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BACKGROUND: Chronic kidney disease (CKD) is highly prevalent in Central America, and genetic factors may contribute to CKD risk. To understand the influences of genetic admixture on CKD susceptibility, we conducted an admixture mapping screening of CKD traits and risk factors in US Hispanic and Latino individuals from Central America country of origin. METHODS: We analyzed 1023 participants of HCHS/SOL (Hispanic Community Health Study/Study of Latinos) who reported 4 grandparents originating from the same Central America country. Ancestry admixture findings were validated on 8191 African Americans from WHI (Women's Health Initiative), 3141 American Indians from SHS (Strong Heart Study), and over 1.1 million European individuals from a multistudy meta-analysis. RESULTS: We identified 3 novel genomic regions for albuminuria (chromosome 14q24.2), CKD (chromosome 6q25.3), and type 2 diabetes (chromosome 3q22.2). The 14q24.2 locus driven by a Native American ancestry had a protective effect on albuminuria and consisted of 2 nearby regions spanning the RGS6 gene. Variants at this locus were validated in American Indians. The 6q25.3 African ancestry-derived locus, encompassing the ARID1B gene, was associated with increased risk for CKD and replicated in African Americans through admixture mapping. The European ancestry type 2 diabetes locus at 3q22.2, encompassing the EPHB1 and KY genes, was validated in European individuals through variant association. CONCLUSIONS: US Hispanic/Latino populations are culturally and genetically diverse. This study focusing on Central America grandparent country of origin provides new loci discovery and insights into the ancestry-of-origin influences on CKD and risk factors in US Hispanic and Latino individuals.
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Hispánicos o Latinos , Insuficiencia Renal Crónica , Humanos , Femenino , América Central/etnología , Hispánicos o Latinos/genética , Insuficiencia Renal Crónica/genética , Insuficiencia Renal Crónica/etnología , Masculino , Factores de Riesgo , Persona de Mediana Edad , Albuminuria/genética , Albuminuria/etnología , Anciano , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/epidemiología , Diabetes Mellitus Tipo 2/etnología , Polimorfismo de Nucleótido Simple , Mapeo Cromosómico , Predisposición Genética a la Enfermedad , Adulto , Población Blanca/genética , Negro o Afroamericano/genéticaRESUMEN
Sulforaphane (SFN), found in cruciferous vegetables, is a known activator of NRF2 (master regulator of cellular antioxidant responses). Patients with chronic kidney disease (CKD) present an imbalance in the redox state, presenting reduced expression of NRF2 and increased expression of NF-κB. Therefore, this study aimed to evaluate the effects of SFN on the mRNA expression of NRF2, NF-κB and markers of oxidative stress in patients with CKD. Here, we observed a significant increase in the mRNA expression of NRF2 (p = 0.02) and NQO1 (p = 0.04) in the group that received 400 µg/day of SFN for 1 month. Furthermore, we observed an improvement in the levels of phosphate (p = 0.02), glucose (p = 0.05) and triglycerides (p = 0.02) also in this group. On the other hand, plasma levels of LDL-c (p = 0.04) and total cholesterol (p = 0.03) increased in the placebo group during the study period. In conclusion, 400 µg/day of SFN for one month improves the antioxidant system and serum glucose and phosphate levels in non-dialysis CKD patients.
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Isotiocianatos , NAD(P)H Deshidrogenasa (Quinona) , Factor 2 Relacionado con NF-E2 , Estrés Oxidativo , ARN Mensajero , Insuficiencia Renal Crónica , Sulfóxidos , Humanos , Isotiocianatos/farmacología , Isotiocianatos/uso terapéutico , Factor 2 Relacionado con NF-E2/metabolismo , Factor 2 Relacionado con NF-E2/genética , NAD(P)H Deshidrogenasa (Quinona)/genética , NAD(P)H Deshidrogenasa (Quinona)/metabolismo , Insuficiencia Renal Crónica/metabolismo , Insuficiencia Renal Crónica/genética , Insuficiencia Renal Crónica/tratamiento farmacológico , Insuficiencia Renal Crónica/patología , Masculino , Persona de Mediana Edad , Femenino , ARN Mensajero/genética , ARN Mensajero/metabolismo , Estrés Oxidativo/efectos de los fármacos , Antioxidantes/metabolismo , Antioxidantes/farmacología , Triglicéridos/sangre , Triglicéridos/metabolismo , Glucemia/metabolismo , Regulación hacia Arriba/efectos de los fármacos , Adulto , Anciano , FN-kappa B/metabolismo , FN-kappa B/genéticaRESUMEN
This JAMA Insights reviews the origin of APOL1 high-risk genetic variants, defines APOL1-mediated kidney disease, and discusses recommendations for screening and management.
