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1.
BMC Med Genet ; 21(1): 195, 2020 10 02.
Artigo em Inglês | MEDLINE | ID: mdl-33008311

RESUMO

BACKGROUND: Alagille syndrome is an autosomal dominant disorder usually caused by pathogenic variants of the JAG1 gene. In the past, cholestasis was a condition sine qua non for diagnosis of the syndrome. However, recent advancements in genetic testing have revealed that clinical presentations vary from lack of symptoms, to multiorgan involvement. Tetralogy of Fallot, the most frequent complex congenital heart defect in Alagille Syndrome, very rarely leads to renal failure requiring dialysis - there are only single reports of such cases in the literature, with none of them in Alagille Syndrome. CASE PRESENTATION: A 41-year-old woman suffering from cyanosis, dyspnea and plethora was admitted to the hospital. The patient suffered from chronic kidney disease and tetralogy of Fallot and had been treated palliatively with Blalock-Taussig shunts in the past; at admission, only minimal flow through the left shunt was preserved. These symptoms, together with impaired mental status and dysmorphic facial features, led to extensive clinical and genetic testing including whole exome sequencing. A previously unknown missense variant c.587G > A within the JAG1 gene was identified. As there were no signs of cholestasis, and subclinical liver involvement was only suggested by elevated alkaline phosphatase levels, the patient was diagnosed with incomplete Alagille Syndrome. End-stage renal disease required introduction of renal replacement therapy. Continuous ambulatory peritoneal dialysis was chosen and the patient's quality of life significantly increased. However, after refusal of further treatment, the patient died at the age of 45. CONCLUSIONS: Tetralogy of Fallot should always urge clinicians to evaluate for Alagille Syndrome and offer patients early nephrological care. Although tetralogy of Fallot rarely leads to end-stage renal disease requiring dialysis, if treated palliatively and combined with renal dysplasia (typical of Alagille Syndrome), it can result in severe renal failure as in the presented case. There is no standard treatment for such cases, but based on our experience, peritoneal dialysis is worth consideration. Finally, clinical criteria for the diagnosis of Alagille Syndrome require revision. Previously, diagnosis was based on cholestasis - however, cardiovascular anomalies are found to be more prevalent. Furthermore, the criteria do not include renal impairment, which is also common.


Assuntos
Síndrome de Alagille/terapia , Proteína Jagged-1/genética , Mutação de Sentido Incorreto , Diálise Peritoneal/métodos , Insuficiência Renal Crônica/terapia , Tetralogia de Fallot/terapia , Adulto , Síndrome de Alagille/diagnóstico , Síndrome de Alagille/genética , Evolução Fatal , Feminino , Testes Genéticos , Humanos , Cuidados Paliativos/métodos , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/genética , Tetralogia de Fallot/diagnóstico , Tetralogia de Fallot/genética
2.
Am J Physiol Renal Physiol ; 319(4): F624-F635, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32830539

RESUMO

Recently, we reported a mutation in γ-adducin (ADD3) was associated with an impaired myogenic response of the afferent arteriole and hypertension-induced chronic kidney disease (CKD) in fawn hooded hypertensive (FHH) rats. However, the mechanisms by which altered renal blood flow (RBF) autoregulation promotes hypertension-induced renal injury remain to be determined. The present study compared the time course of changes in renal hemodynamics and the progression of CKD during the development of DOCA-salt hypertension in FHH 1BN congenic rats [wild-type (WT)] with an intact myogenic response versus FHH 1BN Add3KO (Add3KO) rats, which have impaired myogenic response. RBF was well autoregulated in WT rats but not in Add3KO rats. Glomerular capillary pressure rose by 6 versus 14 mmHg in WT versus Add3KO rats when blood pressure increased from 100 to 150 mmHg. After 1 wk of hypertension, glomerular filtration rate increased by 38% and glomerular nephrin expression decreased by 20% in Add3KO rats. Neither were altered in WT rats. Proteinuria doubled in WT rats versus a sixfold increase in Add3KO rats. The degree of renal injury was greater in Add3KO than WT rats after 3 wk of hypertension. RBF, glomerular filtration rate, and glomerular capillary pressure were lower by 20%, 28%, and 19% in Add3KO rats than in WT rats, which was associated with glomerular matrix expansion and loss of capillary filtration area. The results indicated that impaired RBF autoregulation and eutrophic remodeling of preglomerular arterioles increase the transmission of pressure to glomeruli, which induces podocyte loss and accelerates the progression of CKD in hypertensive Add3KO rats.


Assuntos
Pressão Sanguínea , Taxa de Filtração Glomerular , Hipertensão/complicações , Glomérulos Renais/irrigação sanguínea , Proteinúria/etiologia , Circulação Renal , Insuficiência Renal Crônica/etiologia , Animais , Arteríolas/metabolismo , Arteríolas/fisiopatologia , Proteínas de Ligação a Calmodulina/genética , Proteínas de Ligação a Calmodulina/metabolismo , Acetato de Desoxicorticosterona , Modelos Animais de Doenças , Progressão da Doença , Homeostase , Hipertensão/genética , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Masculino , Desenvolvimento Muscular , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/fisiopatologia , Proteinúria/genética , Proteinúria/metabolismo , Proteinúria/fisiopatologia , Ratos Transgênicos , Insuficiência Renal Crônica/genética , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/fisiopatologia , Cloreto de Sódio na Dieta , Remodelação Vascular
3.
Am J Physiol Renal Physiol ; 319(4): F603-F611, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32830538

