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Article in Chinese | WPRIM | ID: wpr-879143


Pharmacology network was used to investigate the common key target and signaling pathway of Notoginseng Radix et Rhizoma in the protection against diabetic nephropathy(DN), diabetic encephalopathy(DE) and diabetic cardiomyopathy(DCM). The chemical components of Notoginseng Radix et Rhizoma were obtained through TCMSP database and literature mining, and SwissTargetPrediction database was used to predict potential targets of Notoginseng Radix et Rhizoma. The disease targets of DN, DE and DCM were obtained through OMIM and GeneCards databases. The overlapped targets of component targets and disease targets of DN, DE and DCM were obtained, and the network of "chemical component-target-disease" was established. The enriched GO and KEGG of the overlapped genes were investigated by using ClueGo plug-in with Cytoscape. At the same time, the PPI network was constructed through STRING database, and the common key targets for the treatment of three diseases by Notoginseng Radix et Rhizoma were obtained through topological parametric mathematical analysis by Cytoscape. A total of 166 chemical components and 835 component targets were screened out from Notoginseng Radix et Rhizoma. Briefly, 216, 194 and 230 disease targets of DN, DE and DCM were collected, respectively. And 54, 45 and 57 overlapped targets were identified when overlapping these disease targets with component targets of Notoginseng Radix et Rhizoma, respectively. Enrichment analysis indicated that the AGE-RAGE signaling pathway and FoxO signaling pathway were the common pathways in the protection of Notoginseng Radix et Rhizoma against DN, DE and DCM. Network analysis of the overlapped targets showed that TNF, STAT3, IL6, VEGFA, MAPK8, CASP3 and SIRT1 were identified as key targets of Notoginseng Radix et Rhizoma against DN, DE and DCM, the selected key targets were verified by literature review, and it was found that TNF, IL6, VEGFA, CASP3 and SIRT1 had been reported in the literature. In addition, there were the most compounds corresponding to the commom core target STAT3, indicating that more compounds in Notoginseng Radix et Rhizoma could regulate STAT3. This study indicated that Notoginseng Radix et Rhizoma potentially protected against DN, DE and DCM through regulating AGE-RAGE signaling pathway and FoxO signaling pathway and 7 common targets including TNF, STAT3, IL6, VEGFA, MAPK8, CASP3 and SIRT1. This study provided a reference for the research of "different diseases with same treatment" and also elucidated the potential mechanism of Notoginseng Radix et Rhizoma against DN, DE and DCM.

Brain Diseases , Diabetes Mellitus , Diabetic Cardiomyopathies/genetics , Diabetic Nephropathies/genetics , Humans , Research Design , Signal Transduction
Braz. j. med. biol. res ; 53(4): e9288, 2020. graf
Article in English | LILACS | ID: biblio-1089349


Diabetic nephropathy (DN) is one of the leading causes of mortality in diabetic patients. Long non-coding RNA zinc finger E-box binding homeobox 1 antisense 1 (ZEB1-AS1) plays a crucial role in the development of various diseases, including DN. However, the molecular mechanism of ZEB1-AS1 in DN pathogenesis remains elusive. An in vitro DN model was established by treating HK-2 cells with high glucose (HG). Quantitative polymerase chain reaction (qRT-PCR) was utilized to detect the expression levels of ZEB1-AS1, microRNA-216a-5p (miR-216a-5p), and bone morphogenetic protein 7 (BMP7). Western blot assay was used to evaluate the protein levels of BMP7, epithelial-to-mesenchymal transition (EMT)-related proteins, and fibrosis markers. Additionally, the interaction among ZEB1-AS1, miR-216a-5p, and BMP7 was predicted by MiRcode ( and starBase 2.0 (omics_06102, omicX), and confirmed by luciferase reporter assay. ZEB1-AS1 and BMP7 were down-regulated, while miR-216a-5p was highly expressed in kidney tissues of DN patients. Consistently, HG treatment decreased the levels of ZEB1-AS1 and BMP7, whereas HG increased miR-216a-5p expression in HK-2 cells in a time-dependent manner. ZEB1-AS1 upregulation inhibited HG-induced EMT and fibrogenesis. Furthermore, ZEB1-AS1 directly targeted miR-216a-5p, and overexpression of miR-216a-5p restored the inhibitory effects of ZEB1-AS1 overexpression on EMT and fibrogenesis. BMP7 was negatively targeted by miR-216a-5p. In addition, ZEB1-AS1 suppressed HG-induced EMT and fibrogenesis by regulating miR-216a-5p and BMP-7. lncRNA ZEB1-AS1 inhibited high glucose-induced EMT and fibrogenesis via regulating miR-216a-5p/BMP7 axis in diabetic nephropathy, providing a potential target for DN therapy.