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Apolipoproteína L1 , Negro o Afroamericano , Insuficiencia Renal Crónica , Tripanosomiasis Africana , Animales , Humanos , Ratones , Apolipoproteína L1/genética , Enfermedades Renales/diagnóstico , Enfermedades Renales/epidemiología , Enfermedades Renales/etnología , Enfermedades Renales/genética , Negro o Afroamericano/genética , Negro o Afroamericano/estadística & datos numéricos , Estados Unidos/epidemiología , Insuficiencia Renal Crónica/diagnóstico , Insuficiencia Renal Crónica/epidemiología , Insuficiencia Renal Crónica/etnología , Insuficiencia Renal Crónica/genética , Frecuencia de los Genes/genética , Población Negra/genética , Población Negra/estadística & datos numéricos , Pruebas Genéticas , África del Sur del Sahara/epidemiología , Región del Caribe/epidemiología , América Central/epidemiología , América del Sur/epidemiología , Tripanosomiasis Africana/epidemiología , Tripanosomiasis Africana/etnología , Tripanosomiasis Africana/genéticaRESUMEN
MicroRNAs (miRNAs) and long non-coding RNAs (lncRNAs) are two crucial classes of transcripts that belong to the major group of non-coding RNAs (ncRNAs). These RNA molecules have significant influence over diverse molecular processes due to their crucial role as regulators of gene expression. However, the dysregulated expression of these ncRNAs constitutes a fundamental factor in the etiology and progression of a wide variety of multifaceted human diseases, including kidney diseases. In this context, over the past years, compelling evidence has shown that miRNAs and lncRNAs could be prospective targets for the development of next-generation drugs against kidney diseases as they participate in a number of disease-associated processes, such as podocyte and nephron death, renal fibrosis, inflammation, transition from acute kidney injury to chronic kidney disease, renal vascular changes, sepsis, pyroptosis, and apoptosis. Hence, in this current review, we critically analyze the recent findings concerning the therapeutic inferences of miRNAs and lncRNAs in the pathophysiological context of kidney diseases. Additionally, with the aim of driving advances in the formulation of ncRNA-based drugs tailored for the management of kidney diseases, we discuss some of the key challenges and future prospects that should be addressed in forthcoming investigations.
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MicroARNs , ARN Largo no Codificante , Insuficiencia Renal Crónica , Humanos , MicroARNs/genética , MicroARNs/metabolismo , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , ARN no Traducido , Insuficiencia Renal Crónica/tratamiento farmacológico , Insuficiencia Renal Crónica/genética , Insuficiencia Renal Crónica/metabolismo , FibrosisRESUMEN
Collapsing glomerulopathy (CG) is most often associated with fast progression to kidney failure with an incidence apparently higher in Brazil than in other countries. However, the reason for this occurrence is unknown. To better understand this, we performed an integrated analysis of clinical, histological, therapeutic, causative genetic and genetic ancestry data in a highly genetically admixed cohort of 70 children and adult patients with idiopathic CG (ICG). The disease onset occurred at 23 (interquartile range: 17-31) years and approximately half of patients progressed to chronic kidney disease requiring kidney replacement therapy (CKD-KRT) 36 months after diagnosis. Causative genetic bases, assessed by targeted-gene panel or whole-exome sequencing, were identified in 58.6% of patients. Among these cases, 80.5% harbored APOL1 high-risk genotypes (HRG) and 19.5% causative Mendelian variants (MV). Self-reported non-White patients more frequently had HRG. MV was an independent risk factor for progression to CKD-KRT by 36 months and the end of follow-up, while remission was an independent protective factor. All patients with HRG manifested CG at 9-44 years of age, whereas in those with APOL1 low-risk genotype, the disease arose throughout life. HRGs were associated with higher proportion of African genetic ancestry. Novel causative MVs were identified in COL4A5, COQ2 and PLCE1 and previously described causative MVs were identified in MYH9, TRPC6, COQ2, COL4A3 and TTC21B. Three patients displayed HRG combined with a variant of uncertain significance (ITGB4, LAMA5 or PTPRO). MVs were associated with worse kidney prognosis. Thus, our data reveal that the genetic status plays a major role in ICG pathogenesis, accounting for more than half of cases in a highly admixed Brazilian population.
