RESUMEN
Our previous study identified 8 risk and 9 protective plasma miRNAs associated with progression to end-stage kidney disease (ESKD) in diabetes. This study aimed to elucidate preanalytical factors that influence the quantification of circulating miRNAs. Using the EdgeSeq platform, which quantifies 2,002 miRNAs in plasma, including ESKD-associated miRNAs, we compared miRNA profiles in whole plasma versus miRNA profiles in RNA extracted from the same plasma specimens. Less than half of the miRNAs were detected in standard RNA extraction from plasma. Detection of individual and concentrations of miRNAs were much lower when RNA extracted from plasma was quantified by RNA sequencing (RNA-Seq) or quantitative reverse transcription PCR (qRT-PCR) platforms compared with EdgeSeq. Plasma profiles of miRNAs determined by the EdgeSeq platform had excellent reproducibility in assessment and had no variation with age, sex, hemoglobin A1c, BMI, and cryostorage time. The risk ESKD-associated miRNAs were detected and measured accurately only in whole plasma and using the EdgeSeq platform. Protective ESKD-associated miRNAs were detected by all platforms except qRT-PCR; however, correlations among concentrations obtained with different platforms were weak or nonexistent. In conclusion, preanalytical factors have a profound effect on detection and quantification of circulating miRNAs in ESKD in diabetes. Quantification of miRNAs in whole plasma and using the EdgeSeq platform may be the preferable method to study profiles of circulating cell-free miRNAs associated with ESKD and possibly other diseases.
Asunto(s)
MicroARN Circulante , Fallo Renal Crónico , Humanos , MicroARN Circulante/sangre , MicroARN Circulante/genética , Fallo Renal Crónico/sangre , Fallo Renal Crónico/genética , Masculino , Femenino , Persona de Mediana Edad , Nefropatías Diabéticas/sangre , Nefropatías Diabéticas/genética , Nefropatías Diabéticas/diagnóstico , Biomarcadores/sangre , Anciano , Reproducibilidad de los Resultados , Adulto , MicroARNs/sangre , MicroARNs/genética , Progresión de la Enfermedad , Diabetes Mellitus/sangre , Diabetes Mellitus/genética , Diabetes Mellitus/diagnósticoRESUMEN
Variation in DNA methylation (DNAmet) in white blood cells and other cells/tissues has been implicated in the etiology of progressive diabetic kidney disease (DKD). However, the specific mechanisms linking DNAmet variation in blood cells with risk of kidney failure (KF) and utility of measuring blood cell DNAmet in personalized medicine are not clear. We measured blood cell DNAmet in 277 individuals with type 1 diabetes and DKD using Illumina EPIC arrays; 51% of the cohort developed KF during 7 to 20 years of follow-up. Our epigenome-wide analysis identified DNAmet at 17 CpGs (5'-cytosine-phosphate-guanine-3' loci) associated with risk of KF independent of major clinical risk factors. DNAmet at these KF-associated CpGs remained stable over a median period of 4.7 years. Furthermore, DNAmet variations at seven KF-associated CpGs were strongly associated with multiple genetic variants at seven genomic regions, suggesting a strong genetic influence on DNAmet. The effects of DNAmet variations at the KF-associated CpGs on risk of KF were partially mediated by multiple KF-associated circulating proteins and KF-associated circulating miRNAs. A prediction model for risk of KF was developed by adding blood cell DNAmet at eight selected KF-associated CpGs to the clinical model. This updated model significantly improved prediction performance (c-statistic = 0.93) versus the clinical model (c-statistic = 0.85) at P = 6.62 × 10-14. In conclusion, our multiomics study provides insights into mechanisms through which variation of DNAmet may affect KF development and shows that blood cell DNAmet at certain CpGs can improve risk prediction for KF in T1D.
