/efeitos dos fármacosRESUMO
Recently repeated heat stress and dehydration have been reported to cause oxidative stress and kidney damage that is enhanced by rehydrating with fructose solutions. We hypothesized that antioxidants might provide a novel way to prevent kidney damage. To test this hypothesis, mild heat stress was induced by exposing rats to 37 °C during 1 h in a closed chamber. The supplementation with water-soluble antioxidants (Antiox), ascorbic acid 1% plus N-acetyl cysteine 600 mg/L was done either in the 10% fructose 2 h rehydration fluid immediately after heat stress (Fructose 10% + Antiox), and/or in the tap water (Water + Antiox) for the remainder of the day, or in both fluids. After 4 weeks, control rats exposed to heat with fructose rehydration developed impaired renal function, tubular injury, intrarenal oxidative stress, a reduction in Nrf2-Keap1 antioxidant pathway, stimulation of vasopressin and the intrarenal polyol-fructokinase pathway. In contrast, dosing the antioxidants in the tap water (i.e., before the heat exposure and rehydration with fructose) preserved renal function, prevented renal tubule dysfunction and avoided the increase in systemic blood pressure. These effects were likely due to the amplification of the antioxidant defenses through increased Nrf2 nuclear translocation stimulated by the antioxidants and by the prevention of polyol fructokinase pathway overactivation. More studies to understand the mechanisms implicated in this pathology are warranted as there is recent evidence that they may be operating in humans as well.
Assuntos
Antioxidantes/farmacologia , Bebidas , Frutose/efeitos adversos , Resposta ao Choque Térmico , Nefropatias/metabolismo , Transporte Ativo do Núcleo Celular , Aldeído Redutase/metabolismo , Animais , Antioxidantes/administração & dosagem , Pressão Sanguínea , Núcleo Celular/metabolismo , Desidratação , Hidratação , Frutoquinases/metabolismo , Glutationa/metabolismo , Masculino , Óxido Nítrico Sintase Tipo III/metabolismo , Polímeros/metabolismo , Transporte Proteico , Ratos , Ratos WistarRESUMO
Patients suffering from chronic mountain sickness (CMS) have excessive erythrocytosis. Low -level cobalt toxicity as a likely contributor has been demonstrated in some subjects. We performed a randomized, placebo controlled clinical trial in Cerro de Pasco, Peru (4380m), where 84 participants with a hematocrit (HCT) ≥65% and CMS score>6, were assigned to four treatment groups of placebo, acetazolamide (ACZ, which stimulates respiration), N-acetylcysteine (NAC, an antioxidant that chelates cobalt) and combination of ACZ and NAC for 6 weeks. The primary outcome was change in hematocrit and secondary outcomes were changes in PaO2, PaCO2, CMS score, and serum and urine cobalt concentrations. The mean (±SD) hematocrit, CMS score and serum cobalt concentrations were 69±4%, 9.8±2.4 and 0.24±0.15µg/l, respectively for the 66 participants. The ACZ arm had a relative reduction in HCT of 6.6% vs. 2.7% (p=0.048) and the CMS score fell by 34.9% vs. 14.8% (p=0.014) compared to placebo, while the reduction in PaCO2 was 10.5% vs. an increase of 0.6% (p=0.003), with a relative increase in PaO2 of 13.6% vs. 3.0%. NAC reduced CMS score compared to placebo (relative reduction of 34.0% vs. 14.8%, p=0.017), while changes in other parameters failed to reach statistical significance. The combination of ACZ and NAC was no better than ACZ alone. No changes in serum and urine cobalt concentrations were seen within any treatment arms. ACZ reduced polycythemia and CMS score, while NAC improved CMS score without significantly lowering hematocrit. Only a small proportion of subjects had cobalt toxicity, which may relate to the closing of contaminated water sources and several other environmental protection measures.