Humans , Diabetic Nephropathies/metabolism , Bone Morphogenetic Protein 7/metabolism , Epithelial-Mesenchymal Transition/physiology , RNA, Long Noncoding/physiology , Zinc Finger E-box-Binding Homeobox 1/metabolism , Down-Regulation , Up-Regulation , Cells, Cultured , MicroRNAs/metabolism , Diabetic Nephropathies/genetics , Real-Time Polymerase Chain Reaction
J. bras. nefrol ; 41(3): 412-422, July-Sept. 2019. tab, graf
Article in English | LILACS | ID: biblio-1040242


Abstract Diabetic kidney disease (DKD) is a chronic complication of diabetes mellitus associated with significant morbidity and mortality regarded as a global health issue. MicroRNAs - small RNA molecules responsible for the post-transcriptional regulation of gene expression by degradation of messenger RNA or translational repression of protein synthesis - rank among the factors linked to the development and progression of DKD. This study aimed to offer a narrative review on investigations around the use of microRNAs in the diagnosis, monitoring, and treatment of DKD. Various microRNAs are involved in the pathogenesis of DKD, while others have a role in nephroprotection and thus serve as promising therapeutic targets for DKD. Serum and urine microRNAs levels have also been considered in the early diagnosis and monitoring of individuals with DKD, since increases in albuminuria, decreases in the glomerular filtration rate, and progression of DKD have been linked to changes in the levels of some microRNAs.

Resumo A doença renal do diabetes (DRD) é uma complicação crônica do diabetes mellitus associada à elevada morbidade e mortalidade, considerada um problema de saúde mundial. Dentre os fatores associados ao desenvolvimento e à progressão da DRD, destacam-se os microRNAs, que consistem em pequenas moléculas de RNA que regulam a expressão gênica por meio da degradação pós-transcricional do RNA mensageiro ou inibição translacional da síntese proteica. Este estudo teve como objetivo realizar uma revisão narrativa buscando investigar os microRNAs como auxiliares no diagnóstico, monitoramento e tratamento da DRD. Vários microRNAs estão envolvidos na patogênese da DRD, enquanto que outros têm papel nefroprotetor, consistindo assim em alvos terapêuticos promissores para o tratamento da DRD. A dosagem laboratorial dos microRNAs no soro e na urina também é muito promissora para o diagnóstico precoce e o monitoramento da DRD, já que os níveis de alguns microRNAs se alteram antes do aumento da albuminúria e da diminuição da taxa de filtração glomerular e podem ainda se alterar com a progressão da DRD.

Humans , Animals , Rats , MicroRNAs/urine , MicroRNAs/blood , Diabetic Nephropathies/drug therapy , Biomarkers/urine , Biomarkers/blood , Diabetes Mellitus, Type 1/complications , Diabetes Mellitus, Type 2/complications , Diabetic Nephropathies/diagnosis , Diabetic Nephropathies/genetics , Diabetic Nephropathies/pathology , Albuminuria , Molecular Targeted Therapy , Glomerular Filtration Rate
Arch. endocrinol. metab. (Online) ; 63(3): 250-257, May-June 2019. tab, graf
Article in English | LILACS | ID: biblio-1011159


ABSTRACT Objective To verify the presence of variants in HNF1B in a sample of the Brazilian population selected according to the presence of renal cysts associated with hyperglycemia. Subjects and methods We evaluated 28 unrelated patients with clinical suspicion of HNF1B mutation because of the concomitant presence of diabetes mellitus (DM) or prediabetes and renal cysts. Genotyping was accomplished using Sanger sequencing or multiplex ligation-dependent probe amplification (MLPA). In positive cases, available relatives were recruited. Results We found two patients with HNF1B mutations. The first presented the variant p.Pro328Leufs*48(c.983delC) and had DM, renal cysts, and hypomagnesemia. The second presented a heterozygous whole gene deletion in HNF1B, DM, renal cysts, body and tail pancreatic agenesis, and hypomagnesemia; this alteration was also found in his two siblings and his father. Conclusion The recruitment of suspected cases of HNF1B gene mutations in Brazilians due to hyperglycemia and renal cysts presents two positive cases. Our cases contribute to the annotation of clinical and biochemical phenotypes of this rare form of maturity-onset diabetes of the young (MODY).

Humans , Adult , Middle Aged , Diabetic Nephropathies/genetics , Kidney Diseases, Cystic/genetics , Hepatocyte Nuclear Factor 1-beta/genetics , Hyperglycemia/genetics , Mutation , Phenotype , Polymorphism, Genetic/genetics , Brazil , Cohort Studies , Gene Deletion , Diabetic Nephropathies/complications , Kidney Diseases, Cystic/complications , Hyperglycemia/complications
Indian J Biochem Biophys ; 2015 Apr; 52 (2): 209-212
Article in English | IMSEAR | ID: sea-158225


Diabetic nephropathy (DN) is a major cause of morbidity and mortality in diabetes. Vascular endothelial growth factor (VEGF) is a potent multi-functional cytokine which plays a key role in the pathogenesis of DN. In this study, we evaluated the possible association of the VEGF gene (I/D) polymorphisms with DN in type 2 diabetes patients in West Indian population. Genotyping (I/D) of the VEGF gene polymorphism was done by the polymerase chain reaction. A total of 103 patients with type 2 diabetes, 102 patients with DN, 108 patients with non-diabetic nephropathy and 143 healthy controls were genotyped. The frequency of VEGF genotype distribution and biochemical parameters like creatinine and HbA1c were compared in diabetic, diabetic nephropathy, non diabetic nephropathy and control groups. We found significant difference in creatinine level in DN and NDN groups on comparison with control group. Our study suggests that I/D polymorphism in the promoter region of the VEGF gene is not associated with DN in type 2 diabetes patients, but might have a role in development of non-diabetic nephropathy.

