RESUMO
Diabetic patients often develop Diabetic Nephropathy (DN) despite severe long-lasting hyperglycemia, while others develop DN even under intensive insulin therapy. This indicates that factors other than chronic hyperglycemia may also contribute to the susceptibility to the development of DN. The purpose of this case-control study was to investigate the possible role of GSTM1 and GSTT1 deletion polymorphisms, and Single Nucleotide Polymorphism (SNP), GSTP1 313 Aâ¯>â¯G (Ile105Val), in DN susceptibility. Multiple logistic regression analysis revealed that the occurrence of GST polymorphisms in the Central Brazilian population was not associated with increased risk of DN. However, the presence GSTT1 null genotype suggest an increase trend in systolic blood pressure and opposite inference was observed for the GSTP1 genotype (Ile/Val or Val/Val). On the order hand, other studies may clarify the relationship of these polymorphisms with DN and help in the prevention of this disease.
Assuntos
Nefropatias Diabéticas/enzimologia , Nefropatias Diabéticas/genética , Predisposição Genética para Doença , Glutationa S-Transferase pi/genética , Glutationa Transferase/genética , Polimorfismo Genético , Feminino , Humanos , Masculino , Polimorfismo de Nucleotídeo Único/genéticaRESUMO
Quantitative polymerase chain reaction was employed to quantify expression of two genes coding for advanced glycation end-product receptors [RAGE ( AGER) and AGER1 ( DDOST)] and of the gene coding the deacetylase SIRT1 ( SIRT1) in peripheral blood mononuclear cells from type 1 diabetes patients without [Group A, n = 35; 28.5 (24-39) years old; median (interquartile interval)] or with at least one microvascular complication [Group B, n = 117; 34.5 (30-42) years old]; 31 healthy controls were also included. In a subgroup of 48 patients, daily advanced glycation end-products intake before blood collection was assessed. Lower expression of DDOST was found in patients than in controls after adjustment for sex, age, use of statins, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. Higher expressions of AGER, DDOST and SIRT1 were observed in Group A. Stratifying by complications, AGER and DDOST expressions were higher in those without retinopathy and without diabetic kidney disease, respectively, compared to patients with these complications. Patients using statins or angiotensin receptor blockers presented higher expression of DDOST. Expression of SIRT1 was higher in patients consuming ≥12,872 KU daily of advanced glycation end-products. Although AGER, DDOST and SIRT1 are differently expressed in peripheral blood mononuclear cells from type 1 diabetes patients with and without microvascular complications, they are also influenced by dietary advanced glycation end-products and by statins and angiotensin receptor blockers.
Assuntos
Diabetes Mellitus Tipo 1/sangue , Dieta , Produtos Finais de Glicação Avançada/sangue , Hexosiltransferases/sangue , Leucócitos Mononucleares/enzimologia , Proteínas de Membrana/sangue , Sirtuína 1/sangue , Adulto , Antagonistas de Receptores de Angiotensina/uso terapêutico , Biomarcadores/sangue , Estudos de Casos e Controles , Estudos Transversais , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 1/enzimologia , Diabetes Mellitus Tipo 1/genética , Angiopatias Diabéticas/sangue , Angiopatias Diabéticas/enzimologia , Nefropatias Diabéticas/sangue , Nefropatias Diabéticas/enzimologia , Feminino , Regulação Enzimológica da Expressão Gênica , Hexosiltransferases/genética , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Leucócitos Mononucleares/efeitos dos fármacos , Masculino , Proteínas de Membrana/genética , Estresse Oxidativo , RNA Mensageiro/sangue , Receptor para Produtos Finais de Glicação Avançada/sangue , Receptor para Produtos Finais de Glicação Avançada/genética , Sirtuína 1/genéticaRESUMO
Hypertension and diabetes are clinical conditions which contribute to the development of chronic kidney disease as well as risk factors for cardiovascular events. In recent years, lipocalin-type-prostaglandin-D-synthase (beta trace protein; BTP) has increasingly been studied as an alternative to creatinine for the evaluation of renal function as well as for being a possible biomarker for cardiovascular disease. It is expected that the levels of BTP in patients with cardiovascular disease are elevated, as is the case with patients with renal dysfunction. The objective of this study is to realize a systematic review of the pertinent literature in respect to BTP as a biomarker of renal dysfunction in diabetic patients. Using the database MEDLINE, a search up to year 2014 was conducted using the follow descriptors: "lipocalin type prostaglandin d synthase" AND "diabetes"; "lipocalin type prostaglandin d synthase" and "diabetic nephropathy"; "beta trace protein" AND "diabetes"; "beta trace protein" AND "diabetic nephropathy". The criteria used for inclusion were the presence of the referring to terms in title or abstract and study conducted in humans. About 17 articles were selected, of which six articles were duplicates, and of which six articles did not investigate any possible relationship between the protein (BTP) and either diabetes or nephropathy. The final result yielded five articles to be analyzed. This review found BTP is not influenced by race, by body mass index nor by patient's sex. BTP can be considered as a reliable early biomarker of renal dysfunction in diabetics. BTP is associated with metabolic syndrome and is also associated with greater cardiovascular risk. Prospective data establishing a correlation between BTP and mortality would have been of great interest, but such articles were not found in this review.