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Apolipoproteína L1 , Insuficiencia Renal Crónica , Adulto , Niño , Humanos , Apolipoproteína L1/genética , Genotipo , Riñón/patología , Insuficiencia Renal Crónica/epidemiología , Insuficiencia Renal Crónica/genética , Insuficiencia Renal Crónica/patología , Factores de Riesgo , Adolescente , Adulto JovenRESUMEN
Fabry disease (FD) is an X-linked lysosomal storage disease caused by pathogenic variants in the GLA gene. It has a wide range of clinical manifestations, typically related to the specific underlying GLA variant. One of the main features of FD is kidney involvement; therefore, several studies have addressed the prevalence of FD in all types of patients with chronic kidney disease. We performed a systematic review and meta-analysis of screening studies in chronic kidney disease patients, including those on dialysis, had undergone a kidney transplantation, and those who did not receive kidney replacement therapy, and assessed the prevalence of pathogenic variants in these cohorts. Fifty-five studies were included, involving a total of 84,062 individuals. Of these, 251 cases were positive for FD; a third of the reported GLA variants were of a benign phenotype (37.8%), followed by classical phenotype (31.7%), late onset (15.5%), and of uncertain significance (14.7%). The overall prevalence among dialysis patients was 0.10% (CI95%, 0.06-0.15), 0.28% (CI95%, 0.06-0.15) among patients with kidney transplantation, and 0.17% (CI95%, 0.11-0.39) among those without kidney replacement therapy. Although the overall prevalence of FD is low in patients with kidney involvement, screening, especially in patients who have not yet undergone kidney replacement therapy, is important, in order to provide timely and effective treatment interventions, including disease modifying therapies. The prevalence of kidney involvement in females with Fabry Disease is lower but this should not lead to inadequate follow up. Further research is also needed on the impact of genetic variants of uncertain significance to elucidate their role in Fabry disease.
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Enfermedad de Fabry , Insuficiencia Renal Crónica , Femenino , Humanos , Enfermedad de Fabry/complicaciones , Enfermedad de Fabry/epidemiología , Enfermedad de Fabry/genética , alfa-Galactosidasa/genética , Prevalencia , Insuficiencia Renal Crónica/epidemiología , Insuficiencia Renal Crónica/genética , Insuficiencia Renal Crónica/terapia , Fenotipo , MutaciónRESUMEN
INTRODUCTION: BTB and CNC homology 1 (Bach1) is a protein that antagonizes some actions of nuclear factor erythroid 2-related factor-2 (Nrf2), the master regulator of cytoprotective responses. Bach1 binds to genomic DNA and inhibits the synthesis of antioxidant enzymes, thereby increasing inflammation. Bach1 may be a therapeutic target for mitigating inflammation in chronic kidney disease (CKD) patients. However, no clinical study has been reported on Bach1 in this population. This study aimed to evaluate Bach1 mRNA expression with different treatments for CKD, including conservative treatment (nondialysis), hemodialysis (HD), and peritoneal dialysis (PD). METHODS: Twenty patients undergoing HD (56.5 [19] years), 15 on PD (54 [24] years) and 13 nondialysis patients (63 [10] years, with an estimated glomerular filtration rate of 41 [14] mL/min/1.73 m2 ) were enrolled in the study. The mRNA expression of Nrf2, NF-kB, heme oxygenase 1 (HO-1), and Bach1 was evaluated in peripheral blood mononuclear cells using quantitative real-time polymerase chain reaction. Malondialdehyde (MDA) was evaluated as a lipid peroxidation marker. Routine biochemical parameters were also evaluated. FINDINGS: As expected, patients on dialysis were more inflamed. Bach1 mRNA expression was significantly higher in patients undergoing HD than in PD and nondialysis patients (p < 0.007). The mRNA expression of HO-1, NF-kB, and Nrf2 was not different in the groups. CONCLUSION: In conclusion, CKD patients on HD exhibited an upregulation of Bach1 mRNA expression compared to patients on PD treatment and nondialysis CKD patients. The association between Nrf2 and Bach1 expression in these patients warrants further investigation.
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Factor 2 Relacionado con NF-E2 , Insuficiencia Renal Crónica , Humanos , Factor 2 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/metabolismo , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/genética , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/metabolismo , FN-kappa B/metabolismo , Leucocitos Mononucleares/metabolismo , Diálisis Renal , Hemo-Oxigenasa 1/genética , Hemo-Oxigenasa 1/metabolismo , Insuficiencia Renal Crónica/genética , Insuficiencia Renal Crónica/terapia , Inflamación , ARN Mensajero/genética , ARN Mensajero/metabolismoRESUMEN
OBJECTIVE: Chronic kidney disease (CKD) remains one of the major common health problems, and the number of people affected by the disease is progressively increasing in Turkey and worldwide. This study aimed to investigate molecular defects in Alport syndrome (AS) and other genes in patients with clinically suspected CKD using whole-exome sequencing (WES). METHODS: Patients with clinical suspicion of CKD were included in the study. Molecular genetic analyses were performed on genomic DNA by using WES. RESULTS: A total of 15 with 5 different pathogenic or likely pathogenic variants were identified in CKD patients, with a diagnostic rate of 30%. Eight variants of uncertain significance were also detected. In this study, 10 variants were described for the first time. As a result, we detected variants associated with CKD in our study population and found AS as the most common CKD after other related kidney diseases. CONCLUSIONS: Our results suggest that in heterogeneous diseases such as CKD, WES analysis enables accurate identification of underlying molecular defects promptly. Although CKD accounts for 10-14% of all renal dysfunction, molecular genetic diagnosis is necessary for optimal long-term treatment, prognosis, and effective genetic counseling. .