Asunto(s)
Metilación de ADN , Diabetes Mellitus Tipo 1 , Variación Genética , Humanos , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/sangre , Diabetes Mellitus Tipo 1/complicaciones , Metilación de ADN/genética , Masculino , Femenino , Insuficiencia Renal/genética , Insuficiencia Renal/sangre , MicroARNs/genética , MicroARNs/sangre , Adulto , Islas de CpG/genética , Nefropatías Diabéticas/genética , Nefropatías Diabéticas/sangre , Factores de RiesgoRESUMEN
INTRODUCTION: Recently, circulating neuroblastoma suppressor of tumorigenicity 1 (NBL1) was shown to be strongly associated with kidney disease progression and histological lesions in patients with diabetic kidney disease. This study aimed to examine whether serum NBL1 level was also associated with kidney function and renal histological findings in patients with IgA nephropathy. METHODS: We evaluated the levels of NBL1 in 109 patients with newly diagnosed biopsy-proven primary IgAN, between 2009 and 2018, at the Nihon University School of Medicine Itabashi Hospital, Tokyo, Japan, using serum obtained immediately before the renal biopsy, and examined the relationship between serum NBL1, renal function and renal histological findings assessed using the Oxford Classification (MEST score). Furthermore, we analyzed the association of serum NBL1 with kidney function decline over time in patients with IgA nephropathy who had follow-up data on the estimated glomerular filtration rate (n = 76). RESULTS: Serum NBL1 levels in patients with newly diagnosed IgA nephropathy were elevated, as compared to those in healthy individuals (n = 93). Logistic regression analysis demonstrated that the serum NBL1 level was independently and significantly associated with tubular atrophy/interstitial fibrosis. Immunohistochemical staining revealed that NBL1 was highly expressed in the tubulointerstitium. Furthermore, Spearman's rank correlation identified a significant correlation between serum NBL1 level and estimated glomerular filtration rate slope. CONCLUSIONS: The serum NBL1 level was significantly associated with the severity of renal interstitial fibrosis and kidney disease progression in patients with newly diagnosed IgA nephropathy. Thus, circulating NBL1 may serve as a good biomarker for evaluating renal interstitial fibrosis and the risk of kidney disease progression.
Asunto(s)
Glomerulonefritis por IGA , Neuroblastoma , Humanos , Progresión de la Enfermedad , Fibrosis , Tasa de Filtración Glomerular , Glomerulonefritis por IGA/patología , Riñón , Neuroblastoma/complicaciones , Neuroblastoma/patologíaRESUMEN
Circulating proteins associated with transforming growth factor-ß (TGF-ß) signaling are implicated in the development of diabetic kidney disease (DKD). It remains to be comprehensively examined which of these proteins are involved in the pathogenesis of DKD and its progression to end-stage kidney disease (ESKD) in humans. Using the SOMAscan proteomic platform, we measured concentrations of 25 TGF-ß signaling family proteins in four different cohorts composed in total of 754 Caucasian or Pima Indian individuals with type 1 or type 2 diabetes. Of these 25 circulating proteins, we identified neuroblastoma suppressor of tumorigenicity 1 (NBL1, aliases DAN and DAND1), a small secreted protein known to inhibit members of the bone morphogenic protein family, to be most strongly and independently associated with progression to ESKD during 10-year follow-up in all cohorts. The extent of damage to podocytes and other glomerular structures measured morphometrically in 105 research kidney biopsies correlated strongly with circulating NBL1 concentrations. Also, in vitro exposure to NBL1 induced apoptosis in podocytes. In conclusion, circulating NBL1 may be involved in the disease process underlying progression to ESKD, and its concentration in circulation may identify subjects with diabetes at increased risk of progression to ESKD.
Asunto(s)
Proteínas de Ciclo Celular/sangre , Diabetes Mellitus Tipo 2 , Fallo Renal Crónico , Neuroblastoma , Diabetes Mellitus Tipo 2/complicaciones , Progresión de la Enfermedad , Humanos , Proteómica , Factor de Crecimiento Transformador betaRESUMEN
This study applies a large proteomics panel to search for new circulating biomarkers associated with progression to kidney failure in individuals with diabetic kidney disease. Four independent cohorts encompassing 754 individuals with type 1 and type 2 diabetes and early and late diabetic kidney disease were followed to ascertain progression to kidney failure. During ten years of follow-up, 227 of 754 individuals progressed to kidney failure. Using the SOMAscan proteomics platform, we measured baseline concentration of 1129 circulating proteins. In our previous publications, we analyzed 334 of these proteins that were members of specific candidate pathways involved in diabetic kidney disease and found 35 proteins strongly associated with risk of progression to kidney failure. Here, we examined the remaining 795 proteins using an untargeted approach. Of these remaining proteins, 11 were significantly associated with progression to kidney failure. Biological processes previously reported for these proteins were related to neuron development (DLL1, MATN2, NRX1B, KLK8, RTN4R and ROR1) and were implicated in the development of kidney fibrosis (LAYN, DLL1, MAPK11, MATN2, endostatin, and ROR1) in cellular and animal studies. Specific mechanisms that underlie involvement of these proteins in progression of diabetic kidney disease must be further investigated to assess their value as targets for kidney-protective therapies. Using multivariable LASSO regression analysis, five proteins (LAYN, ESAM, DLL1, MAPK11 and endostatin) were found independently associated with risk of progression to kidney failure. Thus, our study identified proteins that may be considered as new candidate prognostic biomarkers to predict risk of progression to kidney failure in diabetic kidney disease. Furthermore, three of these proteins (DLL1, ESAM, and MAPK11) were selected as candidate biomarkers when all SOMAscan results were evaluated.