Assuntos
Acetazolamida/uso terapêutico , Acetilcisteína/uso terapêutico , Doença da Altitude/tratamento farmacológico , Inibidores da Anidrase Carbônica/uso terapêutico , Sequestradores de Radicais Livres/uso terapêutico , Adulto , Doença da Altitude/sangue , Doença da Altitude/urina , Análise de Variância , Gasometria , Distribuição de Qui-Quadrado , Doença Crônica , Cobalto/sangue , Cobalto/urina , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Hematócrito/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Peru , Estudos Prospectivos , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
OBJECTIVES: To study Mesoamerican nephropathy (MeN) and its risk factors in three hot occupations. DESIGN: Cross-sectional. SETTING: Chinandega and León municipalities, a MeN hotspot on the Nicaraguan Pacific coast, January-February 2013. PARTICIPANTS: 194 male workers aged 17-39â years: 86 sugarcane cutters, 56 construction workers, 52 small-scale farmers. OUTCOME MEASURES: (1) Differences between the three occupational groups in prevalences/levels of socioeconomic, occupational, lifestyle and health risk factors for chronic kidney disease (CKD) and in biomarkers of kidney function and hydration; (2) differences in prevalences/levels of CKD risk factors between workers with reduced estimated glomerular filtration rate (eGFRCKD-EPI <80â mL/min/1.73â m2) and workers with normal kidney function (eGFRCKD-EPI ≥80â mL/min/1.73â m2). RESULTS: Sugarcane cutters were more exposed to heat and consumed more fluid on workdays and had less obesity, lower blood sugar, lower blood pressure and a better lipid profile. Reduced eGFR occurred in 16%, 9% and 2% of sugarcane cutters, construction workers and farmers, respectively (trend cane > construction > farming, p=0.003). Significant trends (cane > construction > farming) were also observed for high serum urea nitrogen (blood urea nitrogen (BUN) >20â mg/dL), high serum creatinine (SCr >1.2â mg/dL), low urinary pH (≤5.5) and high BUN/SCr ratio (>20) but not for high urinary specific gravity (≥1.030). Sugarcane cutters also more often had proteinuria and blood and leucocytes in the urine. Workers with eGFR <80â mL/min/1.73â m2 reported a higher intake of water and lower intake of sugary beverages. Serum uric acid levels related strongly and inversely to eGFR levels (adj ß -10.4â mL/min/1.73â m2, 95% CI -12.2 to -8.5, p<0.001). No associations were observed for other metabolic risk factors, pesticides, non-steroidal anti-inflammatory drugs or alcohol. Among cane cutters, consumption of electrolyte hydration solution appeared preventive (adj ß 8.1â mL/min/1.73â m2, p=0.09). CONCLUSIONS: Heat stress, dehydration and kidney dysfunction were most common among sugarcane cutters. Kidney dysfunction also occurred to a lesser extent among construction workers, but hardly at all among small-scale farmers. High serum uric acid was associated with reduced kidney function.
Assuntos
Desidratação/etiologia , Transtornos de Estresse por Calor/etiologia , Temperatura Alta , Exposição Ocupacional/efeitos adversos , Ocupações , Insuficiência Renal Crônica/etiologia , Ácido Úrico/sangue , Adolescente , Adulto , Agricultura , Nitrogênio da Ureia Sanguínea , Indústria da Construção , Creatinina/sangue , Estudos Transversais , Taxa de Filtração Glomerular , Humanos , Rim/patologia , Rim/fisiopatologia , Testes de Função Renal , Masculino , Nicarágua , Doenças Profissionais/etiologia , Fatores de Risco , Adulto JovemRESUMO
Climate change has led to significant rise of 0.8°C-0.9°C in global mean temperature over the last century and has been linked with significant increases in the frequency and severity of heat waves (extreme heat events). Climate change has also been increasingly connected to detrimental human health. One of the consequences of climate-related extreme heat exposure is dehydration and volume loss, leading to acute mortality from exacerbations of pre-existing chronic disease, as well as from outright heat exhaustion and heat stroke. Recent studies have also shown that recurrent heat exposure with physical exertion and inadequate hydration can lead to CKD that is distinct from that caused by diabetes, hypertension, or GN. Epidemics of CKD consistent with heat stress nephropathy are now occurring across the world. Here, we describe this disease, discuss the locations where it appears to be manifesting, link it with increasing temperatures, and discuss ongoing attempts to prevent the disease. Heat stress nephropathy may represent one of the first epidemics due to global warming. Government, industry, and health policy makers in the impacted regions should place greater emphasis on occupational and community interventions.
Assuntos
Mudança Climática , Epidemias , Calor Extremo/efeitos adversos , Transtornos de Estresse por Calor/epidemiologia , Insuficiência Renal Crônica/epidemiologia , América Central/epidemiologia , Desidratação/etiologia , Transtornos de Estresse por Calor/etiologia , Humanos , Índia/epidemiologia , América do Norte/epidemiologia , Esforço Físico , Insuficiência Renal Crônica/etiologia , América do Sul/epidemiologia , Sri Lanka/epidemiologiaRESUMO
BACKGROUND: Chronic kidney disease is common among sugarcane workers in Central America. The main risk factor seems to be repeated high-intensity work in hot environments. Several cross-sectional studies have been performed but few longitudinal studies. OBJECTIVES: The aim of the study was to examine whether kidney function changes over a few months of work during the harvest period. METHODS: A group of male sugarcane cutters in Nicaragua (N=29, aged 17-38 years) was examined with renal biomarkers before and after shift on the first day at the start of harvest, on the sixth day during acclimatization, and then in mid-harvest 9 weeks later. A reference group (N=25, mainly office workers) was examined with the same biomarkers at start of harvest, and then at end of harvest 5 months later. RESULTS: The pre-shift renal function decreased significantly during 9 weeks of work in the cane cutters. Mean serum creatinine increased (20%), mean estimated glomerular filtration rate decreased (9%, 10mL/min), serum urea N (BUN) increased (41%), and mean urinary neutrophil gelatinase-associated lipocalin (NGAL) increased (four times). The cane cutters also developed cross-shift increases in these biomarkers, in particular serum creatinine and BUN, and in urinary uric acid. The longitudinal decrease in eGFR tended to be associated with the cross-shift increase in serum creatinine. CONCLUSIONS: There was a remarkable decrease of glomerular kidney function, after only 9 weeks of harvest. The cross-shift increase in serum creatinine may be caused by dehydration (pre-renal dysfunction), and when repeated on a daily basis this may cause permanently reduced GFR.