Diabetes Mellitus, Type 2/epidemiology , Diabetes Mellitus, Type 2/genetics , Diabetic Nephropathies/epidemiology , Diabetic Nephropathies/genetics , Gene Deletion , Genotyping Techniques/methods , Humans , India , Mutagenesis, Insertional/genetics , Polymorphism, Genetic/genetics , Vascular Endothelial Growth Factor A/genetics
Indian J Hum Genet ; 2013 Apr; 19(2): 179-182
Article in English | IMSEAR | ID: sea-149426


INTRODUCTION: We studied the impact of small ubiquitin-like modifier 4 (SUMO4) M55V polymorphism on susceptibility to diabetic nephropathy in Iranian type 2 diabetes patients. MATERIALS AND METHODS: The patient group consisted of 50 Iranian type 2 diabetes patients with nephropathy, and the control group consisted of 50 Iranian type 2 diabetes patients without nephropathy. Genotyping was performed using polymerase chain reaction-restriction fragment length polymorphism method for the M55V. RESULTS: The frequency of SUMO4 AA, AG, and GG genotypes were 23%, 18%, and 9% in the patient group and 10%, 22%, and 18% in the control group. There was no significant difference in frequency of SUMO4 genotypes in patients compared to controls. CONCLUSION: These findings indicate that SUMO4 M55V polymorphism is not associated with diabetic nephropathy in Iranian type 2 diabetes patients.

Diabetic Nephropathies/epidemiology , Diabetic Nephropathies/genetics , Diabetes Mellitus, Type 2/epidemiology , Diabetes Mellitus, Type 2/genetics , Genotype , Humans , Iran
Rev. AMRIGS ; 56(3): 204-212, jul.-set. 2012. tab
Article in Portuguese | LILACS | ID: biblio-848047


Introdução: O fator de crescimento transformante beta-1 (TGFß1) é uma citocina multifuncional que regula a proliferação, a diferenciação e a formação da matriz extracelular de vários tipos de células. Existem evidências de que os polimorfismos -509C>T e 869T>C no gene do TGFß1 alteram a sua expressão gênica e podem estar envolvidos na patogênese das complicações crônicas do diabetes mellitus tipo 2 (DM2). O objetivo deste estudo foi analisar o papel dos polimorfismos funcionais -509C>T e 869T>C no gene do TGFß1 na patogênese da retinopatia (RD) e da nefropatia (ND) diabéticas, em pacientes com DM2. Métodos: Foi realizado um estudo de caso-controle aninhado a um estudo transversal. Foram selecionados pacientes caucasoides com DM2 que realizaram exames clínicos, laboratoriais e uma entrevista com questionário padronizado. A genotipagem dos polimorfismos foi realizada por meio de PCR. Resultados: As frequências genotípicas e alélicas obtidas para o polimorfismo -509C>T nos pacientes com RD ou ND não diferiram daquelas observadas nos pacientes sem estas complicações. Mas quando a gravidade das complicações foi analisada, observou-se que o alelo C foi menos frequente entre os pacientes com insuficiência renal crônica não tratada com diálise, assim como a frequência de homozigotos para o alelo C foi maior nos pacientes dialíticos. Conclusão: Após a análise multivariada, o genótipo CC permaneceu como um fator de risco associado com a progressão da ND (RC = 2,68, IC 95% 1,08-6,68). Assim, os resultados sugerem que o polimorfismo 869T>C no gene do TGFß1 está associado com a progressão da ND em pacientes com DM2 (AU)

Introduction: The transforming growth factor-beta 1 (TGFß1) is a multifunctional cytokine that regulates proliferation, differentiation and extracellular matrix formation of multiple cell types. There is evidence that polymorphisms -509C> T and 869T> C in the TGFß1 gene alter its gene expression and may be involved in the pathogenesis of chronic complications of diabetes mellitus type 2 (DM2). The aim of this study was to analyze the role of functional polymorphisms -509C> T and 869T> C in the TGFß1 gene in the pathogenesis of diabetic retinopathy (DR) and diabetic nephropathy (DN) in patients with DM2. Methods: We conducted a case-control study nested in a cross-sectional study. We selected Caucasian patients with DM2 who underwent clinical and laboratory tests and an interview with a standardized questionnaire. Polymorphism genotyping was performed by PCR. Results: The allele and genotype frequencies obtained for polymorphism -509C> T in patients with DR or DN did not differ from those observed in patients without these complications. But when the severity of complications was analyzed, the C allele was found to be less frequent among patients with chronic renal failure untreated with dialysis, and the frequency of homozygous for the C allele was higher in dialysis patients. Conclusion: After multivariate analysis, the CC genotype remained a risk factor associated with progression of DN (OR = 2.68, 95% CI 1.08 to 6.68). Thus, the results suggest that polymorphism 869T> C in THE TGFß1 gene is associated with progression of DN in patients with DM2 (AU)

Humans , Male , Female , Middle Aged , Aged , Diabetic Nephropathies/genetics , Diabetic Retinopathy/genetics , Genetic Predisposition to Disease/epidemiology , Polymorphism, Genetic/genetics , Transforming Growth Factor beta1/genetics , Case-Control Studies , Cross-Sectional Studies , Diabetes Mellitus, Type 2/complications , Diabetic Nephropathies/etiology , Diabetic Retinopathy/etiology
Arq. bras. endocrinol. metab ; 55(9): 677-685, dez. 2011. ilus, tab
Article in English | LILACS | ID: lil-610474


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.