RESUMO

The acyl-CoA synthetase medium-chain family member 2 (Acsm2) gene was first identified and cloned by our group as a kidney-specific "KS" gene. However, its expression pattern and function remain to be clarified. In the present study, we found that the Acsm2 gene was expressed specifically and at a high level in normal adult kidneys. Expression of Acsm2 in kidneys followed a maturational pattern: it was low in newborn mice and increased with kidney development and maturation. In situ hybridization and immunohistochemistry revealed that Acsm2 was expressed specifically in proximal tubular cells of adult kidneys. Data from the Encyclopedia of DNA Elements database revealed that the Acsm2 gene locus in the mouse has specific histone modifications related to the active transcription of the gene exclusively in kidney cells. Following acute kidney injury, partial unilateral ureteral obstruction, and chronic kidney diseases, expression of Acsm2 in the proximal tubules was significantly decreased. In human samples, the expression pattern of ACSM2A, a homolog of mouse Acsm2, was similar to that in mice, and its expression decreased with several types of renal injuries. These results indicate that the expression of Acsm2 parallels the structural and functional maturation of proximal tubular cells. Downregulation of its expression in several models of kidney disease suggests that Acms2 may serve as a novel marker of proximal tubular injury and/or dysfunction.


Assuntos
Coenzima A Ligases/metabolismo , Células Epiteliais/metabolismo , Túbulos Renais Proximais/metabolismo , Lesão Renal Aguda/enzimologia , Lesão Renal Aguda/genética , Lesão Renal Aguda/patologia , Animais , Coenzima A Ligases/genética , Modelos Animais de Doenças , Células Epiteliais/patologia , Fibrose , Regulação da Expressão Gênica no Desenvolvimento , Regulação Enzimológica da Expressão Gênica , Humanos , Integrina beta1/genética , Integrina beta1/metabolismo , Túbulos Renais Proximais/patologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Insuficiência Renal Crônica/enzimologia , Insuficiência Renal Crônica/genética , Insuficiência Renal Crônica/patologia , Renina/genética , Renina/metabolismo , Traumatismo por Reperfusão/enzimologia , Traumatismo por Reperfusão/genética , Traumatismo por Reperfusão/patologia
4.
Arch Biochem Biophys ; 692: 108530, 2020 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-32768395

RESUMO

Fibrosis is the final common pathological feature of a wide variety of chronic kidney disease (CKD). However, an understanding of the mechanisms underlying the development of renal fibrosis remains challenging and controversial. As the current focus of molecular research, noncoding RNAs (ncRNAs), mainly microRNAs (miRNAs), long noncoding RNAs (lncRNAs) and circular noncoding RNAs (circRNAs), have powerful and abundant biological functions, which essentially makes them mediators of the physiological and pathological processes of various system diseases. The role of ncRNAs in renal fibrosis has also received great attention in recent years, but most research has mainly focused on miRNAs. In fact, although a large number of studies of lncRNAs have emerged recently, the role these molecules play in renal fibrosis haven't been fully understood till now. Thus, this review discusses the discovery of lncRNAs and their biological functions in different types of renal fibrosis, as well as the imminent applications of these findings in clinical use. Undoubtedly, in the future, further understanding of the function of all types of lncRNAs will reveal large breakthroughs in the treatment of renal fibrosis.


Assuntos
Rim/metabolismo , RNA Longo não Codificante/metabolismo , Insuficiência Renal Crônica/metabolismo , Fibrose , Humanos , Rim/patologia , MicroRNAs/genética , MicroRNAs/metabolismo , RNA Longo não Codificante/genética , Insuficiência Renal Crônica/genética , Insuficiência Renal Crônica/patologia
5.
Life Sci ; 261: 118121, 2020 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-32693242

RESUMO

AIMS: Pathological vascular calcification (VC), a major risk factor for cardiovascular mortality, is a highly prevalent finding in patients with chronic kidney disease (CKD). We previously analyzed several pathways protecting against high phosphate-induced VC through induction of autophagy. Here, we explored how O-GlcNAc transferase (OGT) affected high phosphate-induced VC of CKD though mediation of autophagy. MAIN METHODS: In the rats with CKD induced by 5/6 nephrectomy, the VC process was accelerated by a high phosphate diet. The calcification of vascular smooth muscle cells (VSMCs) was induced by high phosphate treatment. We then experimentally tested the effect of OGT on high phosphate-induced VC by conducting loss-of-function experiments. Co-immunoprecipitation and GST pull-down assays were performed to evaluate interaction between OGT and Yes-associated protein (YAP). In mechanistic studies of this pathway, we measured autophagy protein expression and autophagosome formation, as well as calcium deposition and calcium content in VSMCs and in vivo in response to altered expression of OGT and/or YAP. KEY FINDINGS: OGT was up-regulated in high phosphate-induced VC models in vitro and in vivo. High phosphate-induced calcification in the rat aorta and VSMCs were suppressed by OGT silencing. OGT promoted the glycosylation of YAP to enhance its stability. Importantly, over-expressing YAP reduced autophagy and OGT expedited high phosphate-induced VC by inhibiting autophagy through upregulation of YAP. SIGNIFICANCE: OGT silencing downregulated YAP to induce autophagy activation, thus suppressing high phosphate-induced VC, which highlighted a promising preventive target against high phosphate-induced VC in CKD.