Assuntos
Diabetes Mellitus Tipo 2/enzimologia , Nefropatias Diabéticas/enzimologia , Oxirredutases Intramoleculares/metabolismo , Rim/enzimologia , Lipocalinas/metabolismo , Animais , Biomarcadores/metabolismo , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/fisiopatologia , Nefropatias Diabéticas/diagnóstico , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/fisiopatologia , Diagnóstico Precoce , Humanos , Rim/fisiopatologia , Testes de Função Renal , Valor Preditivo dos Testes , Prognóstico , Reprodutibilidade dos Testes , Fatores de RiscoRESUMO
The potential association between the K121Q (A/C, rs1044498) polymorphism in the ectonucleotide pyrophosphatase/phosphodiesterase (ENPP1) gene and risk of diabetic kidney disease (DKD) has been investigated. Nevertheless, the effect of this variant on DKD risk is still under debate, and conflicting results have been reported. To this date, no meta-analysis has evaluated the association of the K121Q polymorphism with DKD. This paper describes the first meta-analysis conducted to evaluate whether the ENPP1K121Q polymorphism is associated with DKD. A literature search was conducted to identify all case-control or cross-sectional studies that evaluated associations between the ENPP1K121Q polymorphism and DKD. Pooled odds ratios (OR) and 95% confidence intervals (95% CI) were calculated for allele contrast, additive, dominant and recessive inheritance models. Seven studies were eligible for inclusion in the meta-analysis, providing data on 3571 type 1 or type 2 diabetic patients (1606 cases with DKD and 1965 diabetic controls without this complication). No significant heterogeneity was observed among the studies included in the meta-analysis when assuming different inheritance models (I² < 50% or P > 0.10 for the entire sample and after stratification by ethnicity). Meta-analysis results revealed significant associations between the K121Q polymorphism and risk of DKD in Asians and Europeans when assuming the different inheritance models analyzed. The most powerful association was observed for the additive model (OR = 1.74, 95% CI 1.27-2.38 for the total sample). In conclusion, the present meta-analysis detected a significant association between the ENPP1K121Q polymorphism and increased susceptibility of DKD in European and Asian populations.
Assuntos
Substituição de Aminoácidos , Nefropatias Diabéticas/enzimologia , Nefropatias Diabéticas/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Diester Fosfórico Hidrolases/genética , Polimorfismo de Nucleotídeo Único/genética , Pirofosfatases/genética , Humanos , Padrões de Herança/genética , Modelos Genéticos , Razão de Chances , Fatores de RiscoRESUMO
Diabetic nephropathy (DN) is a major complication of diabetic patients and the leading cause of end-stage renal disease. Glomerular dysfunction plays a critical role in DN, but deterioration of renal function also correlates with tubular alterations. Human DN is characterized by glycogen accumulation in tubules. Although this pathological feature has long been recognized, little information exists about the triggering mechanism. In this study, we detected over-expression of muscle glycogen synthase (MGS) in diabetic human kidney. This enhanced expression suggests the participation of MGS in renal metabolic changes associated with diabetes. HK2 human renal cell line exhibited an intrinsic ability to synthesize glycogen, which was enhanced after over-expression of protein targeting to glycogen. A correlation between increased glycogen amount and cell death was observed. Based on a previous transcriptome study on human diabetic kidney disease, significant differences in the expression of genes involved in glycogen metabolism were analyzed. We propose that glucose, but not insulin, is the main modulator of MGS activity in HK2 cells, suggesting that blood glucose control is the best approach to modulate renal glycogen-induced damage during long-term diabetes.