Humans , /enzymology , Diabetic Nephropathies/enzymology , Insulin Resistance/genetics , Phosphoric Diester Hydrolases/genetics , Polymorphism, Genetic/genetics , Pyrophosphatases/genetics , /genetics , Diabetic Nephropathies/genetics , Genetic Markers , Genetic Predisposition to Disease
Egyptian Journal of Medical Human Genetics [The]. 2011; 12 (2): 187-192
in English | IMEMR | ID: emr-126715


Reported to date, strong evidence exists in multiple studies for genetic predisposing in the development of diabetic nephropathy, and no studies addressed this issue among Egyptian population. The results of angiotensin converting enzyme gene [ACE] in the susceptibility to nephropathy in type 1 diabetes with nephropathy are conflicting. We aim to identify the associations of two ACE gene polymorphisms [PstI, A > G substitution and a 287-bp insertion/deletion] with nephropathy in type 1 diabetes in Egyptian children/adolescents. Our case-control study contained 140 diabetic individuals; 80 diabetic with nephropathy as cases, and 60 diabetic subjects without nephropathy as control group. Amplified DNA from peripheral leucocytes/buccal mucosa was genotyped for using polymerase chain reaction and enzymatic assay. We found no significant differences in the distribution of ACE insertion/deletion and PstI genotypes or allele frequencies were observed between the examined groups. Frequencies of PstI-indel haplotypes were similar in all of our study groups. In both cases and control subjects, ACE activity and microalbuminuria were highest among D/D homozygotes and lowest in I/I homozygotes, while a dissimilar result was seen in PstI polymorphism. Our findings in Egyptian population strongly conclude that there is no association between the ACE gene I/D and PstI polymorphisms with nephropathy in type 1 diabetes

Humans , Male , Female , Diabetic Nephropathies/genetics , Polymorphism, Genetic , Peptidyl-Dipeptidase A/blood
Indian J Hum Genet ; 2010 May; 16(2): 78-86
Article in English | IMSEAR | ID: sea-138903


BACKGROUND: Wide inter-ethnic allelic variations of the Angiotensin Converting Enzyme (ACE) i nsertion-deletion (I/D) gene polymorphism were thought to be responsible for the conflicting gene–diabetic nephropathy disease association worldwide. We have investigated the genetic susceptibility of the ACE gene to diabetic nephropathy in the multiethnic Malaysian population. MATERIALS AND METHODS: A total of 137 healthy (control) and 256 diabetic subjects were recruited. The diabetic subjects were further subdivided according to their nephropathy status based on urinary albumin-creatinine ratio (ACR) and glomerular filtration rate (GFR). Triple primer polymerase chain reaction (PCR) was used for ACE I/D genotyping. Subsequently, populationwide genetic analysis and gene-disease association studies were performed. RESULTS: The genotype frequencies in all subgroups were in Hardy-Weinberg equilibrium. Similar allelic and genotypic frequency of ACE I/D gene polymorphism was observed between healthy controls versus pooled type 2 diabetes mellitus (T2DM) subjects, and normoalbuminuria versus microalbuminuria, macroalbuminuria and End Stage Renal Failure (ESRF) (P > 0.05). Neither ethnicity nor gender exerted any influence on the ACE I/D gene polymorphism (P > 0.05), with the exception of the Chinese ethnic group which exhibited a higher frequency of ID genotype (P = 0.042). A multinomial logistic regression model showed that predictive factors including age, systolic blood pressure (SBP), high density lipoprotein (HDL) and glycosylated hemoglobin (HbA1C) were independently associated with diabetic nephropathy, in that order. CONCLUSION: The I/D polymorphism of the ACE gene is not significantly associated with both T2DM and/or diabetic nephropathy in this Malaysian population regardless of ethnicity and gender.

Diabetes Mellitus, Type 2/genetics , Diabetic Nephropathies/epidemiology , Diabetic Nephropathies/genetics , Ethnic Groups/genetics , Female , Genetic Association Studies , Genetic Predisposition to Disease , Genotype , Humans , Male , Malaysia/epidemiology , Peptidyl-Dipeptidase A/genetics , Polymorphism, Genetic , Population Groups/epidemiology
Indian J Biochem Biophys ; 2010 Apr; 47(2): 100-103
Article in English | IMSEAR | ID: sea-135251


Association of diabetic nephropathy (DN) with the deletion of GSTT1 and GSTM1 genes is well reported. Oxidative stress (OS) has also been associated with the development of DN. The present study was conducted to find out, whether these deletions had any contributory role in the development of OS in patients with DN. Pre-dialysis venous blood samples were obtained from 60 patients with diabetic end-stage renal disease (stages 4 and 5). Reduced-glutathione (GSH), glutathione S-transferase (GST) activity and malondialdehyde (MDA) levels were measured for the assessment of OS. Genetic polymorphism analysis of DN patients revealed the following distribution pattern: GSTM1 null 46.7%; GSTT1 null 55%; both null 30% and both positive 28.3%. Patients with both null genotypes were found to have significantly increased levels of MDA and low GST activity as compared to other genotypic groups. Lower GSH levels were observed in all the genotypic groups as compared to both positives. Double deletions involving GSTT1 and GSTM1 may result in decreased GST levels, leading to increased OS as reflected by increased MDA levels. As GST is a multi-functional enzyme involved in xenobiotic metabolism, this double null genotype population has a greater risk of development of DN. Further studies using increased sample size to find out the allelic distribution and their role in the development of DN are in progress.