Assuntos
Proteínas Reguladoras de Apoptose/genética , Autofagia/genética , N-Acetilglucosaminiltransferases/genética , Insuficiência Renal Crônica/fisiopatologia , Calcificação Vascular/genética , Animais , Regulação para Baixo , Técnicas de Silenciamento de Genes , Masculino , Miócitos de Músculo Liso/metabolismo , Fosfatos/administração & dosagem , Ratos , Ratos Sprague-Dawley , Insuficiência Renal Crônica/genética , Calcificação Vascular/patologia
6.
PLoS One ; 15(7): e0232741, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32649699

RESUMO

INTRODUCTION: Inflammation plays a major role in the development of atherosclerosis and cardiovascular morbidity and mortality in chronic kidney disease (CKD) patients. Toll-like receptor-4 (TLR4) is a major receptor for lipopolysaccharides (endotoxin) and other ligands involved in the pathogenesis of inflammation. We determined whether endotoxin levels and the presence of TLR4 polymorphisms are associated with markers of inflammation and atherosclerosis among South African CKD patients. MATERIALS AND METHODS: Endotoxin, lipopolysaccharide binding protein (LBP), serum CD14 (sCD14), interleukin-8 (IL-8), monocyte chemoattractant protein-1 (MCP-1) and carotid intima media thickness (CIMT) were measured in 160 participants (120 CKD patients and 40 controls). Associations between endotoxins and CIMT in the presence of sCD14, IL-8 and MCP-1, were assessed using odds ratios. Participants were screened for the presence of Asp299Gly and Thr399Ile TLR4 polymorphisms, and CIMT and inflammatory markers were compared between subjects with and without TLR4 polymorphisms. RESULTS: Endotoxin levels correlated with sCD14 (r = 0.441, p<0.001) and MCP-1 (r = 0.388, p<0.001) levels while increased CIMT was associated with MCP-1 (r = 0.448, p<0.001), sCD14 levels (r = 0.476, p<0.001), LBP (r = 0.340, p<0.001), and IL-8 (r = 0.395, p<0.001). Atherosclerosis was associated with endotoxin levels (odds ratio: 4.95; 95% confidence interval: 2.52-9.73; p<0.001), and was predicted by higher serum levels of inflammatory markers. Analysis of patients with TLR4 polymorphisms showed reduced serum levels of inflammatory markers and CIMT values compared with the patients carrying the wild type TLR4 alleles. CONCLUSION: The study demonstrated associations between circulating endotoxaemia, systemic inflammation and accelerated atherosclerosis among South African CKD patients, and showed that the atherogenic predictive power of endotoxaemia was significantly increased by the presence of elevated levels of inflammatory markers. Additional findings, which must be confirmed, suggest that TLR4 polymorphisms are associated with low levels of inflammatory markers and CIMT values.


Assuntos
Grupo com Ancestrais do Continente Africano/estatística & dados numéricos , Aterosclerose/complicações , Grupos Populacionais/estatística & dados numéricos , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/epidemiologia , Adulto , Espessura Intima-Media Carotídea , Estudos de Coortes , Suscetibilidade a Doenças , Feminino , Genótipo , Humanos , Inflamação/complicações , Masculino , Polimorfismo Genético , Insuficiência Renal Crônica/genética , Insuficiência Renal Crônica/metabolismo , Risco , Receptor 4 Toll-Like/genética
7.
Life Sci ; 257: 118061, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32652137

RESUMO

Obesity is an independent risk factor for the development of chronic kidney disease. The pathophysiology of the obesity-induced kidney injury is complex, but evidence suggests the involvement of reduced adiponectin levels and signaling. We investigated the extent by which adiponectin contributes to the establishment and progression of renal disease in wild type (WT) and adiponectin null (adipoKO) mice fed a control or a high-fat diet (HFD) for 16 weeks. HFD induced obesity, kidney hypertrophy, albuminuria, renal lipid accumulation and decreased nephrin expression in both mice genotypes. Notably, HFD in adipoKO mice exacerbated progression of albuminuria in comparison to WT mice. In addition, lack of adiponectin per se increased kidney weight, reduced nephrin levels, up-regulated Fabp4 expression, reduced Cpt1a expression and increased miR-130 levels in kidney. Our results demonstrate that lack of adiponectin combined with a HFD contributes to accelerated kidney dysfunction.


Assuntos
Adiponectina/genética , Albuminúria/fisiopatologia , Dieta Hiperlipídica/efeitos adversos , Obesidade/complicações , Insuficiência Renal Crônica/fisiopatologia , Albuminúria/genética , Animais , Carnitina O-Palmitoiltransferase/genética , Modelos Animais de Doenças , Progressão da Doença , Proteínas de Ligação a Ácido Graxo/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , MicroRNAs/genética , Insuficiência Renal Crônica/genética
8.
Medicine (Baltimore) ; 99(29): e21045, 2020 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-32702845

RESUMO

BACKGROUND: Previous meta-analyses have explored the association between the C677T polymorphism of methyltetrahydrofolate reductase (MTHFR) and chronic kidney disease (CKD) but there were no studies with a decisive conclusion. Furthermore, the high heterogeneity among different populations is not yet interpreted. OBJECTIVES: This study used trial sequential analysis (TSA) to evaluate whether the nowadays conclusion supported by current cumulative samples. We also applied case-weighted meta-regression to explore the potential gene-environment interactions. METHODS: For the first stage of this study we conducted a case-control study involving 847 dialysis patients from 7 hemodialysis centers in Taipei during 2015 to 2018 and 755 normal controls from a health center in the Tri-Service General Hospital. The second stage combined the results from the first stage with previous studies. The previous studies were collected from PubMed, EMBASE, and Web of Science databases before January 2018. RESULTS: From the case-control study, the T allele of MTHFR C677T appeared to have a protective effect on end-stage renal disease compared with the C allele [odds ratio (OR): 0.80, 95% CI (confidence interval) = 0.69-0.93]. However, the meta-analysis contradicted the results in Asian (OR = 1.12, 95% CI = 0.96-1.30). The same analysis was also applied in Caucasian and presented similar results from Asian (OR = 1.18, 95% CI = 0.98-1.42). The TSA showed our case-control study to be the decisive sample leading to a null association among Asian population. The high heterogeneity (I = 75%) could explain the contradictory results between the case-control study and the meta-analysis. However, further case-weighted meta-regression did not find any significant interaction between measured factors and MTHFR C677T on CKD. CONCLUSIONS: High heterogeneities were found in both Caucasian and Asian, which caused the null relationship in meta-analysis while there were significant effects in individual studies. Future studies should further explore the high heterogeneity that might be hidden in unmeasured gene-environment interactions, to explain the diverse findings among different populations.