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Nefritis Hereditaria , Insuficiencia Renal Crónica , ADN , Humanos , Nefritis Hereditaria/genética , Pronóstico , Insuficiencia Renal Crónica/genética , Secuenciación del Exoma/métodosRESUMEN
Background: Type 2 diabetes mellitus (T2DM) and high blood pressure (HBP) are the main risk factors for chronic kidney disease (CKD). Relationships between variants within the NFE2L2 gene and the presence of environmental risk factors for CKD, such as HBP and hyperglycemia have been suggested; however, their interactions remains unclear. Aim: To analyze the association of NFE2L2 variants with metabolic and kidney parameters. Materials and Methods: Six-hundred and fifty-one patients grouped according to the diagnosis of T2DM (n =166), T2DM+HBP (n =348) and HBP (n =137) were included. Metabolic characteristics were evaluated to identify risk factors and presence of CKD. Genotyping was performed by polymerase chain reaction (PCR) using two pairs primers for rs35652124 and rs6721961 and by real-time PCR for rs2364723. Logistic regression analyses, adjusted for confounding factors and correction for multiple tests were performed. Results: Significant associations between decreased risk for presenting with CKD and the rs35652124 (A allele) and the rs2364723 (G allele) variants were detected. Other variables consistently associated with these alleles were HBP, BMI, waist circumference, uric acid and triglycerides. Haplotypes AAC and GCG (loci order: rs35652124-rs6721961-rs2364723) showed similar trends. After adjustment for age and sex and correction for multiple tests, only rs35652124 (Odds Ratio [OR] = 0.5; Confidence Interval at 95% (CI95%), 0.3-0.9; p = 0.04) and rs2364723 (OR = 0.3; CI95%, 0.1-0.8; p = 0.009) variants remained associated with deceased risk for CKD in T2DM patients. Conclusion: This study showed for the first time that NFE2L2 variants are associated with decreased risk for CKD in the presence of environmental/metabolic risk factors related to kidney damage, including HBP, hyperuricemia and albuminuria in Mexican patients with diabetes.
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Diabetes Mellitus Tipo 2 , Insuficiencia Renal Crónica , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Humanos , Hipertensión , Hiperuricemia , Riñón , Factor 2 Relacionado con NF-E2 , Insuficiencia Renal Crónica/genética , Factores de RiesgoRESUMEN
Lupus nephritis (LN) is the most frequent and severe of systemic lupus erythematosus (SLE) clinical manifestations and contributes to the increase of morbidity and mortality of patients due to chronic kidney disease. The NLRP3 (NLR pyrin domain containing 3) is a member of the NLR (NOD-like receptors), and its activation results in the production of pro-inflammatory cytokines, which can contribute to the pathogenesis of LN. In this review manuscript, we approach the relation between the NLRP3 inflammasome, SLE, and LN, highlighting the influence of genetic susceptibility of NLRP3 polymorphisms in the disease; the main functional studies using cellular and animal models of NLRP3 activation; and finally, some mechanisms of NLRP3 inhibition for the development of possible therapeutic drugs for LN.
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Predisposición Genética a la Enfermedad , Lupus Eritematoso Sistémico/genética , Nefritis Lúpica/genética , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Humanos , Inflamasomas/genética , Lupus Eritematoso Sistémico/patología , Nefritis Lúpica/patología , Insuficiencia Renal Crónica/genética , Insuficiencia Renal Crónica/patologíaRESUMEN
Mitochondria are essential organelles in physiology and kidney diseases, because they produce cellular energy required to perform their function. During mitochondrial metabolism, reactive oxygen species (ROS) are produced. ROS function as secondary messengers, inducing redox-sensitive post-translational modifications (PTM) in proteins and activating or deactivating different cell signaling pathways. However, in kidney diseases, ROS overproduction causes oxidative stress (OS), inducing mitochondrial dysfunction and altering its metabolism and dynamics. The latter processes are closely related to changes in the cell redox-sensitive signaling pathways, causing inflammation and apoptosis cell death. Although mitochondrial metabolism, ROS production, and OS have been studied in kidney diseases, the role of redox signaling pathways in mitochondria has not been addressed. This review focuses on altering the metabolism and dynamics of mitochondria through the dysregulation of redox-sensitive signaling pathways in kidney diseases.