Diabetic Nephropathies/blood , Diabetic Nephropathies/genetics , Diabetic Nephropathies/metabolism , Electrophoresis, Agar Gel , Female , Gene Deletion , Genotype , Glutathione Transferase/deficiency , Glutathione Transferase/genetics , Humans , Male , Middle Aged , Oxidative Stress/genetics , Polymorphism, Genetic
Arq. bras. endocrinol. metab ; 54(3): 253-261, Apr.-Mar. 2010. graf, tab
Article in English | LILACS | ID: lil-547552


The increasing prevalence of diabetes mellitus has led to a growing number of chronic complications including diabetic nephropathy (DN). In addition to its high prevalence, DN is associated with high morbidity and mortality especially due to cardiovascular diseases. It is well established that genetic factors play a role in the pathogenesis of DN and genetically susceptible individuals can develop it after being exposed to environmental factors. DN is probably a complex, polygenic disease. Two main strategies have been used to identify genes associated to DN: analysis of candidate genes, and more recently genome-wide scan. Great efforts have been made to identify these main genes, but results are still inconsistent with different genes associated to a small effect in specific populations. The identification of the main genes would allow the detection of those individuals at high risk for DN and better understanding of its pathophysiology as well.

A crescente elevação na prevalência do diabetes melito (DM) acarretou em um aumento de suas complicações crônicas, entre elas a nefropatia diabética (ND). Além da elevada prevalência, a ND está associada à importante morbidade e mortalidade, principalmente por doenças cardiovasculares. É notória a contribuição genética na patogênese da ND, em que, na presença de fatores ambientais propícios, aqueles indivíduos geneticamente predispostos desenvolverão a doença. Trata-se de uma doença com provável transmissão genética do tipo poligênica e complexa. Duas estratégias principais têm sido utilizadas na busca dos genes associados à ND: a avaliação de genes candidatos e, mais recentemente, a utilização de genoma wide scan. Grande empenho tem sido realizado para identificar os principais genes associados à ND, mas os resultados ainda são heterogêneos com diferentes genes apresentando um efeito pequeno em populações específicas. A identificação dos principais genes permitiria prever os indivíduos de maior risco para o desenvolvimento da ND, além de possibilitar um melhor entendimento fisiopatológico da doença.

Humans , Diabetic Nephropathies/genetics , Genetic Predisposition to Disease
Arq. bras. endocrinol. metab ; 53(5): 634-645, jul. 2009. tab
Article in Portuguese | LILACS | ID: lil-525425


O objetivo do presente manuscrito foi revisar o possível papel dos lipídeos dietéticos na nefropatia diabética (ND), considerando as alterações do perfil lipídico associadas e a interação entre aspectos dietéticos e genéticos. Os lipídeos dietéticos podem ter um papel importante no desenvolvimento e na progressão da ND. A composição das gorduras da dieta tem sido associada com a ND, particularmente à microalbuminúria e às anormalidades lipídicas e de função endotelial. Entretanto, ainda não está comprovado o benefício da modificação da ingestão de gorduras em pacientes com ND, em especial sobre desfechos definitivos, como incidência e progressão da ND, insuficiência renal e morte. Além disso, a resposta do perfil lipídico à ingestão de gorduras pode ser influenciada por fatores genéticos. A identificação de polimorfismos genéticos específicos associados a essa interação poderá permitir a individualização de estratégias nutricionais na ND.

The aim of the present study was to review the possible role of dietary lipids in diabetic nephropathy (DN), taking into account associated abnormalities of serum lipids and interaction of dietary and genetic aspects. Dietary lipids may have an important role in the development and progression of DN. The fat diet composition has been associated with DN, particularly with microalbuminuria, serum lipids abnormalities, and endothelial function. However, the beneficial effect of fat intake modification for these patients is not fully established, especially regarding hard outcomes, such as DN incidence and progression, kidney failure, and death. Moreover, genetic factors may influence the response of serum lipids to fat intake. The identification of specific genetic polymorphisms associated with this interaction could allow adoption of individual nutritional strategies in DN.