Assuntos
Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Polimorfismo de Nucleotídeo Único , Insuficiência Renal Crônica/genética , Idoso , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Interação Gene-Ambiente , Predisposição Genética para Doença , Humanos , Masculino , Taiwan
9.
J Clin Pathol ; 73(8): 441-443, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32404472

RESUMO

Apolipoprotein L1 (APOL1) is a protein encoded by the APOL1 gene, found only in humans and several primates. Two variants encoding two different isoforms exist for APOL1, namely G1 and G2. These variants confer increased protection against trypanosome infection, and subsequent African sleeping sickness, and also increase the likelihood of renal disease in individuals of African ancestry. APOL1 mutations are associated with increased risk of chronic kidney disease, inflammation, and exacerbation of systemic lupus erythematosus-associated renal dysfunction. This review serves to outline the structure and function of APOL1, as well as its role in several disease outcomes.


Assuntos
Apolipoproteína L1/genética , Apolipoproteína L1/fisiologia , Autofagia/genética , Evolução Molecular , Variação Genética , Humanos , Inflamação/genética , Mutação/genética , Insuficiência Renal Crônica/genética , Tripanossomíase Africana/genética
10.
Am J Kidney Dis ; 76(1): 100-108, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32354559

RESUMO

RATIONALE & OBJECTIVE: Recent studies in the human immunodeficiency virus (HIV)-infected population have suggested that there are genetic predispositions to the development of chronic kidney disease (CKD) in this context. We investigated the association of genetic polymorphisms of the genes encoding apolipoprotein L1 (APOL1), transforming growth factor ß1 (TGF-ß1; a profibrotic cytokine), and heme oxygenase 1 (HMOX1) with prevalent CKD among adults with and without HIV infection. STUDY DESIGN: Case-control study. SETTING & PARTICIPANTS: West African adults including 217 HIV-infected patients with CKD (HIV+/CKD+ group), 595 HIV-infected patients without CKD (HIV+/CKD- group), 269 with CKD and no HIV infection (HIV-/CKD+ group), and 114 with neither CKD nor HIV (HIV-/CKD- group). EXPOSURE: The genetic polymorphisms with reference single-nucleotide polymorphism (rs) identification numbers rs1800469 (TGF-ß1), rs1800470 (TGF-ß1), rs121918282 (TGF-ß1); rs60910145 (APOL1 G1 risk allele), rs73885319 (APOL1 G1 risk allele), rs71785313 (APOL1 G2 risk allele), and rs743811 (HMOX1); HIV. OUTCOME: CKD. ANALYTICAL APPROACH: Single-nucleotide polymorphism (SNP) genotyping of rs1800469 (TGF-ß1), rs1800470 (TGF-ß1), rs121918282 (TGF-ß1); rs60910145 (APOL1), rs73885319 (APOL1), rs71785313 (APOL1), and rs743811 (HMOX1) was performed. Hardy-Weinberg equilibrium was evaluated for all SNPs, and minor allele frequencies were reported. A case-control analysis was performed, and multivariable logistic regression was used to control for potential confounders. RESULTS: Minor allele frequencies for TGF-ß1 (rs1800469, rs1800470, and rs1800471), APOL1 (rs60910145, rs73885319, and rs71785313), and HMOX1 (rs743811) were 0.25, 0.46, 0.46, 0.44, 0.45, 0.17, and 0.14, respectively. Among HIV-positive individuals, only TGF-ß1 rs1800470 (GG vs AA), APOL1 (in the recessive model), and hypertension were associated with prevalent CKD (adjusted ORs of 0.44 [95% CI, 0.20-0.97], 2.54 [95% CI, 1.44-4.51], and 2.17 [95% CI, 1.35-3.48], respectively). No SNP polymorphisms were associated with prevalent CKD among HIV-negative individuals. LIMITATIONS: The lack of histopathology data for proper categorization of the type of HIV-related nephropathy. CONCLUSIONS: APOL1 polymorphisms were highly prevalent in this population and among adult patients infected with HIV and were associated with increased CKD risk. The TGF-ß1 (rs1800470) polymorphism was associated with reduced risk, and HMOX1 polymorphisms were unassociated with CKD.


Assuntos
Apolipoproteína L1/genética , Infecções por HIV/genética , Heme Oxigenase-1/genética , Polimorfismo de Nucleotídeo Único/genética , Insuficiência Renal Crônica/genética , Fator de Crescimento Transformador beta1/genética , Adulto , Idoso , Feminino , Estudos de Associação Genética , Infecções por HIV/diagnóstico , Infecções por HIV/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Nigéria/epidemiologia , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/epidemiologia
11.
Am J Hum Genet ; 106(5): 659-678, 2020 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-32386536