Assuntos
Fazendeiros , Testes de Função Renal , Rim/fisiologia , Saccharum , Adolescente , Adulto , Biomarcadores/análise , Humanos , Estudos Longitudinais , Masculino , Nicarágua , Estações do Ano , Adulto JovemRESUMO
BACKGROUND: An epidemic of chronic kidney disease (CKD) of unknown cause has emerged along the Pacific Coast of Central America. The disease primarily affects men working manually outdoors, and the major group affected is sugarcane workers. The disease presents with an asymptomatic rise in serum creatinine that progresses to end-stage renal disease over several years. Renal biopsies show chronic tubulointerstitial disease. While the cause remains unknown, recent studies suggest that it is driven by recurrent dehydration in the hot climate. Potential mechanisms include the development of hyperosmolarity with the activation of the aldose reductase-fructokinase pathway in the proximal tubule leading to local injury and inflammation, and the possibility that renal injury may be the consequence of repeated uricosuria and urate crystal formation as a consequence of both increased generation and urinary concentration, similar to a chronic tumor lysis syndrome. The epidemic is postulated to be increasing due to the effects of global warming. SUMMARY: An epidemic of CKD has led to the death of more than 20,000 lives in Central America. The cause is unknown, but appears to be due to recurrent dehydration. Potential mechanisms for injury are renal damage as a consequence of recurrent hyperosmolarity and/or injury to the tubules from repeated episodes of uricosuria. KEY MESSAGES: The epidemic of CKD in Mesoamerica may be due to chronic recurrent dehydration as a consequence of global warming and working conditions. This entity may be one of the first major diseases attributed to climate change and the greenhouse effect.
Assuntos
Doenças dos Trabalhadores Agrícolas/diagnóstico , Desidratação/diagnóstico , Aquecimento Global , Falência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/diagnóstico , Adulto , Doenças dos Trabalhadores Agrícolas/sangue , Doenças dos Trabalhadores Agrícolas/epidemiologia , Doenças dos Trabalhadores Agrícolas/patologia , Aldeído Redutase/metabolismo , América Central/epidemiologia , Creatinina/sangue , Desidratação/sangue , Desidratação/epidemiologia , Desidratação/patologia , Progressão da Doença , Ativação Enzimática , Frutoquinases/metabolismo , Temperatura Alta , Humanos , Falência Renal Crônica/sangue , Falência Renal Crônica/epidemiologia , Falência Renal Crônica/patologia , Túbulos Renais Proximais/metabolismo , Túbulos Renais Proximais/patologia , Masculino , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/epidemiologia , Insuficiência Renal Crônica/patologia , Ácido Úrico/sangueRESUMO
Mesoamerican nephropathy (MeN), an epidemic in Central America, is a chronic kidney disease of unknown cause. In this article, we argue that MeN may be a uric acid disorder. Individuals at risk for developing the disease are primarily male workers exposed to heat stress and physical exertion that predisposes to recurrent water and volume depletion, often accompanied by urinary concentration and acidification. Uric acid is generated during heat stress, in part consequent to nucleotide release from muscles. We hypothesize that working in the sugarcane fields may result in cyclic uricosuria in which uric acid concentrations exceed solubility, leading to the formation of dihydrate urate crystals and local injury. Consistent with this hypothesis, we present pilot data documenting the common presence of urate crystals in the urine of sugarcane workers from El Salvador. High end-of-workday urinary uric acid concentrations were common in a pilot study, particularly if urine pH was corrected to 7. Hyperuricemia may induce glomerular hypertension, whereas the increased urinary uric acid may directly injure renal tubules. Thus, MeN may result from exercise and heat stress associated with dehydration-induced hyperuricemia and uricosuria. Increased hydration with water and salt, urinary alkalinization, reduction in sugary beverage intake, and inhibitors of uric acid synthesis should be tested for disease prevention.