Assuntos
Diabetes Mellitus Tipo 2/enzimologia , Nefropatias Diabéticas/enzimologia , Regulação Enzimológica da Expressão Gênica , Glicogênio Sintase/biossíntese , Músculos/enzimologia , Idoso , Células Cultivadas , Diabetes Mellitus Tipo 2/patologia , Nefropatias Diabéticas/patologia , Feminino , Perfilação da Expressão Gênica , Glicogênio Sintase/metabolismo , Humanos , Imuno-Histoquímica , Masculino , Reação em Cadeia da Polimerase em Tempo RealRESUMO
BACKGROUND: Nitric oxide (NO) has numerous functions in the kidney, including control of renal and glomerular hemodynamics, by interfering at multiple pathological and physiologically critical steps of nephron function. Endothelial NOS (eNOS) gene has been considered a potential candidate gene to diabetic nephropathy (DN) susceptibility. Endothelial nitric oxide synthase gene (eNOS-3) polymorphisms have been associated with DN, however some studies do not confirm this association. The analyzed polymorphisms were 4b/4a, T-786C, and G986T. METHODS: The Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement was used in this report. Case-control studies that had diabetic patients with DN as cases and diabetic patients without nephropathy as controls, as well as that evaluated at least one of the three polymorphisms of interest were considered eligible. All studies published up until December 31st, 2012 were identified by searching electronic databases. Hardy-Weinberg equilibrium assessment was performed. Gene-disease association was measured using odds ratio estimation based on the following genetic contrast/models: (1) allele contrast; (2) additive model; (3) recessive model; (4) dominant model and (4) co-dominant model. RESULTS: Twenty-two studies were eligible for meta-analysis (4b/a: 15 studies, T-786C: 5 studies, and G984T: 12 studies). Considering 4b/a polymorphism, an association with DN was observed for all genetic models: allele contrast (OR = 1.14, CI: 1.04-1.25); additive (OR = 1.77, CI: 1.37-2.28); recessive (OR = 1.77, CI: 1.38-2,27); dominant (OR = 1.12, CI: 1.01-1.24), with the exception for co-dominance model. As well, T-786C polymorphism showed association with all models, with exception for co-dominance model: allele contrast (OR = 1.22, CI: 1.07-1.39), additive (OR = 1.52, CI: 1.18-1.97), recessive (OR = 1.50, CI: 1.16-1.93), and dominant (OR = 1.11, CI: 1.01-1.23). For the G894T polymorphism, an association with DN was observed in allelic contrast (OR = 1.12, CI: 1.03-1.25) and co-dominance models (OR = 1.13, CI: 1.04-1.37). CONCLUSIONS: In the present study, there was association of DN with eNOS 4b/a and T-786C polymorphism, which held in all genetic models tested, except for co-dominance model. G894T polymorphism was associated with DN only in allele contrast and in co-dominance model. This data suggested that the eNOS gene could play a role in the development of DN.
