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1.
Endocr Connect ; 10(10): 1299-1306, 2021 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-34524970

RESUMO

Objective: To investigate the relationship between serum uric acid (SUA) level and renal outcome in patients with type 2 diabetes mellitus (T2DM) and diabetic nephropathy (DN). Methods: A total of 393 Chinese patients with T2DM and biopsy-proven DN and followed at least 1 year were enrolled in this study. Patients were stratified by the quartiles of baseline level of SUA: Q1 group: 286.02 ± 46.66 µmol/L (n = 98); Q2 group: 358.23 ± 14.03 µmol/L (n = 99); Q3 group: 405.50 ± 14.59 µmol/L (n = 98) and Q4 group: 499.14 ± 56.97µmol/L (n = 98). Renal outcome was defined by progression to end-stage renal disease (ESRD). Kaplan-Meier survival analysis and Cox proportional hazards model were used to analyze the association between SUA quartiles and the renal outcomes. Results: During the median 3-year follow-up period, there were 173 ESRD outcome events (44.02%). No significant difference between SUA level and the risk of progression of DN (P = 0.747) was shown in the Kaplan-Meier survival analysis. In multivariable-adjusted model, hazard ratios for developing ESRD were 1.364 (0.621-2.992; P = 0.439), 1.518 (0.768-3.002; P = 0.230) and 1.411 (0.706-2.821; P = 0.330) for the Q2, Q3 and Q4, respectively, in comparison with the Q1 (P = 0.652). Conclusions: No significant association between SUA level and renal outcome of ESRD in Chinese patients with T2DM and DN was found in our study. Besides, the role of uric acid-lowering therapy in delaying DN progression and improving ESRD outcome had not yet been proven. Further study was needed to clarify the renal benefit of the uric acid-lowering therapy in the treatment of DN.

4.
Nat Rev Nephrol ; 17(11): 708-709, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34385677
5.
Front Endocrinol (Lausanne) ; 12: 670674, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34393995

RESUMO

Background: To investigate the association between sex differences and end-stage kidney disease (ESKD) in patients with biopsy-confirmed diabetic kidney disease (DKD). Method: We performed a retrospective cohort study. A total of 336 patients with biopsy-confirmed DKD who were followed up for at least 12 months were enrolled. Baseline clinical and pathological data at the time of biopsy were collected. ESKD was defined by an estimated glomerular filtration rate of <15 ml/min/1.73 m2 or initiation of renal replacement therapy. The association between sex differences and ESKD was assessed using the log-rank test and Cox regression. Result: There were 239 (71%) male and 97 (29%) female patients in our cohort. Female patients had higher systolic blood pressure, total cholesterol and low-density lipoprotein cholesterol levels compared with male. There were a lower proportion of female patients in the very high risk grade according to the chronic kidney disease categories (37% of female vs. 44% of male). During a median follow-up time of 20 months, 101 (57.7%) male and 43 (44.3%) female entered into ESKD, with no significant difference by the log-rank test (P >0.05). Univariate [male: hazard ratio (HR) [95% confidence interval (CI)], 1.005, (0.702-1.439)] and multivariable ([male: HR (95%CI), 1.164, (0.675-2.007)]. Cox regression further showed that sex difference was not significantly associated with ESKD. Conclusion: Female patients had the higher systolic blood pressure, total cholesterol, LDL-C, compared with male patients. However, there was no significant association observed between sex difference and ESKD in our study.

6.
Nat Rev Nephrol ; 17(11): 725-739, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34282342

RESUMO

Obesity, diabetes mellitus, hypertension and cardiovascular disease are risk factors for chronic kidney disease (CKD) and kidney failure. Chronic, low-grade inflammation is recognized as a major pathogenic mechanism that underlies the association between CKD and obesity, impaired glucose tolerance, insulin resistance and diabetes, through interaction between resident and/or circulating immune cells with parenchymal cells. Thus, considerable interest exists in approaches that target inflammation as a strategy to manage CKD. The initial phase of the inflammatory response to injury or metabolic dysfunction reflects the release of pro-inflammatory mediators including peptides, lipids and cytokines, and the recruitment of leukocytes. In self-limiting inflammation, the evolving inflammatory response is coupled to distinct processes that promote the resolution of inflammation and restore homeostasis. The discovery of endogenously generated lipid mediators - specialized pro-resolving lipid mediators and branched fatty acid esters of hydroxy fatty acids - which promote the resolution of inflammation and attenuate the microvascular and macrovascular complications of obesity and diabetes mellitus highlights novel opportunities for potential therapeutic intervention through the targeting of pro-resolution, rather than anti-inflammatory pathways.