Asunto(s)
Diabetes Mellitus Tipo 2 , Nefropatías Diabéticas , Insuficiencia Renal , Biomarcadores/metabolismo , Diabetes Mellitus Tipo 2/complicaciones , Nefropatías Diabéticas/complicaciones , Nefropatías Diabéticas/etiología , Progresión de la Enfermedad , Endostatinas , Humanos , Lectinas Tipo C , Proteómica/métodosRESUMEN
Extracellular vesicle (EV)-based therapy was hypothesized as a promising regenerative approach which has led to intensive research of EVs in various pathologies. In this study, we performed a comprehensive systematic review of the current experimental evidence regarding the protective properties of EVs in chronic kidney disease (CKD). We evaluated the EV-based experiments, EV characteristics, and effector molecules with their involvement in CKD pathways. Including all animal records with available creatinine or urea data, we performed a stratified univariable meta-analysis to assess the determinants of EV-based therapy effectiveness. We identified 35 interventional studies that assessed nephroprotective role of EVs and catalogued them according to their involvement in CKD mechanism. Systematic assessment of these studies suggested that EVs had consistently improved glomerulosclerosis, interstitial fibrosis, and cell damage, among different CKD models. Moreover, EV-based therapy reduced the progression of renal decline in CKD. The stratified analyses showed that the disease model, administered dose, and time of therapeutic intervention were potential predictors of therapeutic efficacy. Together, EV therapy is a promising approach for CKD progression in experimental studies. Further standardisation of EV-methods, continuous improvement of the study quality, and better understanding of the determinants of EV effectiveness will facilitate preclinical research, and may help development of clinical trials in people with CKD.
Asunto(s)
Vesículas Extracelulares , Células Madre Mesenquimatosas , Insuficiencia Renal Crónica , Animales , Vesículas Extracelulares/metabolismo , Humanos , Riñón , Células Madre Mesenquimatosas/metabolismo , Modelos Teóricos , Insuficiencia Renal Crónica/metabolismo , Insuficiencia Renal Crónica/patología , Insuficiencia Renal Crónica/terapiaRESUMEN
Diabetic kidney disease (DKD) and its major clinical manifestation, progressive renal decline that leads to end-stage renal disease (ESRD), are a major health burden for individuals with diabetes. The disease process that underlies progressive renal decline comprises factors that increase risk as well as factors that protect against this outcome. Using untargeted proteomic profiling of circulating proteins from individuals in two independent cohorts with type 1 and type 2 diabetes and varying stages of DKD followed for 7 to 15 years, we identified three elevated plasma proteins-fibroblast growth factor 20 (OR, 0.69; 95% CI, 0.54 to 0.88), angiopoietin-1 (OR, 0.72; 95% CI, 0.57 to 0.91), and tumor necrosis factor ligand superfamily member 12 (OR, 0.75; 95% CI, 0.59 to 0.95)-that were associated with protection against progressive renal decline and progression to ESRD. The combined effect of these three protective proteins was demonstrated by very low cumulative risk of ESRD in those who had baseline concentrations above median for all three proteins, whereas the cumulative risk of ESRD was high in those with concentrations below median for these proteins at the beginning of follow-up. This protective effect was shown to be independent from circulating inflammatory proteins and clinical covariates and was confirmed in a third cohort of diabetic individuals with normal renal function. These three protective proteins may serve as biomarkers to stratify diabetic individuals according to risk of progression to ESRD and might also be investigated as potential therapeutics to delay or prevent the onset of ESRD.