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Lesión Renal Aguda/metabolismo , Mitocondrias/metabolismo , Estrés Oxidativo , Procesamiento Proteico-Postraduccional , Especies Reactivas de Oxígeno/metabolismo , Insuficiencia Renal Crónica/metabolismo , Lesión Renal Aguda/genética , Lesión Renal Aguda/patología , Apoptosis/genética , Ácidos Grasos/metabolismo , Humanos , Riñón/metabolismo , Riñón/patología , Mitocondrias/genética , Mitocondrias/patología , Dinámicas Mitocondriales , Mitofagia/genética , NADPH Oxidasa 1/genética , NADPH Oxidasa 1/metabolismo , FN-kappa B/genética , FN-kappa B/metabolismo , Fosforilación Oxidativa , Insuficiencia Renal Crónica/genética , Insuficiencia Renal Crónica/patología , Transducción de Señal , Superóxido Dismutasa/genética , Superóxido Dismutasa/metabolismoRESUMEN
ABSTRACT: Corrêa, HdL, Deus, LA, Neves, RVP, Reis, AL, de Freitas, GS, de Araújo, TB, da Silva Barbosa, JM, Prestes, J, Simões, HG, Amorim, CE, dos Santos, MAP, Haro, A, de Melo, GF, Gadelha, AB, Neto, LS, and Rosa, TdS. Influence of angiotensin converting enzyme I/D polymorphism on hemodynamic and antioxidant response to long-term intradialytic resistance training in patients with chronic kidney disease: a randomized controlled trial. J Strength Cond Res 35(10): 2902-2909, 2021-The aim of the study was to verify the influence of Angiotensin-converting enzyme (ACE) I/D genotype on blood pressure, muscle mass, and redox balance response to long-term resistance training (RT) in end-stage renal disease patients. Three hundred and twenty subjects were randomized into 4 groups: II + ID control (II + ID CTL, n = 80), II + ID RT (II + ID RT, n = 79), DD control (DD CTL n = 83), and DD RT (DD RT, n = 78). The RT lasted 24 weeks with a frequency of 3 times per week, on alternative days. Each section consisted of 3 sets of 8-12 repetitions in 11 exercises, with training loads at 6 point (somewhat hard) to 8 point (hard) based on OMNI-RES scale and was prescribed during dialysis (intradialytic). Statistical significance was accepted with p < 0.05. The most relevant benefits in blood pressure were found for DD homozygotes (p < 0.0001), whereas allele I carriers displayed a higher increase in muscle mass (p < 0.0001). Hemodialysis clinics that already use RT for their patients could include the genotyping of ACE to identify the predisposal of the patients to respond to RT and to counteract kidney disease-related comorbidities.
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Insuficiencia Renal Crónica , Entrenamiento de Fuerza , Antioxidantes , Genotipo , Hemodinámica , Humanos , Peptidil-Dipeptidasa A/genética , Insuficiencia Renal Crónica/genética , Insuficiencia Renal Crónica/terapiaRESUMEN
INTRODUCTION: Single nucleotide polymorphisms (SNP) in the fat mass and obesity-associated (FTO) gene have been associated with type 2 diabetes (T2D) and its complications. The aim of the present research was to investigate which and how (directly or indirectly) clinical and metabolic variables mediate the association between fat mass and the FTO gene and early chronic kidney disease (CKD) in individuals with T2D. METHODS: This cross-sectional study was conducted in a sample of 236 participants with T2D (53.4% women, mean age 60 ± 10 years). DNA samples were genotyped for the rs7204609 polymorphism (C/T) in the FTO gene. Clinical, anthropometric, and metabolic data were collected. Path analysis was used to evaluate the associations. RESULTS: Of the sample, 78 individuals with T2D had CKD (33%). Presence of the risk allele (C) was higher among participants with CKD (21.8 vs. 10.8%; p = 0.023). This polymorphism was positively associated with higher waist circumference, which in turn was associated with higher glycated hemoglobin and higher blood pressure. A higher blood-pressure level was associated with higher urinary albumin excretion (UAE) and as expected, higher UAE was associated with CKD. Path analysis showed an indirect relationship between the FTO gene and early CKD, mediated by waist circumference, blood-pressure levels, and UAE. CONCLUSIONS: These findings suggest that the C allele may contribute to genetic susceptibility to CKD in individuals with T2D through the presence of central obesity, hypertension, and high albuminuria.