RESUMO

Access to large-scale genomics datasets has increased the utility of hypothesis-free genome-wide analyses. However, gene signals are often insufficiently powered to reach experiment-wide significance, triggering a process of laborious triaging of genomic-association-study results. We introduce mantis-ml, a multi-dimensional, multi-step machine-learning framework that allows objective assessment of the biological relevance of genes to disease studies. Mantis-ml is an automated machine-learning framework that follows a multi-model approach of stochastic semi-supervised learning to rank disease-associated genes through iterative learning sessions on random balanced datasets across the protein-coding exome. When applied to a range of human diseases, including chronic kidney disease (CKD), epilepsy, and amyotrophic lateral sclerosis (ALS), mantis-ml achieved an average area under curve (AUC) prediction performance of 0.81-0.89. Critically, to prove its value as a tool that can be used to interpret exome-wide association studies, we overlapped mantis-ml predictions with data from published cohort-level association studies. We found a statistically significant enrichment of high mantis-ml predictions among the highest-ranked genes from hypothesis-free cohort-level statistics, indicating a substantial improvement over the performance of current state-of-the-art methods and pointing to the capture of true prioritization signals for disease-associated genes. Finally, we introduce a generic mantis-ml score (GMS) trained with over 1,200 features as a generic-disease-likelihood estimator, outperforming published gene-level scores. In addition to our tool, we provide a gene prioritization atlas that includes mantis-ml's predictions across ten disease areas and empowers researchers to interactively navigate through the gene-triaging framework. Mantis-ml is an intuitive tool that supports the objective triaging of large-scale genomic discovery studies and enhances our understanding of complex genotype-phenotype associations.


Assuntos
Esclerose Amiotrófica Lateral/genética , Epilepsia/genética , Genômica/métodos , Insuficiência Renal Crônica/genética , Aprendizado de Máquina Supervisionado , Animais , Área Sob a Curva , Aprendizado Profundo , Modelos Animais de Doenças , Exoma/genética , Estudos de Associação Genética , Humanos , Camundongos , Redes Neurais de Computação , Curva ROC , Reprodutibilidade dos Testes , Processos Estocásticos
12.
Sci Rep ; 10(1): 6586, 2020 04 20.
Artigo em Inglês | MEDLINE | ID: mdl-32313061

RESUMO

Matrix Gla protein (MGP) is a potent inhibitor of vascular calcification (VC) and requires carboxylation by vitamin K to exert calcification inhibition. Chronic kidney disease (CKD) patients undergo early vascular aging often involving extensive VC. The present cross-sectional study investigated the association between circulating dp-ucMGP levels, MGP expression in vascular tissue and MGP polymorphisms. In 141 CKD stage 5 patients, CAC score was significantly increased in the highest tertile of dp-ucMGP (p = 0.002), and a high medial VC score was associated with elevated dp-ucMGP levels. MGP vascular expression was associated with increased circulating dp-ucMGP and CAC scores. MGP SNP analysis revealed that patients homozygous for the C allele of the rs1800801 variant had a higher CAC score (median 15 [range 0-1312]) compared to patients carrying a T allele (median 0 [range 0-966] AU). These results indicate that plasma levels of dp-ucMGP are an independent predictor of increased VC in CKD5 patients and correlate with both higher CAC scores and degree of medial calcification. Additionally, high vascular expression of MGP was associated with higher CAC scores and plasma dp-ucMGP levels. Taken together, our results support that MGP is involved in the pathogenesis of VC.


Assuntos
Proteínas de Ligação ao Cálcio/sangue , Proteínas da Matriz Extracelular/sangue , Falência Renal Crônica/sangue , Insuficiência Renal Crônica/sangue , Calcificação Vascular/sangue , Adulto , Biomarcadores/sangue , Proteínas de Ligação ao Cálcio/genética , Espessura Intima-Media Carotídea , Proteínas da Matriz Extracelular/genética , Feminino , Regulação da Expressão Gênica/genética , Humanos , Falência Renal Crônica/genética , Falência Renal Crônica/patologia , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Insuficiência Renal Crônica/genética , Insuficiência Renal Crônica/patologia , Fatores de Risco , Calcificação Vascular/genética , Calcificação Vascular/patologia
13.
Mutat Res ; 852: 503167, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32265040

RESUMO

Chronic kidney disease (CKD) is a multifactorial disorder with an important genetic component, and several studies have demonstrated potential associations with allelic variants. In addition, CKD patients are also characterized by high levels of genomic damage. Nevertheless, no studies have established relationships between DNA damage, or genomic instability present in CKD patients, and gene polymorphisms. To fill in this gap, the potential role of polymorphisms in genes involved in base excision repair (OGG1, rs1052133; MUTYH, rs3219489; XRCC1, rs25487), nucleotide excision repair (ERCC2/XPD, rs1799793, rs171140, rs13181; ERCC4, rs3136166); phase II metabolism (GSTP1, rs749174; GSTO1, rs2164624; GSTO2, rs156697), and antioxidant enzymes (SOD1, rs17880135, rs1041740, rs202446; SOD2, rs4880; CAT, rs1001179; GPX1, rs17080528; GPX3, rs870406: GPX4, rs713041) were inquired. In addition, some genes involved in CKD (AGT, rs5050; GLO1, rs386572987; SHROOM3, rs17319721) were also evaluated. The genomic damage, the genomic instability, and oxidative damage were evaluated by using the micronucleus and the comet assay in 589 donors (415 CKD patients and 174 controls). Our results showed significant associations between genomic damage and genes directly involved in DNA repair pathways (XRCC1, and ERCC2), and with genes encoding for antioxidant enzymes (SOD1 and GPX1). GSTO2, as a gene involved in phase II metabolism, and MUTYH showed also an association with genomic instability. Interestingly, the three genes associated with CKD (AGT, GLO1, and SHROOM3) showed associations with both the high levels of oxidatively damaged DNA and genomic instability. These results support our view that genomic instability can be considered a biomarker of the CKD status.