Asunto(s)
Diabetes Mellitus Tipo 2 , Fallo Renal Crónico , Biomarcadores , Progresión de la Enfermedad , Tasa de Filtración Glomerular , Humanos , Riñón/fisiología , Proteómica , Factores de RiesgoRESUMEN
BACKGROUND: Rare variants in gene coding regions likely have a greater impact on disease-related phenotypes than common variants through disruption of their encoded protein. We searched for rare variants associated with onset of ESKD in individuals with type 1 diabetes at advanced kidney disease stage. METHODS: Gene-based exome array analyses of 15,449 genes in five large incidence cohorts of individuals with type 1 diabetes and proteinuria were analyzed for survival time to ESKD, testing the top gene in a sixth cohort (n=2372/1115 events all cohorts) and replicating in two retrospective case-control studies (n=1072 cases, 752 controls). Deep resequencing of the top associated gene in five cohorts confirmed the findings. We performed immunohistochemistry and gene expression experiments in human control and diseased cells, and in mouse ischemia reperfusion and aristolochic acid nephropathy models. RESULTS: Protein coding variants in the hydroxysteroid 17-ß dehydrogenase 14 gene (HSD17B14), predicted to affect protein structure, had a net protective effect against development of ESKD at exome-wide significance (n=4196; P value=3.3 × 10-7). The HSD17B14 gene and encoded enzyme were robustly expressed in healthy human kidney, maximally in proximal tubular cells. Paradoxically, gene and protein expression were attenuated in human diabetic proximal tubules and in mouse kidney injury models. Expressed HSD17B14 gene and protein levels remained low without recovery after 21 days in a murine ischemic reperfusion injury model. Decreased gene expression was found in other CKD-associated renal pathologies. CONCLUSIONS: HSD17B14 gene is mechanistically involved in diabetic kidney disease. The encoded sex steroid enzyme is a druggable target, potentially opening a new avenue for therapeutic development.
Asunto(s)
17-Hidroxiesteroide Deshidrogenasas/genética , 17-Hidroxiesteroide Deshidrogenasas/metabolismo , Nefropatías Diabéticas/genética , Fallo Renal Crónico/genética , Adulto , Animales , Estudios de Casos y Controles , Diabetes Mellitus Tipo 1/complicaciones , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/metabolismo , Nefropatías Diabéticas/complicaciones , Nefropatías Diabéticas/metabolismo , Progresión de la Enfermedad , Exoma , Femenino , Expresión Génica , Variación Genética , Humanos , Fallo Renal Crónico/etiología , Fallo Renal Crónico/metabolismo , Túbulos Renales Proximales/enzimología , Masculino , Ratones , Persona de Mediana Edad , Elementos Estructurales de las Proteínas/genética , Daño por Reperfusión/complicaciones , Estudios Retrospectivos , Tasa de SupervivenciaRESUMEN
BACKGROUND: Mechanisms underlying the pro gression of diabetic kidney disease to ESKD are not fully understood. METHODS: We performed global microRNA (miRNA) analysis on plasma from two cohorts consisting of 375 individuals with type 1 and type 2 diabetes with late diabetic kidney disease, and targeted proteomics analysis on plasma from four cohorts consisting of 746 individuals with late and early diabetic kidney disease. We examined structural lesions in kidney biopsy specimens from the 105 individuals with early diabetic kidney disease. Human umbilical vein endothelial cells were used to assess the effects of miRNA mimics or inhibitors on regulation of candidate proteins. RESULTS: In the late diabetic kidney disease cohorts, we identified 17 circulating miRNAs, represented by four exemplars (miR-1287-5p, miR-197-5p, miR-339-5p, and miR-328-3p), that were strongly associated with 10-year risk of ESKD. These miRNAs targeted proteins in the axon guidance pathway. Circulating levels of six of these proteins-most notably, EFNA4 and EPHA2-were strongly associated with 10-year risk of ESKD in all cohorts. Furthermore, circulating levels of these proteins correlated with severity of structural lesions in kidney biopsy specimens. In contrast, expression levels of genes encoding these proteins had no apparent effects on the lesions. In in vitro experiments, mimics of miR-1287-5p and miR-197-5p and inhibitors of miR-339-5p and miR-328-3p upregulated concentrations of EPHA2 in either cell lysate, supernatant, or both. CONCLUSIONS: This study reveals novel mechanisms involved in progression to ESKD and points to the importance of systemic factors in the development of diabetic kidney disease. Some circulating miRNAs and axon guidance pathway proteins represent potential targets for new therapies to prevent and treat this condition.