Humans , Diet , Diabetic Nephropathies/etiology , Dietary Fats/adverse effects , Lipids/blood , Apolipoproteins/genetics , Cholesterol/blood , Diabetic Nephropathies/diet therapy , Diabetic Nephropathies/genetics , Diabetic Nephropathies/physiopathology , Diet/adverse effects , Dietary Fats/administration & dosage , Dietary Proteins/administration & dosage , Fatty Acids/administration & dosage , Genetic Variation , Kidney/drug effects , Lipids/genetics , Polymorphism, Genetic , Triglycerides/blood
J. bras. pneumol ; 35(7): 669-675, jul. 2009. tab
Article in English, Portuguese | LILACS | ID: lil-521396


Objective: To assess proteinuria in patients with cystic fibrosis (CF), and to correlate proteinuria with genotype, CF-related diabetes and disease severity. Methods: A prospective study was carried out over a six-month period and involving 22 CF patients. After the collection and analysis of 24-h urine samples, the patients were divided into two subgroups: protein excretion < 150 mg/day (low-proteinuria); and protein excretion ≥ 150 mg/day (highproteinuria). Patient charts were reviewed to obtain data on genotype and CF-related diabetes. Disease severity was assessed based on acute exacerbations in the last six months and FEV1 measured during the study period. To assess the correlation between genotype and proteinuria, the two main mutations (ΔF508 and R334W) were evaluated. Due to the existence of genotype ΔF508/R334W, two categories were created to enable statistical analysis, ΔF508 being evaluated in category 1 and R334W being evaluated in category 2. Results: The ΔF508 mutation tended to be associated with normal protein excretion: 100% of the low-proteinuria subgroup patients were consideredΔF508 in category 1, compared with 86.7% in category 2. Protein excretion tended to be higher in patients withthe R334W mutation: 60.0% of the high-proteinuria subgroup patients were considered R334W in category 1, compared with 80.0% in category 2 (p = 0.009 and p = 0.014, respectively). No significant association was foundfor any of the other variables. Conclusions: The results suggest that genotype is associated with renal phenotype, depending on the mechanism by which the genotype alters the function of the cystic fibrosis transmembrane conductance regulator gene.

Objetivo: Avaliar a proteinúria em pacientes com fibrose cística (FC) e correlacioná-la com o genótipo, com adiabetes relacionada à FC e com a gravidade da doença. Métodos: Estudo prospectivo realizado num período deseis meses com 22 pacientes com FC. Efetuada proteinúria de 24 h com a divisão dos pacientes em dois subgrupos:proteinúria < 150 mg/dia (proteinúria-baixa); e proteinúria ≥ 150 mg/dia (proteinúria-alta). Revisamos os prontuários clínicos para a coleta de informações sobre o genótipo e a presença de diabetes relacionada à FC. A gravidade da doença foi avaliada pelas exacerbações agudas no último semestre e pelo VEF1 durante o período de estudo. Para avaliar a correlação entre genótipo e proteinúria, consideraram-se as duas principais mutações, ΔF508 e R334W. Dada a existência do genótipo ΔF508/R334W, foram criadas duas categorias para se proceder à avaliação estatística, sendo esse genótipo considerado ΔF508 na categoria 1 e R334W na categoria 2. Resultados: A mutação ΔF508 se associou com valores normais de proteinúria: 100% dos pacientes do subgrupo proteinúria-baixa foram considerados ΔF508 na categoria 1, comparados a 86,7% na categoria 2. Em pacientes com a mutação R334W, osvalores de proteinuria foram mais elevados: 60,0% dos pacientes do subgrupo proteinúria-alta foram considerados R334W na categoria 1, comparados a 80,0% na categoria 2 (p = 0,009 e p = 0,014, respectivamente). Para as outras variáveis, não houve associação significativa. Conclusões: Os resultados sugerem que há uma associação entre o genótipo e o fenótipo renal, dependendo do mecanismo pelo qual o genótipo altera a função do generegulador de condutância transmembrana da fibrose cística.

Adolescent , Adult , Female , Humans , Male , Young Adult , Cystic Fibrosis/genetics , Diabetic Nephropathies/genetics , Proteinuria/genetics , Acute Disease , Cystic Fibrosis/complications , Diabetic Nephropathies/pathology , Genotype , Phenotype , Prospective Studies , Proteinuria/etiology , Severity of Illness Index , Young Adult
Salud(i)ciencia (Impresa) ; 16(7): 751-754, mayo 2009.
Article in Spanish | LILACS | ID: lil-526826


Durante la última década se ha debatido la asociación entre el polimorfismo de inserción/deleción de la enzima convertidora de angiotensina (ECA) y la nefropatía diabética. Para aclarar esta situación actualizamos nuestro metanálisis previo para incluir algunos estudios pertinentes publicados desde 1994, lo que arroja un total de 17 791 sujetos provenientes de 53 estudios. Los casos (n = 9 556) eran personas con diabetes tipo 1 o tipo 2 con nefropatía diabética incipiente o avanzada, mientras que los controles (n = 8 235) eran en su mayor parte normoalbuminúricos. No se detectó ningún sesgo obvio de publicación. Con el uso de una definición de caso mínima sobre la base de la nefropatía diabética incipiente, los sujetos con genotipo II tuvieron una disminución del 22% en el riesgo de enfermedad en comparación con los portadores del alelo D (OR acumulada = 0.78, IC 95% = 0.70-0.87). Si bien se observó una disminución del riesgo entre pacientes de raza blanca con diabetes tipo 1 o tipo 2, la asociación fue más pronunciada entre los asiáticos (chinos, japoneses, coreanos) con diabetes tipo 2 (OR = 0.64, IC 95% = 0.51-0.80); este OR es significativamente diferente del obtenido para los pacientes de raza blanca con diabetes tipo 2 (OR = 0.89, IC 95% = 0.78-1.01) (p = 0.0105). Con una definición de caso más estricta, basada en la nefropatía diabética avanzada, se observó una reducción comparable del riesgo del 19% al 30% entre los tres subgrupos. Esta reducción fue estadísticamente significativa entre los asiáticos con diabetes tipo 2 y los caucásicos con diabetes tipo 1, pero no entre los de raza blanca con diabetes tipo 2. Este metanálisis actualizado fortalece la hipótesis de que la variación genética en el locus de la ECA contribuye al riesgo de la nefropatía diabética.