Assuntos
Exercício Físico , Transtornos de Estresse por Calor/etiologia , Insuficiência Renal Crônica/etiologia , Ácido Úrico/urina , Adulto , América Central , Cristalização , Humanos , MasculinoRESUMO
An epidemic of chronic kidney disease (CKD) in Mesoamerica is providing new insights into the mechanisms by which salt and water might drive hypertension and CKD. Increasingly, evidence suggests that recurrent dehydration and salt loss might be a mechanism that causes CKD, and experimental studies suggest a key role for increased plasma osmolarity in activating both intrarenal (polyol-fructokinase) and extrarenal (vasopressin) pathways that drive renal injury. Thus, we propose that water and salt might influence blood pressure and kidney disease through the timing and combination of their intake, which affect plasma osmolarity as well as intrarenal and extrarenal mechanisms of renal injury. The type of fluid intake might also be important, as fluids containing fructose can trigger activation of these pathways. Future studies should investigate the effects of salt, sugar and fluid intake on plasma osmolarity as a potential pathogenetic mechanism in renal injury and high blood pressure.
Assuntos
Doenças dos Trabalhadores Agrícolas/etiologia , Desidratação/complicações , Hipertensão/etiologia , Concentração Osmolar , Plasma , Insuficiência Renal Crônica/etiologia , América Central , Frutoquinases/sangue , Humanos , Nefropatias/complicaçõesRESUMO
UNLABELLED: Fructose intake from added sugars has been implicated as a cause of nonalcoholic fatty liver disease. Here we tested the hypothesis that fructose may interact with a high-fat diet to induce fatty liver, and to determine if this was dependent on a key enzyme in fructose metabolism, fructokinase. Wild-type or fructokinase knockout mice were fed a low-fat (11%), high-fat (36%), or high-fat (36%) and high-sucrose (30%) diet for 15 weeks. Both wild-type and fructokinase knockout mice developed obesity with mild hepatic steatosis and no evidence of hepatic inflammation on a high-fat diet compared to a low-fat diet. In contrast, wild-type mice fed a high-fat and high-sucrose diet developed more severe hepatic steatosis with low-grade inflammation and fibrosis, as noted by increased CD68, tumor necrosis factor alpha, monocyte chemoattractant protein-1, alpha-smooth muscle actin, and collagen I and TIMP1 expression. These changes were prevented in the fructokinase knockout mice. CONCLUSION: An additive effect of high-fat and high-sucrose diet on the development of hepatic steatosis exists. Further, the combination of sucrose with high-fat diet may induce steatohepatitis. The protection in fructokinase knockout mice suggests a key role for fructose (from sucrose) in this development of steatohepatitis. These studies emphasize the important role of fructose in the development of fatty liver and nonalcoholic steatohepatitis.
Assuntos
Dieta Hiperlipídica , Fígado Gorduroso/etiologia , Frutoquinases/fisiologia , Sacarose/administração & dosagem , Animais , Ingestão de Energia , Frutose/metabolismo , Fígado/metabolismo , Fígado/patologia , Camundongos , Camundongos Endogâmicos C57BL , Aumento de PesoRESUMO
Fructose in sweetened beverages (SB) increases the risk for metabolic and cardiorenal disorders, and these effects are in part mediated by a secondary increment in uric acid (UA). Rodents have an active uricase, thus requiring large doses of fructose to increase plasma UA and to induce metabolic syndrome and renal hemodynamic changes. We therefore hypothesized that the effects of fructose in rats might be enhanced in the setting of uricase inhibition. Four groups of male Sprague-Dawley rats (n = 7/group) were studied during 8 wk: water + vehicle (V), water + oxonic acid (OA; 750 mg/k BW), sweetened beverage (SB; 11% fructose-glucose combination) + V, and SB + OA. Systemic blood pressure, plasma UA, triglycerides (TG), glucose and insulin, glomerular hemodynamics, renal structural damage, renal cortex and liver UA, TG, markers of oxidative stress, mitDNA, fructokinase, and fatty liver synthase protein expressions were evaluated at the end of the experiment. Chronic hyperuricemia and SB induced features of the metabolic syndrome, including hypertension, hyperuricemia, hyperglycemia, and systemic and hepatic TG accumulation. OA alone also induced glomerular hypertension, and SB alone induced insulin resistance. SB + OA induced a combined phenotype including metabolic and renal alterations induced by SB or OA alone and in addition also acted synergistically on systemic and glomerular pressure, plasma glucose, hepatic TG, and oxidative stress. These findings explain why high concentrations of fructose are required to induce greater metabolic changes and renal disease in rats whereas humans, who lack uricase, appear to be much more sensitive to the effects of fructose.