Asunto(s)
Orientación del Axón/fisiología , Diabetes Mellitus Tipo 1/sangre , Diabetes Mellitus Tipo 2/sangre , Nefropatías Diabéticas/etiología , Fallo Renal Crónico/etiología , MicroARNs/sangre , Adulto , Estudios de Cohortes , Diabetes Mellitus Tipo 1/complicaciones , Diabetes Mellitus Tipo 2/complicaciones , Nefropatías Diabéticas/sangre , Femenino , Humanos , Fallo Renal Crónico/sangre , Masculino , Persona de Mediana EdadRESUMEN
We recently identified a kidney risk inflammatory signature (KRIS), comprising 6 TNF receptors (including TNFR1 and TNFR2) and 11 inflammatory proteins. Elevated levels of these proteins in circulation were strongly associated with risk of the development of end-stage kidney disease (ESKD) during 10-year follow-up. It has been hypothesized that elevated levels of these proteins in circulation might reflect (be markers of) systemic exposure to TNFα. In this in vitro study, we examined intracellular and extracellular levels of these proteins in human umbilical vein endothelial cells (HUVECs) exposed to TNFα in the presence of hyperglycemia. KRIS proteins as well as 1300 other proteins were measured using the SOMAscan proteomics platform. Four KRIS proteins (including TNFR1) were down-regulated and only 1 protein (IL18R1) was up-regulated in the extracellular fraction of TNFα-stimulated HUVECs. In the intracellular fraction, one KRIS protein was down-regulated (CCL14) and 1 protein was up-regulated (IL18R1). The levels of other KRIS proteins were not affected by exposure to TNFα. HUVECs exposed to a hyperglycemic and inflammatory environment also showed significant up-regulation of a distinct set of 53 proteins (mainly in extracellular fraction). In our previous study, circulating levels of these proteins were not associated with progression to ESKD in diabetes.
Asunto(s)
Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Hiperglucemia/metabolismo , Inflamación/metabolismo , Receptores del Factor de Necrosis Tumoral/metabolismo , Factor de Necrosis Tumoral alfa/farmacología , Regulación hacia Abajo/efectos de los fármacos , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Humanos , Regulación hacia Arriba/efectos de los fármacosRESUMEN
This study comprehensively evaluated the association between known circulating tumor necrosis factor (TNF) superfamily ligands and receptors and the development of early progressive kidney decline (PKD) leading to end-stage kidney disease (ESKD) in Type 1 diabetes. Participants for the study were from the Macro-Albuminuria Study (198 individuals), and the Micro-Albuminuria Study (148 individuals) of the Joslin Kidney Study. All individuals initially had normal kidney function and were followed for seven-fifteen years to determine the slope of the estimate glomerular filtration rate and to ascertain onset of ESKD. Plasma concentrations of 25 TNF superfamily proteins were measured using proximity extension assay applied in the OLINK proteomics platform. In the both studies risk of early PKD, determined as estimated glomerular filtration rate loss greater than or equal to three ml/min/1.73m2/year, was associated with elevated circulating levels of 13 of 19 TNF receptors examined. In the Macro-Albuminuria Study, we obtained similar findings for risk of progression to ESKD. These receptors comprised: TNF-R1A, -R1B, -R3, -R4, -R6, -R6B, -R7, -R10A, -R10B, -R11A, -R14, -R21, and -R27. Serial measurements showed that circulating levels of these TNF receptors had increased before the onset of PKD. In contrast, none of the six measured TNF ligands showed association with risk of early PKD. Of significance, the disease process that underlies PKD leading to ESKD in Type 1 diabetes has a profile also seen in autoimmune disorders. The mechanisms of this enrichment may be causally related to the development of PKD in Type 1 diabetes and must be investigated further. Thus, some of these receptors may be used as new risk predictors of ESKD.
Asunto(s)
Diabetes Mellitus Tipo 1 , Nefropatías Diabéticas , Albuminuria , Diabetes Mellitus Tipo 1/complicaciones , Nefropatías Diabéticas/diagnóstico , Nefropatías Diabéticas/etiología , Progresión de la Enfermedad , Tasa de Filtración Glomerular , Humanos , Riñón , Receptores del Factor de Necrosis Tumoral , Factores de RiesgoRESUMEN
OBJECTIVE: The role of fibrosis in early progressive renal decline in type 2 diabetes is unknown. Circulating WFDC2 (WAP four-disulfide core domain protein 2) and matrix metalloproteinase 7 (MMP-7; Matrilysin) are postulated to be biomarkers of renal fibrosis. This study examined an association of circulating levels of these proteins with early progressive renal decline. RESEARCH DESIGN AND METHODS: Individuals with type 2 diabetes enrolled in the Joslin Kidney Study with an estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m2 were monitored for 6-12 years to ascertain fast early progressive renal decline, defined as eGFR loss ≥5 mL/min/1.73 m2/year. RESULTS: A total of 1,181 individuals were studied: 681 without and 500 with albuminuria. Median eGFR and albumin-to-creatinine ratio (ACR) at baseline were 97 mL/min/1.73 m2 and 24 mg/g, respectively. During follow-up, 152 individuals experienced fast early progressive renal decline: 6.9% in those with normoalbuminuria and 21% with albuminuria. In both subgroups, the risk of renal decline increased with increasing baseline levels of WFDC2 (P < 0.0001) and MMP-7 (P < 0.0001). After adjustment for relevant clinical characteristics and known biomarkers, an increase by one quartile in the fibrosis index (combination of levels of WFDC2 and MMP-7) was associated with higher risk of renal decline (odds ratio 1.63; 95% CI 1.30-2.04). The association was similar and statistically significant among patients with and without albuminuria. CONCLUSIONS: Elevation of circulating profibrotic proteins is associated with the development of early progressive renal decline in type 2 diabetes. This association is independent from albuminuria status and points to the importance of the fibrotic process in the development of early renal decline.