Humans , Diabetic Nephropathies/epidemiology , Diabetic Nephropathies/genetics , Polymorphism, Genetic , Peptidyl-Dipeptidase A/genetics
Biol. Res ; 42(2): 189-198, 2009. ilus, tab
Article in English | LILACS | ID: lil-524889


We present the analysis of an intronic polymorphism of the nephrin gene and its relationship to the development of diabetic nephropathy in a study of diabetes type 1 and type 2 patients. The frequency of the single nucleotide polymorphism rs#466452 in the nephrin gene was determined in 231 patients and control subjects. The C/T status of the polymorphism was assessed using restriction enzyme digestions and the nephrin transcript from a kidney biopsy was examined. Association between the polymorphism and clinical parameters was evaluated using multivaríate correspondence analysis. A bioinformatics analysis of the single nucleotide polymorphism rs#466452 suggested the appearance of a splicing enhancer sequence in intron 24 of the nephrin gene and a modification of proteins that bind to this sequence. However, no change in the splicing of a nephrin transcript from a renal biopsy was found. No association was found between the polymorphism and diabetes or degree of renal damage in diabetes type 1 or 2 patients. The single nucleotide polymorphism rs#466452 of the nephrin gene seems to be neutral in relation to diabetes and the development of diabetic nephropathy, and does not affect the splicing of a nephrin transcript, in spite of a splicing enhancer site.

Adult , Aged , Female , Humans , Male , Middle Aged , Diabetes Mellitus, Type 1/complications , /complications , Diabetic Nephropathies/genetics , Membrane Proteins/genetics , Polymorphism, Single Nucleotide/genetics , Biopsy , Case-Control Studies , Genotype , Introns/genetics , Multivariate Analysis , Reverse Transcriptase Polymerase Chain Reaction , RNA Splicing/genetics , Transcription, Genetic/genetics
Rev. chil. endocrinol. diabetes ; 1(3): 174-180, jul. 2008. ilus
Article in Spanish | LILACS | ID: lil-612515


This review describes the advances in the knowledge about the genetic aspects of common chronic complications of diabetes with prognostic significance, such as diabetic nephropathy and cardiovascular diseases. It is well known that the genetic factors responsible for chronic complications are different from those that cause diabetes mellitus. Until recently, the studies were limited to the analysis of individual genes associated or related to multifactorial diseases. However at the present time the “genome wide association studies” lead to a great advance in knowledge. The analysis of genetic variations or polymorphisms allows the understanding of human individuality and the predisposition towards certain diseases. A new research field appeared in 2004, when small messenger RNAs, called microRNA related to diabetes mellitus and its chronic complications, were identified. The function of these RNAs is to regulate several target genes. These affect insulin secretion and action and genes related to microangiopathic and specific macroangiopahic complications. This new knowledge will identify new genes related to the disease and will allow the development of therapeutic strategies devised according to individual susceptibility towards specific chronic complication.

Humans , /complications , /genetics , Chronic Disease , Cardiovascular Diseases/genetics , Gene Expression Regulation , Genetic Predisposition to Disease , MicroRNAs/genetics , Diabetic Nephropathies/genetics
Arq. bras. endocrinol. metab ; 52(2): 375-386, mar. 2008. ilus
Article in Portuguese | LILACS | ID: lil-481007


Acredita-se que o controle glicêmico e a duração do diabetes sejam os fatores de risco mais importantes para o desenvolvimento das microangiopatias diabéticas, contudo, as velocidades de progressão da nefropatia, da retinoaptia e da polineuropatia variam consideravelmente entre os pacientes. Além da presença de fatores de risco, como a hipertensão arterial, a dislipidemia e o fumo, existem evidências sugerindo que uma predisposição genética desempenha um papel na susceptibilidade para as complicações microvasculares. Com base na patogênese dessas complicações crônicas do diabetes, polimorfismos de vários genes candidatos que atuam em diferentes vias desse processo têm sido investigados, como os genes relacionados aos mecanismos dos danos induzidos pela hiperglicemia (os produtos finais de glicação avançada, o aumento na formação de espécies reativas de oxigênio e a atividade aumentada da via da aldose-redutase), os genes relacionados ao sistema renina-angiotensina; os genes que codificam a síntese das citoquinas, dos fatores de crescimento e dos seus receptores e dos transportadores de glicose entre muitos outros. Este artigo discute alguns estudos que corroboram com a importância da predisposição genética no desenvolvimento da microangiopatia diabética.