Assuntos
Angiotensinogênio/genética , Reparo do DNA , Instabilidade Genômica , Lactoilglutationa Liase/genética , Proteínas dos Microfilamentos/genética , Insuficiência Renal Crônica/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Angiotensinogênio/metabolismo , Estudos de Casos e Controles , Ensaio Cometa , Dano ao DNA , DNA Glicosilases/genética , DNA Glicosilases/metabolismo , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Predisposição Genética para Doença , Genoma Humano , Glutationa Peroxidase/genética , Glutationa Peroxidase/metabolismo , Glutationa Transferase/genética , Glutationa Transferase/metabolismo , Humanos , Lactoilglutationa Liase/metabolismo , Masculino , Proteínas dos Microfilamentos/metabolismo , Testes para Micronúcleos , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/fisiopatologia , Superóxido Dismutase-1/genética , Superóxido Dismutase-1/metabolismo , Proteína 1 Complementadora Cruzada de Reparo de Raio-X/genética , Proteína 1 Complementadora Cruzada de Reparo de Raio-X/metabolismo , Proteína Grupo D do Xeroderma Pigmentoso/genética , Proteína Grupo D do Xeroderma Pigmentoso/metabolismo
14.
Am J Physiol Renal Physiol ; 318(5): F1210-F1219, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32200666

RESUMO

Contrast-induced acute kidney injury (CI-AKI) is a vexing problem, and more than 70 million patients undergo studies using iodinated contrast. The molecular mechanisms responsible for CI-AKI are poorly understood. The goal of the present article was to determine the role of transforming growth factor-ß1 (TGF-ß1)/mothers against decapentaplegic homolog (SMAD)3 and associated collagen expression in a murine model of intra-arterial CI-AKI. The murine model of CI-AKI after intra-arterial contrast agent administration was created by first performing a partial nephrectomy to induce chronic kidney disease. Twenty-eight days later, 100 µL of contrast agent [iodixanol (320 mg/mL)] or saline were administered via the carotid artery. Two days after contrast administration, compared with saline, average serum creatinine was significantly elevated (P < 0.05). In the cortex, there was a significant increase in phosphorylated SMAD3 and gene expression of TGF-ß1, TGF-ß receptor type I, and TGF-ß receptor type II at day 2 in the contrast group compared with the saline group. Average gene expressions of connective tissue growth factor, matrix metalloproteinase-2 and -9, and collagen type I-α and type IV-α were significantly increased at 2 days after contrast administration (all P < 0.05). Moreover, there was a decrease in Ki-67 staining in the cortex, with an increase in terminal deoxynucleotidyl transferase dUTP nick-end labeling in the cortex and medulla after contrast administration (P < 0.05). In the murine intra-arterial CI-AKI model, there was increased hypoxia and TGF-ß1/SMAD3 pathway activation and collagen expression, resulting in renal fibrosis. Together, these results suggest that the TGF-ß1/SMAD3 pathway could be a potential target in alleviating tissue fibrosis in CI-AKI.


Assuntos
Lesão Renal Aguda/etiologia , Meios de Contraste , Rim/metabolismo , Insuficiência Renal Crônica/complicações , Ácidos Tri-Iodobenzoicos , Lesão Renal Aguda/genética , Lesão Renal Aguda/metabolismo , Lesão Renal Aguda/patologia , Animais , Apoptose , Artérias Carótidas , Hipóxia Celular , Proliferação de Células , Colágeno/genética , Colágeno/metabolismo , Meios de Contraste/administração & dosagem , Modelos Animais de Doenças , Fibrose , Regulação da Expressão Gênica , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Injeções Intra-Arteriais , Rim/patologia , Masculino , Camundongos Endogâmicos C57BL , Nefrectomia , Fosforilação , Receptor do Fator de Crescimento Transformador beta Tipo I/genética , Receptor do Fator de Crescimento Transformador beta Tipo I/metabolismo , Receptor do Fator de Crescimento Transformador beta Tipo II/genética , Receptor do Fator de Crescimento Transformador beta Tipo II/metabolismo , Insuficiência Renal Crônica/genética , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/patologia , Transdução de Sinais , Proteína Smad3/metabolismo , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/metabolismo , Ácidos Tri-Iodobenzoicos/administração & dosagem
15.
J Steroid Biochem Mol Biol ; 199: 105587, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32004706

RESUMO

Chronic kidney disease (CKD) is associated with elevated circulating fibroblast growth factor 23 (FGF23), impaired renal biosynthesis of 1α,25-dihydroxyvitamin D (1α,25(OH)2D), low bone mass, and increased fracture risk. Our previous data with human mesenchymal stem cells (hMSCs) indicated that vitamin D metabolism in hMSCs is regulated as it is in the kidney and promotes osteoblastogenesis in an autocrine/paracrine manner. In this study, we tested the hypothesis that FGF23 inhibits vitamin D metabolism and action in hMSCs. hMSCs were isolated from discarded marrow during hip arthroplasty, including two subjects receiving hemodialysis and a series of 20 subjects (aged 49-83 years) with estimated glomerular filtration rate (eGFR) data. The direct in vitro effects of rhFGF23 on hMSCs were analyzed by RT-PCR, Western immunoblot, and biochemical assays. Ex vivo analyses showed positive correlations for both secreted and membrane-bound αKlotho gene expression in hMSCs with eGFR of the subjects from whom hMSCs were isolated. There was downregulated constitutive expression of αKlotho, but not FGFR1 in hMSCs obtained from two hemodialysis subjects. In vitro, rhFGF23 countered vitamin D-stimulated osteoblast differentiation of hMSCs by reducing the vitamin D receptor, CYP27B1/1α-hydroxylase, biosynthesis of 1α,25(OH)2D3, and signaling through BMP-7. These data demonstrate that dysregulated vitamin D metabolism in hMSCs may contribute to impaired osteoblastogenesis and altered bone and mineral metabolism in CKD subjects due to elevated FGF23. This supports the importance of intracellular vitamin D metabolism in autocrine/paracrine regulation of osteoblast differentiation in hMSCs.