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Diabetes Mellitus Tipo 2 , Hipertensión , Insuficiencia Renal Crónica , Anciano , Albuminuria/genética , Dioxigenasa FTO Dependiente de Alfa-Cetoglutarato/genética , Índice de Masa Corporal , Estudios Transversales , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/genética , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Obesidad/complicaciones , Obesidad/genética , Obesidad Abdominal , Polimorfismo de Nucleótido Simple , Insuficiencia Renal Crónica/etiología , Insuficiencia Renal Crónica/genéticaRESUMEN
Chronic hypoxia is a major contributor to Chronic Kidney Disease (CKD) after Acute Kidney Injury (AKI). However, the temporal relation between the acute insult and maladaptive renal response to hypoxia remains unclear. In this study, we analyzed the time-course of renal hemodynamics, oxidative stress, inflammation, and fibrosis, as well as epigenetic modifications, with focus on HIF1α/VEGF signaling, in the AKI to CKD transition. Sham-operated, right nephrectomy (UNx), and UNx plus renal ischemia (IR + UNx) groups of rats were included and studied at 1, 2, 3, or 4 months. The IR + UNx group developed CKD characterized by progressive proteinuria, renal dysfunction, tubular proliferation, and fibrosis. At first month post-ischemia, there was a twofold significant increase in oxidative stress and reduction in global DNA methylation that was maintained throughout the study. Hif1α and Vegfa expression were depressed in the first and second-months post-ischemia, and then Hif1α but not Vegfa expression was recovered. Interestingly, hypermethylation of the Vegfa promoter gene at the HIF1α binding site was found, since early stages of the CKD progression. Our findings suggest that renal hypoperfusion, inefficient hypoxic response, increased oxidative stress, DNA hypomethylation, and, Vegfa promoter gene hypermethylation at HIF1α binding site, are early determinants of AKI-to-CKD transition.
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Metilación de ADN , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Riñón/irrigación sanguínea , Regiones Promotoras Genéticas , Insuficiencia Renal Crónica/patología , Factor A de Crecimiento Endotelial Vascular/genética , Lesión Renal Aguda/patología , Animales , Progresión de la Enfermedad , Isquemia/patología , Masculino , Estrés Oxidativo , Ratas , Ratas Wistar , Insuficiencia Renal Crónica/genética , Insuficiencia Renal Crónica/metabolismoRESUMEN
ABSTRACT Introduction: Fabry disease is a chronic, progressive, and multi-system hereditary condition, related to an Xq22 mutation in X chromosome, which results in deficiency of alpha-galactosidase enzyme, hence reduced capacity of globotriaosylceramide degradation. Objectives: to evaluate the prevalence of Fabry disease (FD) mutations, as well as its signs and symptoms, among relatives of chronic kidney disease (CKD) patients diagnosed with FD during a previously conducted study, named "Clinical and epidemiological analysis of Fabry disease in dialysis centers in Brazil". Methods: a cross-sectional study was carried out, and data was collected by interviewing the relatives of patients enrolled in the Brazil Fabry Kidney Project and blood tests for both Gb3 dosage and genetic testing. Results: Among 1214 interviewed relatives, 115 (9.47%) were diagnosed with FD, with a predominance of women (66.10%). The most prevalent comorbidities were rheumatologic conditions and systemic hypertension (1.7% each), followed by heart, neurological, cerebrovascular diseases, and depression in 0.9% of individuals. Intolerance to physical exercise and tiredness were the most observed symptoms (1.7%), followed by periodic fever, intolerance to heat or cold, diffuse pain, burn sensation or numbness in hands and feet, reduced or absent sweating, as well as abdominal pain after meals in 0.9%. Conclusion: We found a prevalence of Fabry disease in 9.47% of relatives of CKD patients with this condition, remarkably with a 66.1% predominance of women, which contrasts with previous reports. The screening of family members of FD patients is important, since it can lead to early diagnosis and treatment, thus allowing better quality of life and improved clinical outcomes for these individuals.