Assuntos
Nefropatias Diabéticas/enzimologia , Nefropatias Diabéticas/genética , Predisposição Genética para Doença/genética , Óxido Nítrico Sintase Tipo III/genética , Polimorfismo Genético , Animais , HumanosRESUMO
AIMS/HYPOTHESIS: Oxidative stress is involved in the pathogenesis of diabetic nephropathy. The antioxidant enzyme catalase plays a key role in redox regulation in the kidney. We investigated associations of catalase gene (CAT) polymorphisms and plasma catalase activity with diabetic nephropathy in type 1 diabetic patients. METHODS: We genotyped nine single nucleotide polymorphisms (SNPs) in the CAT region in participants from the Survival Genetic Nephropathy (SURGENE) (340 French participants, 10 year follow-up) and the Génétique de la Néphropathie Diabétique (GENEDIAB) (444 Belgian and French participants, 8 year follow-up) study cohorts. Replication was performed in a Brazilian cross-sectional cohort (n = 451). Baseline plasma catalase activity was measured in SURGENE (n = 120) and GENEDIAB (n = 391) participants. RESULTS: The A allele of rs7947841 was associated with the prevalence of incipient (OR 2.79, 95% CI 1.21, 6.24, p = 0.01) and established or advanced nephropathy (OR 5.72, 95% CI 1.62, 22.03, p = 0.007), and with the incidence of renal events, which were defined as new cases of microalbuminuria or progression to a more severe stage of nephropathy during follow-up (HR 1.82, 95% CI 1.13, 2.81, p = 0.01) in SURGENE participants. The same risk allele was associated with incipient nephropathy (OR 3.13, 95% CI 1.42, 7.24, p = 0.004) and with the incidence of end-stage renal disease (ESRD) (HR 2.11, 95% CI 1.23, 3.60, p = 0.008) in GENEDIAB participants. In both cohorts, the risk allele was associated with lower catalase activity. Associations with incipient and established or advanced nephropathy were confirmed in the replication cohort. CONCLUSIONS/INTERPRETATION: CAT variants were associated with the prevalence and incidence of diabetic nephropathy and ESRD in type 1 diabetic patients. Our results confirm the protective role of catalase against oxidative stress in the kidney.
Assuntos
Catalase/genética , Nefropatias Diabéticas/enzimologia , Nefropatias Diabéticas/genética , Frequência do Gene , Falência Renal Crônica/enzimologia , Falência Renal Crônica/genética , Estresse Oxidativo/genética , Polimorfismo de Nucleotídeo Único , Adulto , Bélgica , Brasil , Catalase/metabolismo , Estudos Transversais , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/fisiopatologia , Feminino , Seguimentos , França , Variação Genética , Taxa de Filtração Glomerular , Humanos , Incidência , Falência Renal Crônica/metabolismo , Falência Renal Crônica/fisiopatologia , Masculino , Polimorfismo de Nucleotídeo Único/genética , Prevalência , Medição de Risco , Fatores de RiscoRESUMO
Spironolactone (SPR), a mineralocorticoid receptor blocker, diminishes hyperglycemia-induced reduction in glucose-6-phosphate dehydrogenase (G6PD) activity, improving oxidative stress damage. This study investigated whether SPR ameliorates nephropathy by increasing G6PD activity and reducing oxidative stress in spontaneously hypertensive diabetic rats (SHRs). The streptozotocin-induced diabetic rats received or not SPR 50 mg/kg per day, for eight weeks. A human mesangial cell line was cultured in normal or high glucose conditions, with or without SPR, for 24 h. Plasma glucose levels and systolic blood pressure were unaltered by diabetes or by SPR treatment. Albuminuria, fibronectin expression, 8-OHdG urinary levels, lipid peroxidation and p47phox expression were higher in the diabetic rats compared with the control and were reduced by SPR. The antioxidant GSH/GSSG ratio was reduced in the diabetic rats and the treatment reestablished it. Diabetes-induced SGK1 up-regulation was inhibited by SPR. Reactive oxygen species (ROS) and superoxide production induced by NADPH oxidase were increased by hyperglycemia and high glucose, in vivo and in vitro, respectively, and were reduced with SPR. Hyperglycemia and high glucose decreased G6PD activity, which was restored with SPR. These results suggest that SPR ameliorates nephropathy in diabetic SHRs by restoring G6PD activity and diminishes oxidative stress without affecting glycaemia and blood pressure.