Assuntos
Fatores de Crescimento de Fibroblastos/genética , Células-Tronco Mesenquimais/metabolismo , Osteogênese/genética , Insuficiência Renal Crônica/genética , Vitamina D/metabolismo , 25-Hidroxivitamina D3 1-alfa-Hidroxilase/genética , Idoso , Idoso de 80 Anos ou mais , Proteína Morfogenética Óssea 7/genética , Diferenciação Celular/genética , Feminino , Regulação da Expressão Gênica no Desenvolvimento/genética , Taxa de Filtração Glomerular , Humanos , Rim/metabolismo , Rim/patologia , Masculino , Pessoa de Meia-Idade , Osteoblastos , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Receptores de Calcitriol/genética , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/patologia , Vitamina D/análogos & derivados , Vitamina D/biossíntese , Vitamina D/genética
16.
Int J Mol Sci ; 21(3)2020 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-32023824

RESUMO

Chronic renal insufficiency (CRI) is characterized by increased endothelin 1 (ET-1) synthesis. We studied rat kidney endothelin receptor A (ETA) and receptor B (ETB) expressions after 12 and 27 weeks of 5/6 nephrectomy, and after 12 weeks of 0.3% adenine diet, representing proteinuric and interstitial inflammation models of CRI, respectively. Uric acid and calcium-phosphate metabolism were modulated after 5/6 nephrectomy, while ETA blocker and calcimimetic were given with adenine. Endothelin receptor mRNA levels were measured using RT-qPCR and protein levels using autoradiography (5/6 nephrectomy) or ELISA (adenine model). Both 12 and 27 weeks after 5/6 nephrectomy, kidney cortex ETA protein was increased by ~60% without changes in ETB protein, and the ETB:ETA ratio was reduced. However, the ETB:ETA mRNA ratio did not change. In the adenine model, kidney ETA protein was reduced by ~70%, while ETB protein was suppressed by ~95%, and the ETB:ETA ratio was reduced by ~85%, both at the protein and mRNA levels. The additional interventions did not influence the observed reductions in the ETB:ETA ratio. To conclude, unfavorable reduction in the ETB:ETA protein ratio was observed in two different models of CRI. Therefore, ETA blockade may be beneficial in a range of diseases that cause impaired kidney function.


Assuntos
Adenina/efeitos adversos , Receptor de Endotelina A/genética , Receptor de Endotelina B/genética , Insuficiência Renal Crônica/genética , Animais , Cálcio/metabolismo , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Córtex Renal/metabolismo , Masculino , Nefrectomia/efeitos adversos , Fosfatos/metabolismo , Ratos , Receptor de Endotelina A/metabolismo , Receptor de Endotelina B/metabolismo , Insuficiência Renal Crônica/induzido quimicamente , Insuficiência Renal Crônica/metabolismo , Ácido Úrico/metabolismo
17.
PLoS One ; 15(1): e0228101, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32004338

RESUMO

OBJECTIVES: The R102G variant in complement 3 (C3) results in two allotypic variants: C3 fast (C3F) and C3 slow (C3S). C3F presents at increased frequency in patients with chronic kidney disease (CKD), our aim is to explore its role in CKD progression and mortality. METHODS: Delta (Δ) eGFR for 2038 patients in the Salford Kidney Study (SKS) was calculated by linear regression; those with ≤-3ml/min/1.73m2/yr were defined as rapid progressors (RP) and those with ΔeGFR between -0.5 and +1ml/min/1.73m2/yr, labelled stable CKD patients (SP).A group of 454 volunteers was used as a control group. In addition, all biopsy-proven glomerulonephritis (GN) patients were studied regardless of their ΔeGFR. R102G was analysed by real-time PCR, and genotypic and allelic frequencies were compared between RP and SP along with the healthy control group. RESULTS: There were 255 SP and 259 RP in the final cohort. Median ΔeGFR was 0.07 vs. -4.7 ml/min/1.73m2/yr in SP vs. RP. C3F allele frequency was found to be significantly higher in our CKD cohort (25.7%) compared with the healthy control group (20.6%); p = 0.008.However, there was no significant difference in C3F allele frequency between the RP and SP groups. In a subgroup analysis of 37 patients with IgA nephropathy in the CKD cohort (21 RP and 16 SP), there was a significantly higher frequency of C3F in RP 40.5% vs. 9.4% in SP; p = 0.003. In the GN group, Cox regression showed an association between C3F and progression only in those with IgA nephropathy (n = 114);HR = 1.9 (95% CI 1.1-3.1; p = 0.018) for individuals heterozygous for the C3F variant, increased further for individuals homozygous for the variant, HR = 2.8 (95% CI 1.2-6.2; p = 0.014). CONCLUSION: The C3 variant R102G is associated with progression of CKD in patients with IgA nephropathy.