RESUMO Introdução: A doença de Fabry é uma condição hereditária crônica, progressiva e multissistêmica, relacionada a uma mutação Xq22 no cromossomo X, que resulta em deficiência da enzima alfa-galactosidase, diminuindo a capacidade de degradação da globotriaosilceramida. Objetivos: avaliar a prevalência de mutações na doença de Fabry, bem como seus sinais e sintomas, em familiares de pacientes com doença renal crônica (DRC) diagnosticados com DF durante um estudo realizado anteriormente, denominado "Análise clínica e epidemiológica da doença de Fabry em centros de diálise no Brasil". Métodos: foi realizado um estudo transversal e os dados foram coletados através da entrevista com familiares de pacientes inscritos no Projeto Rim Fabry Brasil e exames de sangue para dosagem de Gb3 e testes genéticos. Resultados: Dos 1,214 familiares entrevistados, 115 (9,47%) foram diagnosticados com DF, com predomínio de mulheres (66,10%). As comorbidades mais prevalentes foram condições reumatológicas e hipertensão arterial sistêmica (1,7% cada), seguidas por doenças cardíacas, neurológicas, cerebrovasculares e depressão em 0,9% dos indivíduos. Intolerância ao exercício físico e cansaço foram os sintomas mais observados (1,7%), seguidos de febre periódica, intolerância ao calor ou ao frio, dor difusa, sensação de queimação ou dormência nas mãos e nos pés, sudorese reduzida ou ausente, além de dor abdominal após refeições em 0,9%. Conclusão: Encontramos uma prevalência da doença de Fabry em 9,47% dos familiares de pacientes com DRC com essa condição, notadamente com uma predominância de 66,1% de mulheres, o que contrasta com relatos anteriores. A triagem de familiares de pacientes com DF é importante, pois pode levar ao diagnóstico e tratamento precoces, permitindo melhor qualidade de vida e melhores resultados clínicos para esses indivíduos.
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Humanos , Masculino , Femenino , Enfermedad de Fabry/genética , Enfermedad de Fabry/epidemiología , Insuficiencia Renal Crónica/genética , Insuficiencia Renal Crónica/epidemiología , Calidad de Vida , Familia , Estudios Transversales , MutaciónRESUMEN
INTRODUCTION: Fabry disease is a chronic, progressive, and multi-system hereditary condition, related to an Xq22 mutation in X chromosome, which results in deficiency of alpha-galactosidase enzyme, hence reduced capacity of globotriaosylceramide degradation. OBJECTIVES: to evaluate the prevalence of Fabry disease (FD) mutations, as well as its signs and symptoms, among relatives of chronic kidney disease (CKD) patients diagnosed with FD during a previously conducted study, named "Clinical and epidemiological analysis of Fabry disease in dialysis centers in Brazil". METHODS: a cross-sectional study was carried out, and data was collected by interviewing the relatives of patients enrolled in the Brazil Fabry Kidney Project and blood tests for both Gb3 dosage and genetic testing. RESULTS: Among 1214 interviewed relatives, 115 (9.47%) were diagnosed with FD, with a predominance of women (66.10%). The most prevalent comorbidities were rheumatologic conditions and systemic hypertension (1.7% each), followed by heart, neurological, cerebrovascular diseases, and depression in 0.9% of individuals. Intolerance to physical exercise and tiredness were the most observed symptoms (1.7%), followed by periodic fever, intolerance to heat or cold, diffuse pain, burn sensation or numbness in hands and feet, reduced or absent sweating, as well as abdominal pain after meals in 0.9%. CONCLUSION: We found a prevalence of Fabry disease in 9.47% of relatives of CKD patients with this condition, remarkably with a 66.1% predominance of women, which contrasts with previous reports. The screening of family members of FD patients is important, since it can lead to early diagnosis and treatment, thus allowing better quality of life and improved clinical outcomes for these individuals.
Asunto(s)
Enfermedad de Fabry , Insuficiencia Renal Crónica , Estudios Transversales , Enfermedad de Fabry/epidemiología , Enfermedad de Fabry/genética , Familia , Femenino , Humanos , Masculino , Mutación , Calidad de Vida , Insuficiencia Renal Crónica/epidemiología , Insuficiencia Renal Crónica/genéticaRESUMEN
Obstructive nephropathy favors the progression to chronic kidney disease (CKD), a severe health problem worldwide. The unilateral ureteral obstruction (UUO) model is used to study the development of fibrosis. Impairment of renal mitochondria plays a crucial role in several types of CKD and has been strongly related to fibrosis onset. Nevertheless, in the UUO model, the impairment of mitochondria, their relationship with endoplasmic reticulum (ER) stress induction and the participation of both to induce the fibrotic process remain unclear. In this review, we summarize the current information about mitochondrial bioenergetics, redox dynamics, mitochondrial mass, and biogenesis alterations, as well as the relationship of these mitochondrial alterations with ER stress and their participation in fibrotic processes in UUO models. Early after obstruction, there is metabolic reprogramming related to mitochondrial fatty acid ß-oxidation impairment, triggering lipid deposition, oxidative stress, (calcium) Ca2+ dysregulation, and a reduction in mitochondrial mass and biogenesis. Mitochondria and the ER establish a pathological feedback loop that promotes the impairment of both organelles by ER stress pathways and Ca2+ levels dysregulation. Preserving mitochondrial and ER function can prevent or at least delay the fibrotic process and loss of renal function. However, deeper understanding is still necessary for future clinically-useful therapies.