Asunto(s)
Albuminuria/diagnóstico , Biomarcadores/sangre , Diabetes Mellitus Tipo 2/diagnóstico , Nefropatías Diabéticas/diagnóstico , Metaloproteinasa 7 de la Matriz/sangre , Proteína 2 de Dominio del Núcleo de Cuatro Disulfuros WAP/metabolismo , Adulto , Albuminuria/sangre , Albuminuria/complicaciones , Biomarcadores/análisis , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/patología , Nefropatías Diabéticas/sangre , Nefropatías Diabéticas/patología , Progresión de la Enfermedad , Femenino , Fibrosis/sangre , Fibrosis/complicaciones , Fibrosis/diagnóstico , Tasa de Filtración Glomerular , Humanos , Riñón/patología , Fallo Renal Crónico/sangre , Fallo Renal Crónico/diagnóstico , Fallo Renal Crónico/etiología , Fallo Renal Crónico/patología , Estudios Longitudinales , Masculino , Metaloproteinasa 7 de la Matriz/análisis , Metaloproteinasa 7 de la Matriz/metabolismo , Persona de Mediana Edad , New England , Pronóstico , Proteína 2 de Dominio del Núcleo de Cuatro Disulfuros WAP/análisisRESUMEN
Chronic inflammation is postulated to be involved in the development of end-stage renal disease in diabetes, but which specific circulating inflammatory proteins contribute to this risk remain unknown. To study this, we examined 194 circulating inflammatory proteins in subjects from three independent cohorts with type 1 and type 2 diabetes. In each cohort, we identified an extremely robust kidney risk inflammatory signature (KRIS), consisting of 17 proteins enriched in tumor necrosis factor-receptor superfamily members, that was associated with a 10-year risk of end-stage renal disease. All these proteins had a systemic, non-kidney source. Our prospective study findings provide strong evidence that KRIS proteins contribute to the inflammatory process underlying end-stage renal disease development in both types of diabetes. These proteins point to new therapeutic targets and new prognostic tests to identify subjects at risk of end-stage renal disease, as well as biomarkers to measure responses to treatment of diabetic kidney disease.
Asunto(s)
Nefropatías Diabéticas/sangre , Nefropatías Diabéticas/etiología , Fallo Renal Crónico/sangre , Fallo Renal Crónico/etiología , Adulto , Anciano , Biomarcadores/sangre , Proteínas Sanguíneas/genética , Proteínas Sanguíneas/metabolismo , Estudios de Cohortes , Diabetes Mellitus Tipo 1/sangre , Diabetes Mellitus Tipo 1/complicaciones , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/genética , Nefropatías Diabéticas/genética , Progresión de la Enfermedad , Femenino , Humanos , Mediadores de Inflamación/sangre , Fallo Renal Crónico/genética , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Prospectivos , Proteómica , Receptores del Factor de Necrosis Tumoral/sangre , Receptores del Factor de Necrosis Tumoral/genética , Factores de RiesgoRESUMEN
The purpose of this study was to clarify the degree of early postnatal growth by birthweight and detect early predictive factors for pediatric obesity. Body mass index (BMI) and degree of obesity were examined in children in the fourth year of elementary school and second year of junior high school. Their BMI at birth and three years of age were also examined. Based on birthweight, participants were divided into three groups: low (< 2500 g), middle (2500-3500 g), and high (> 3500 g). Furthermore, according to the degree of obesity, they were divided into two groups: obese (20% ≤) and non-obese (20% >). The change of BMI from birth to three years of age (ΔBMI) showed a strong inverse relationship with birthweight and was significantly different among the three birthweight groups (low > middle > high). The ΔBMI and BMI at three years of age were higher in obese than in non-obese children and showed significant positive correlations with the degree of obesity. Early postnatal growth might be determined by birthweight and was higher in obese than in non-obese children. The ΔBMI from birth to three years of age and BMI at age of three years could be predictive factors for pediatric obesity.