Assuntos
Complemento C3/genética , Progressão da Doença , Insuficiência Renal Crônica/genética , Insuficiência Renal Crônica/mortalidade , Idoso , Feminino , Frequência do Gene , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético
18.
Oxid Med Cell Longev ; 2020: 7083575, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32089777

RESUMO

Background. Chronic kidney disease (CKD) is a global health burden with high mortality and morbidity. Clinical efficacy has been demonstrated for Shen Shuai II Recipe (SSR), an approved and widely used Chinese herbal medicine for over 20 years in China, to attenuate CKD progression. In this study, we explored the underlying molecular mechanisms of SSR benefits and studied its effects on apoptosis, a critical process in CKD development and progression. CKD was induced in rats with 5/6 renal ablation and infarction (A/I). Eight weeks after SSR treatment, we mainly assessed the severity of renal injury and fibrosis, the translocation of apoptotic factors in the mitochondrial apoptosis pathway, the degree of mitochondrial dysfunction, and the nuclear and mitochondrial translocation of p53. Furthermore, we detected the interaction of p53 with antiapoptotic Bcl-xL and Bcl-2 proteins. Our results showed that SSR significantly attenuated renal injury and fibrosis and inhibited the mitochondrial accumulation of proapoptotic proteins Bax and Puma and release of cytochrome c from mitochondria to the cytosol in a rat CKD model. In addition, SSR also improved the mitochondrial function and inhibited the nuclear and mitochondrial translocation of p53. In addition, SSR suppressed the p53 transactivation and the interaction of p53 with Bcl-xL and Bcl-2. These results suggested that SSR could block apoptosis in CKD by inhibiting p53 transcriptional-dependent and transcriptional-independent proapoptotic function and the mitochondrial pathway of apoptosis.


Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Mitocôndrias/efeitos dos fármacos , Insuficiência Renal Crônica/tratamento farmacológico , Proteína Supressora de Tumor p53/antagonistas & inibidores , Animais , Apoptose/efeitos dos fármacos , Modelos Animais de Doenças , Masculino , Mitocôndrias/metabolismo , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Insuficiência Renal Crônica/genética , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/patologia , Proteína Supressora de Tumor p53/metabolismo
19.
Sci Rep ; 10(1): 144, 2020 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-31924810

RESUMO

Chronic kidney disease (CKD) patients have many affected physiological pathways. Variations in the genes regulating these pathways might affect the incidence and predisposition to this disease. A total of 722 Spanish adults, including 548 patients and 174 controls, were genotyped to better understand the effects of genetic risk loci on the susceptibility to CKD. We analyzed 38 single nucleotide polymorphisms (SNPs) in candidate genes associated with the inflammatory response (interleukins IL-1A, IL-4, IL-6, IL-10, TNF-α, ICAM-1), fibrogenesis (TGFB1), homocysteine synthesis (MTHFR), DNA repair (OGG1, MUTYH, XRCC1, ERCC2, ERCC4), renin-angiotensin-aldosterone system (CYP11B2, AGT), phase-II metabolism (GSTP1, GSTO1, GSTO2), antioxidant capacity (SOD1, SOD2, CAT, GPX1, GPX3, GPX4), and some other genes previously reported to be associated with CKD (GLO1, SLC7A9, SHROOM3, UMOD, VEGFA, MGP, KL). The results showed associations of GPX1, GSTO1, GSTO2, UMOD, and MGP with CKD. Additionally, associations with CKD related pathologies, such as hypertension (GPX4, CYP11B2, ERCC4), cardiovascular disease, diabetes and cancer predisposition (ERCC2) were also observed. Different genes showed association with biochemical parameters characteristic for CKD, such as creatinine (GPX1, GSTO1, GSTO2, KL, MGP), glomerular filtration rate (GPX1, GSTO1, KL, ICAM-1, MGP), hemoglobin (ERCC2, SHROOM3), resistance index erythropoietin (SOD2, VEGFA, MTHFR, KL), albumin (SOD1, GSTO2, ERCC2, SOD2), phosphorus (IL-4, ERCC4 SOD1, GPX4, GPX1), parathyroid hormone (IL-1A, IL-6, SHROOM3, UMOD, ICAM-1), C-reactive protein (SOD2, TGFB1,GSTP1, XRCC1), and ferritin (SOD2, GSTP1, SLC7A9, GPX4). To our knowledge, this is the second comprehensive study carried out in Spanish patients linking genetic polymorphisms and CKD.


Assuntos
Polimorfismo de Nucleotídeo Único , Insuficiência Renal Crônica/genética , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Espanha
20.
Endokrynol Pol ; 71(1): 66-72, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31909452

RESUMO

INTRODUCTION: Multifactorial pathogenesis of diabetic kidney disease (DKD) consists of a combination of metabolic, environmental, and genetic factors. A genome-wide association study has shown that ELMO1 is a candidate gene for DKD occurrence and progression. The aim of this study was to assess the association of a single nucleotide polymorphism (rs741301) of the ELMO1 gene with DKD in Polish patients with type 2 diabetes (T2DM). MATERIAL AND METHODS: This was a case/control study of 272 T2DM patients with or without DKD. Patients were divided into groups depending on DKD definition according to the American Diabetes Association (ADA) and the National Kidney Foundation (NKF). The association of the rs741301 polymorphism with DKD was assessed in the whole study group as well as in the subgroups stratified according to the presence of DKD. RESULTS: There was no association between rs741301 polymorphisms and the presence of DKD in relation to the ADA definition (p = 0.6) or the NKF definition (p = 0.5) of DKD and with estimated glomelural filtration rate (eGFR) value reflecting the stage of the chronic kidney disease (p = 0.8). CONCLUSIONS: Even though the results of this study are negative, there is still a great need for larger studies assessing the genetic susceptibility to DKD to identify patients who are particularly prone to this complication.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Diabetes Mellitus Tipo 2/genética , Nefropatias Diabéticas/genética , Insuficiência Renal Crônica/genética , Adulto , Estudos de Casos e Controles , Feminino , Estudos de Associação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Polônia , Polimorfismo de Nucleotídeo Único , Fatores de Risco
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