Asunto(s)
Fibrosis/genética , Mitocondrias/genética , Insuficiencia Renal Crónica/genética , Obstrucción Ureteral/genética , Señalización del Calcio/genética , Reprogramación Celular/genética , Estrés del Retículo Endoplásmico/genética , Fibrosis/metabolismo , Fibrosis/patología , Humanos , Mitocondrias/patología , Biogénesis de Organelos , Oxidación-Reducción , Insuficiencia Renal Crónica/metabolismo , Insuficiencia Renal Crónica/patología , Obstrucción Ureteral/metabolismo , Obstrucción Ureteral/patologíaRESUMEN
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.
Asunto(s)
Adiponectina/genética , Albuminuria/fisiopatología , Dieta Alta en Grasa/efectos adversos , Obesidad/complicaciones , Insuficiencia Renal Crónica/fisiopatología , Albuminuria/genética , Animales , Carnitina O-Palmitoiltransferasa/genética , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Proteínas de Unión a Ácidos Grasos/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , MicroARNs/genética , Insuficiencia Renal Crónica/genéticaRESUMEN
Several studies have demonstrated an important association between altered lipid metabolism and the development of kidney injury because of a high-fat diet. Fructose is also closely associated with renal injury. We opted for a combination of fructose and saturated fats in a diet (DH) that is a model known to induce renal damage in order to evaluate whether soy isoflavones could have promising use in the treatment of renal alterations. After two months of ingestion, there was an expansion of visceral fat, which was associated with long-term metabolic disorders, such as sustained hyperglycemia, insulin resistance, polyuria, dyslipidemia, and hypertension. Additionally, we found a decrease in renal blood flow and an increase in renal vascular resistance. Biochemical markers of chronic kidney disease were detected; there was an infiltration of inflammatory cells with an elevated expression of proinflammatory cytokines (tumor necrosis factor-α, interleukin (IL)-6, and IL-1ß), the activation of the renin-angiotensin system, and oxidative/nitrosative stress. Notably, in rats exposed to the DH diet for 120 days, the concomitant treatment with isoflavones after 60 days was able to revert metabolic parameters, renal alterations, and oxidative/nitrosative stress. The beneficial effects of isoflavones in the kidney of the obese rats were found to be mediated by expression of peroxisome proliferator-activated receptor gamma (PPAR-γ).
Asunto(s)
Fructosa/efectos adversos , Expresión Génica/efectos de los fármacos , Isoflavonas/farmacología , Isoflavonas/uso terapéutico , Riñón/metabolismo , Obesidad/tratamiento farmacológico , Obesidad/metabolismo , PPAR gamma/genética , PPAR gamma/metabolismo , Fitoterapia , Insuficiencia Renal Crónica/tratamiento farmacológico , Insuficiencia Renal Crónica/metabolismo , Animales , Citocinas/metabolismo , Dieta Alta en Grasa/efectos adversos , Carbohidratos de la Dieta/efectos adversos , Modelos Animales de Enfermedad , Mediadores de Inflamación/metabolismo , Riñón/irrigación sanguínea , Masculino , Obesidad/etiología , Obesidad/genética , Estrés Oxidativo/efectos de los fármacos , Ratas Wistar , Insuficiencia Renal Crónica/etiología , Insuficiencia Renal Crónica/genéticaRESUMEN
Not much is known about the roles of long non-coding RNAs (lncRNAs) for chronic kidney disease (CKD). In this study, we included CKD patient cohorts and normal controls as a discovery cohort to identify putative lncRNA biomarkers associated with CKD. We first compared the lncRNA expression profiles of CKD patients with normal controls, and identified differentially expressed lncRNAs and mRNAs. Co-expression network based on the enriched differentially expressed mRNAs and lncRNAs was constructed using WGCNA to identify important modules related to CKD. A lncRNA-miRNA-mRNA pathway network based on the hub lncRNAs and mRNAs, related miRNAs, and overlapping pathways was further constructed to reveal putative biomarkers. A total of 821 significantly differentially expressed mRNAs and lncRNAs were screened between CKD and control samples, which were enriched in nine modules using weighted correlation network analysis (WGCNA), especially brown and yellow modules. Co-expression network based on the enriched differentially expressed mRNAs and lncRNAs in brown and yellow modules uncovered 7 hub lncRNAs and 53 hub mRNAs. A lncRNA-miRNA-mRNA pathway network further revealed that lncRNAs of HCP5 and NOP14-AS1 and genes of CCND2, COL3A1, COL4A1, and RAC2 were significantly correlated with CKD. The lncRNAs of NOP14-AS1 and HCP5 were potential prognostic biomarkers for predicting the risk of CKD.