Assuntos
Diabetes Mellitus Experimental/enzimologia , Diabetes Mellitus Experimental/patologia , Nefropatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/enzimologia , Glucosefosfato Desidrogenase/metabolismo , Estresse Oxidativo , Espironolactona/uso terapêutico , Animais , Antioxidantes/metabolismo , Biomarcadores/metabolismo , Dano ao DNA , Diabetes Mellitus Experimental/complicações , Nefropatias Diabéticas/complicações , Nefropatias Diabéticas/patologia , Glucosefosfato Desidrogenase/antagonistas & inibidores , Dissulfeto de Glutationa/metabolismo , Humanos , Proteínas Imediatamente Precoces/metabolismo , Córtex Renal/efeitos dos fármacos , Córtex Renal/enzimologia , Córtex Renal/patologia , Peroxidação de Lipídeos/efeitos dos fármacos , Células Mesangiais/efeitos dos fármacos , Células Mesangiais/enzimologia , Células Mesangiais/patologia , Antagonistas de Receptores de Mineralocorticoides/farmacologia , Antagonistas de Receptores de Mineralocorticoides/uso terapêutico , Modelos Biológicos , NADP/metabolismo , NADPH Oxidases/metabolismo , Oxidantes/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Proteínas Serina-Treonina Quinases/metabolismo , Ratos , Ratos Endogâmicos SHR , Espironolactona/farmacologia , Superóxidos/metabolismo , Regulação para Cima/efeitos dos fármacosRESUMO
The increased prevalence of diabetes mellitus has caused a rise in the occurrence of its chronic complications, such as diabetic nephropathy (DN), which is associated with elevated morbidity and mortality. Familial aggregation studies have demonstrated that besides the known environmental risk factors, DN has a major genetic component. Therefore, it is necessary to identify genes associated with risk for or protection against DN. Ecto-nucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) is expressed in several tissues, including the kidneys. Increased levels of ENPP1 expression inhibit tyrosine-kinase activity of the insulin receptor in several cell types, leading to insulin resistance. K121Q polymorphism of the ENPP1 gene seems to be associated with insulin resistance and DN development. The elucidation of genetic factors and their associations will provide better understanding of the pathogenesis of DN and, may consequently, lead to a more effective approach to prevention and treatment.
A crescente prevalência do diabetes melito tem causado aumento na ocorrência das suas complicações crônicas, como a nefropatia diabética (ND), a qual está associada com elevada morbidade e mortalidade. Estudos de agregação familiar demonstram que a ND tem um importante componente genético, além dos conhecidos fatores de risco ambientais. Portanto, existe a necessidade de se identificarem genes associados ao risco ou proteção à ND. A ectonucleotide pyrophosphatase/phosphodiesterase 1(ENPP1) é expressa em vários tecidos, incluindo nos rins. Foi encontrado que níveis aumentados de expressão da ENPP1 inibem a atividade tirosino-quinase do receptor da insulina em vários tipos celulares, causando resistência à insulina. O polimorfismo K121Q do gene ENNP1parece estar associado com resistência à insulina e com o desenvolvimento da ND. A elucidação dos fatores genéticos e de suas associações permitirá um melhor entendimento da patogênese da ND e, consequentemente, poderemos ter uma abordagem mais efetiva em sua prevenção e tratamento.
Assuntos
Humanos , /enzimologia , Nefropatias Diabéticas/enzimologia , Resistência à Insulina/genética , Diester Fosfórico Hidrolases/genética , Polimorfismo Genético/genética , Pirofosfatases/genética , /genética , Nefropatias Diabéticas/genética , Marcadores Genéticos , Predisposição Genética para DoençaRESUMO
The increased prevalence of diabetes mellitus has caused a rise in the occurrence of its chronic complications, such as diabetic nephropathy (DN), which is associated with elevated morbidity and mortality. Familial aggregation studies have demonstrated that besides the known environmental risk factors, DN has a major genetic component. Therefore, it is necessary to identify genes associated with risk for or protection against DN. Ecto-nucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) is expressed in several tissues, including the kidneys. Increased levels of ENPP1 expression inhibit tyrosine-kinase activity of the insulin receptor in several cell types, leading to insulin resistance. K121Q polymorphism of the ENPP1 gene seems to be associated with insulin resistance and DN development. The elucidation of genetic factors and their associations will provide better understanding of the pathogenesis of DN and, may consequently, lead to a more effective approach to prevention and treatment.