RESUMEN
We investigated plasma microRNA (miRNA) profiles associated with variation of hyperglycemia, measured as hemoglobin A1c (HbA1c), in two panels of patients with type 1 diabetes (T1D). Using the HTG Molecular Diagnostics EdgeSeq platform, 2,083 miRNAs were measured in plasma from 71 patients included in a screening panel. Quantitative real-time PCR was used to measure the candidate miRNAs in plasma from 95 patients included in an independent replication panel. We found 10 miRNAs replicated in both panels and 4 with high statistical significance. The strongest positive correlations with HbA1c were found with miR-125b-5p (rs = 0.40, P = 6.0 × 10-5) and miR-365a-3p (rs = 0.35, P = 5.9 × 10-4). The strongest negative correlations were found with miR-5190 (rs = -0.30, P = 0.003) and miR-770-5p (rs = -0.27, P = 0.008). Pathway analysis revealed that 50 Kyoto Encyclopedia of Genes and Genomes pathways were significantly enriched by genes targeted by these four miRNAs. The axon guidance signaling pathway was enriched (P < 1 × 10-7) by genes targeted by all four miRNAs. In addition, three other pathways (Rap1 signaling, focal adhesion, and neurotrophin signaling) were also significantly enriched but with genes targeted by only by three of the identified miRNAs. In conclusion, our study identified four circulating miRNAs that were influenced by variation in hyperglycemia. Dysregulation of these miRNAs, which are associated with hyperglycemia in patients with T1D, may contribute to the development of diabetes complications. However, there are multitudes of possible mechanisms/pathways through which dysregulation of these miRNAs may impact risk of diabetes complications.
Asunto(s)
MicroARN Circulante/metabolismo , Diabetes Mellitus Tipo 1/metabolismo , Hemoglobina Glucada/metabolismo , Hiperglucemia/metabolismo , Adulto , Glucemia/metabolismo , Femenino , Adhesiones Focales/metabolismo , Humanos , Masculino , Redes y Vías Metabólicas , MicroARNs/metabolismo , Persona de Mediana Edad , Factores de Crecimiento Nervioso/metabolismo , Reacción en Cadena en Tiempo Real de la Polimerasa , Complejo Shelterina , Transducción de Señal , Proteínas de Unión a Telómeros/metabolismoRESUMEN
BACKGROUND: Urinary myo-inositol (UMI) level is elevated in adult diabetic patients, and also increases after glucose loading. However, the relationship between UMI and plasma glucose levels in children is unknown. We aimed to assess whether UMI is a practical marker for glucose intolerance in children or not. METHODS: In Study 1 (328 schoolchildren), fasting and postprandial UMI were measured, with ΔUMI defined as the difference between fasting and postprandial UMI levels. In Study 2, oral glucose tolerance tests and UMI measurements were conducted in 18 children with suspected having diabetes. RESULTS: For Study 1, ΔUMI was observed [-0.65 (-3.9, 1.35) mg/g creatinine]. For Study 2, children with diabetes or impaired glucose tolerance had a significantly higher ΔUMI than children with normal glucose tolerance. CONCLUSIONS: These studies demonstrated the normal range of UMI in children and possibility of a novel biomarker for early detection of glucose intolerance in children.