Glycemic control and diabetes duration are believed to be the most important risk factors for the development of diabetic microangiopathy; however, the rate of progression of nephropathy, retinopathy and polyneuropathy varies considerably among patients. Besides the presence of risk factors such as hypertension, dyslipidaemia and smoking, there is evidence suggesting that genetic predisposition plays a role in the susceptibility to microvascular complications. Based on underlying pathogenesis, polymorphisms of several candidate genes belonging to multiple pathways have been investigated, like the genes related to mechanisms of hyperglycaemia-induced damage (such as advanced glycation end-products and reactive oxygen species increased formation, augmented activity of the aldose reductase pathway); genes related to the renin-angiotensin system; genes coding for cytokines, growth factors and its receptors, glucose transporter; among many others. This article reviews some studies that corroborate the importance of the genetic background in the development of diabetic microangiopathy.

Humans , Diabetes Mellitus, Type 1/genetics , Diabetic Angiopathies/genetics , Genetic Predisposition to Disease/genetics , Albuminuria/metabolism , Base Sequence , Blood Glucose/analysis , Chronic Disease , Diabetic Angiopathies/prevention & control , Diabetic Nephropathies/genetics , Diabetic Neuropathies/genetics , Diabetic Retinopathy/genetics , Glycation End Products, Advanced/biosynthesis , Hyperglycemia/complications , Hyperglycemia/prevention & control , Oxidative Stress/physiology , Polymorphism, Genetic , Risk Factors
Medical Journal of Cairo University [The]. 2008; 76 (4): 589-596
in English | IMEMR | ID: emr-88881


Human serum paraoxonase-I [PON1] is physically associated with high density lippprotein [HDL] and has been implicated in the prevention of LDL lipid peroxidation. PON1 gene displays several polymorphisms that influence both its level of expression and its catalytic activity. The goal of this study was to examine the association between paraoxonase-1 [PON1] activity and gene polymorphism and the micro-vascular complications in children and adolescence suffering from type 1 DM [TIDM]. Case-control study. One study centre at a University hospital. Thirty eight patients, with type 1 diabetes [n=38], 13 patients presenting with diabetic nephropathy [mean age 18.76 +/- 5.59 years. 8 males and 5 females] and 25 without diabetic nephropathy [mean age 14.48 +/- 3.69 years. 14 males and 11 females] and 16 healthy controls [mean age 12.38 +/- 8.25 years, 10 males and 6 females]. The allele variants of PON1 gene polymorphisms in the PON1 coding region Q192R and L55M have been identified by polymerase chain reaction followed by restriction fragment length polymorphism analysis. Serum PON1 enzyme activity was measured spectrophotometrically. Serum PON1 activity was significantly decreased in complicated diabetics when compared to both non-complicated patients and the control persons [103.33 +/- 35.46 nmol/ml/min, 462.57 +/- 200.69 nmol/ml/min and 1132 +/- 317.61 nmol/ml/min respectively]. As regards PON1 Q192R polymorphism, the R allele was more frequent in complicated diabetics versus both non-complicated diabetics and controls [p=0.0113 and p=0.001 respectively]. PON1 192QR genotype is a risk factor for developing type 1 diabetes OR=7.8; 95% CI [1.12-65.7] with p=0.043. PON1 192QR genotype and 192R allele are risk factors for developing micro-vascular complications with OR =6.40 and 4.00; 95% CI [] and [1.15-13.87] with p=0.01 and 0.023 respectively. In PON1 L55M polymorphism, non significant differences in the genotype or allele frequency were found between T TIDM, both complicated and non-complicated diabetics and control persons. The association of PON1 Q192R polymorphisms, lower PON1 activity and poorer diabetic control found in patients with diabetic nephropathy further support an idea of genetic factors contributing to development of vascular complications in diabetes

Humans , Male , Female , Diabetic Nephropathies/genetics , Paraoxon/blood , Polymorphism, Genetic , Glycated Hemoglobin A , Cholesterol , Triglycerides , Case-Control Studies
Biol. Res ; 40(3): 357-364, 2007. tab
Article in English | LILACS | ID: lil-481313


Diabetic nephropathy (DN) is one of the major complications of type 2 diabetes and is associated with coronary disease. Nephrin, a protein mainly expressed in glomeruli, is decreased in DN and other kidney diseases. Since insulin levels are misregulated in type 2 diabetes, a possible connection between DN and its decreased nephrin expression could be the presence of regulatory elements responsive to insulin in the nephrin gene (NPHS1) promoter region. In this work, using bioinformatic tools, we identified a purine-rich GAGA element in the nephrin gene promoter and conducted a genomic study in search of the presence of polymorphisms in this element and its possible association with DN in type 2 diabetic patients. We amplified and sequenced a 514 bp promoter region of 100 individuals and found no genetic variants in the purine-rich GAGA-box of the nephrin gene promoter between groups of patients with diabetes type 2 with and without renal and coronary complications, control patients without diabetes and healthy controls.

Adult , Aged , Female , Humans , Male , Middle Aged , /genetics , Diabetic Nephropathies/genetics , Membrane Proteins/genetics , Promoter Regions, Genetic , Polymorphism, Genetic/genetics , Case-Control Studies , Genetic Predisposition to Disease , Genotype , Genetic Markers/genetics , Pilot Projects