Asunto(s)
Prueba de Tolerancia a la Glucosa , Inositol/orina , Niño , Femenino , Humanos , Japón , MasculinoRESUMEN
BACKGROUND: In Japan, waist circumference (WC) percentiles to screen for childhood metabolic syndrome (MetS) are unavailable. The objectives of this study were to develop WC and WC-to-height ratio (WC/Ht) percentile curves by age and sex for Japanese children, and to test their utility in screening for MetS in children with obesity who are otherwise healthy. METHODS: The WC and WC/Ht percentiles were developed using the LMS method of summarizing growth standards, which monitors changing skewness (L), medians (M), and coefficients of variation (S) in childhood distributions. A representative dataset was used, which consisted of 3,634 boys and 3,536 girls aged 4.5-12.75 years in Shizuoka prefecture, Japan, between 2010 and 2012. Children who were obese (355 boys and 230 girls) aged 6-12 years from Osaka prefecture, Japan, were screened for childhood MetS using the new percentiles and the International Diabetes Federation's (IDF's) definition of MetS. RESULTS: The number of participants with certain metabolic abnormalities (high systolic and diastolic blood pressure, and a high level of triglycerides) was significantly higher in boys aged 10-12 years, with a WC ≥ 90th percentile, than among those with a WC < 90th percentile. None of the participants with a WC < 90th percentile exhibited two or more metabolic abnormalities, regardless of their age or sex. Among the participants aged 10-12 years, 11.4 % of boys and 4.4 % of girls with a WC ≥ 90th percentile were diagnosed with MetS. CONCLUSIONS: The new percentiles may have a certain level of potential to screen Japanese children for childhood MetS in accordance with the IDF definition.
Asunto(s)
Tamizaje Masivo/métodos , Síndrome Metabólico/diagnóstico , Síndrome Metabólico/epidemiología , Obesidad Infantil/epidemiología , Circunferencia de la Cintura , Factores de Edad , Presión Sanguínea , Niño , Estudios Transversales , Femenino , Humanos , Japón , Masculino , Factores Sexuales , Triglicéridos/sangre , Relación Cintura-EstaturaRESUMEN
We investigated whether circulating TGF-ß1-regulated miRNAs detectable in plasma are associated with the risk of rapid progression to end-stage renal disease (ESRD) in a cohort of proteinuric patients with type 1 diabetes (T1D) and normal eGFR. Plasma specimens obtained at entry to the study were examined in two prospective subgroups that were followed for 7-20 years (rapid progressors and nonprogressors), as well as a reference panel of normoalbuminuric T1D patients. Of the five miRNAs examined in this study, let-7c-5p and miR-29a-3p were significantly associated with protection against rapid progression and let-7b-5p and miR-21-5p were significantly associated with the increased risk of ESRD. In logistic analysis, controlling for HbA1c and other covariates, let-7c-5p and miR-29a-3p were associated with more than a 50% reduction in the risk of rapid progression (P ≤ 0.001), while let-7b-5p and miR-21-5p were associated with a >2.5-fold increase in the risk of ESRD (P ≤ 0.005). This study is the first prospective study to demonstrate that circulating TGF-ß1-regulated miRNAs are deregulated early in T1D patients who are at risk for rapid progression to ESRD.
Asunto(s)
Diabetes Mellitus Tipo 1/metabolismo , Nefropatías Diabéticas/genética , MicroARNs/metabolismo , Proteinuria/genética , Factor de Crecimiento Transformador beta1/metabolismo , Adulto , Estudios de Casos y Controles , Diabetes Mellitus Tipo 1/complicaciones , Nefropatías Diabéticas/etiología , Nefropatías Diabéticas/metabolismo , Progresión de la Enfermedad , Femenino , Humanos , Fallo Renal Crónico , Modelos Logísticos , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Prospectivos , Proteinuria/etiología , Proteinuria/metabolismoRESUMEN
BACKGROUND: The prevalence of childhood obesity has increased worldwide over the past decade. Despite evidence that human milk lowers the risk of childhood obesity, the mechanism is not fully understood. AIMS: We investigated the direct effect of human milk on differentiation of 3T3-L1 preadipocytes. STUDY DESIGN AND SUBJECTS: 3T3-L1 preadipocytes were treated with donated human milk only or the combination of the standard hormone mixture; insulin, dexamethasone (DEX), and 3-isobututyl-1-methylxanthine (IBMX). Furthermore, the induction of preadipocyte differentiation by extracted lipids from human milk was tested in comparison to the cells treated with lipid extracts from infant formula. Adipocyte differentiation, specific genes as well as formation of lipid droplets were examined. RESULTS: We clearly show that lipids present in human milk initiate 3T3-L1 preadipocyte differentiation. In contrast, this effect was not observed in response to lipids present in infant formula. The initiation of preadipocyte differentiation by human milk was enhanced by adding the adipogenic hormone, DEX or insulin. The expression of late adipocyte markers in Day 7 adipocytes that have been induced into differentiation with human milk lipid extracts was comparable to those in control cells initiated by a standard adipogenic hormone cocktail. CONCLUSIONS: These results demonstrate that human milk contains bioactive lipids that can initiate preadipocyte differentiation in the absence of the standard adipogenic compounds via a unique pathway.