7.
J Med Chem ; 64(13): 9193-9216, 2021 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-34138563

RESUMO

Failure to resolve inflammation underlies many prevalent pathologies. Recent insights have identified lipid mediators, typified by lipoxins (LXs), as drivers of inflammation resolution, suggesting potential therapeutic benefit. We report the asymmetric preparation of novel quinoxaline-containing synthetic-LXA4-mimetics (QNX-sLXms). Eight novel compounds were screened for their impact on inflammatory responses. Structure-activity relationship (SAR) studies showed that (R)-6 (also referred to as AT-02-CT) was the most efficacious and potent anti-inflammatory compound of those tested. (R)-6 significantly attenuated lipopolysaccharide (LPS)- and tumor-necrosis-factor-α (TNF-α)-induced NF-κB activity in monocytes and vascular smooth muscle cells. The molecular target of (R)-6 was investigated. (R)-6 activated the endogenous LX receptor formyl peptide receptor 2 (ALX/FPR2). The anti-inflammatory properties of (R)-6 were further investigated in vivo in murine models of acute inflammation. Consistent with in vitro observations, (R)-6 attenuated inflammatory responses. These results support the therapeutic potential of the lead QNX-sLXm (R)-6 in the context of novel inflammatory regulators.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Quinoxalinas/farmacologia , Receptores de Formil Peptídeo/metabolismo , Receptores de Lipoxinas/metabolismo , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Humanos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Camundongos , Estrutura Molecular , Monócitos/efeitos dos fármacos , NF-kappa B/antagonistas & inibidores , NF-kappa B/metabolismo , Quinoxalinas/síntese química , Quinoxalinas/química , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/metabolismo
8.
Eur Cardiol ; 16: e14, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33976709

RESUMO

The Asian Pacific Society of Cardiology convened a consensus statement panel for optimising cardiovascular (CV) outcomes in type 2 diabetes, and reviewed the current literature. Relevant articles were appraised using the Grading of Recommendations, Assessment, Development and Evaluation system, and consensus statements were developed in two meetings and were confirmed through online voting. The consensus statements indicated that lifestyle interventions must be emphasised for patients with prediabetes, and optimal glucose control should be encouraged when possible. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are recommended for patients with chronic kidney disease with adequate renal function, and for patients with heart failure with reduced ejection fraction. In addition to SGLT2i, glucagon-like peptide-1 receptor agonists are recommended for patients at high risk of CV events. A blood pressure target below 140/90 mmHg is generally recommended for patients with type 2 diabetes. Antiplatelet therapy is recommended for secondary prevention in patients with atherosclerotic CV disease.

9.
Ann Transl Med ; 9(7): 564, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33987262

RESUMO

Background: To investigate the association between marriage and the prevalence of overweight and obesity in China. Methods: We conducted cross-sectional and retrospective cohort analyses using a nationwide sample of 36,310 individuals from the China Health and Nutrition Survey [2004-2015]. Results: The prevalence of overweight and obesity increased from 28.7% to 36.7% and from 8.0% to 14.5% between 2004 and 2015, respectively. The cross-sectional analysis showed that married individuals were at a higher risk of being overweight (OR =2.18; 95% CI, 1.90-2.51) or obese (OR =1.95; 1.57-2.43) than never-married individuals. Divorced/widowed individuals were also at a greater risk of being overweight (OR =1.80; 1.51-2.13) or obese (OR =1.67; 1.28-2.17) than never-married individuals. Retrospective cohort analysis showed that individuals who married during the study were 1.55 (1.13-2.11) times more likely to be overweight than those who remained never-married. Compared to those who remained never-married, individuals who remained married were 1.71 (1.42-2.07) and 1.45 (1.11-1.89) times more likely to be overweight and obese. Individuals who became divorced or widowed were more likely to be overweight (RR =1.59; 1.18-2.15) or obese (RR =1.63; 1.08-2.46) than those who remained never-married. However, the risk of being overweight or obese among those who became divorced or widowed did not differ significantly from the risk among those who remained married. Conclusions: Marriage contributes to an increased risk of overweight and obesity in China; however, this risk is not significantly reduced by exiting a marriage.

10.
Nutrients ; 13(5)2021 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-33922959

RESUMO

Diabetic kidney disease (DKD) remains the number one cause of end-stage renal disease in the western world. In experimental diabetes, mitochondrial dysfunction in the kidney precedes the development of DKD. Reactive 1,2-dicarbonyl compounds, such as methylglyoxal, are generated from sugars both endogenously during diabetes and exogenously during food processing. Methylglyoxal is thought to impair the mitochondrial function and may contribute to the pathogenesis of DKD. Here, we sought to target methylglyoxal within the mitochondria using MitoGamide, a mitochondria-targeted dicarbonyl scavenger, in an experimental model of diabetes. Male 6-week-old heterozygous Akita mice (C57BL/6-Ins2-Akita/J) or wildtype littermates were randomized to receive MitoGamide (10 mg/kg/day) or a vehicle by oral gavage for 16 weeks. MitoGamide did not alter the blood glucose control or body composition. Akita mice exhibited hallmarks of DKD including albuminuria, hyperfiltration, glomerulosclerosis, and renal fibrosis, however, after 16 weeks of treatment, MitoGamide did not substantially improve the renal phenotype. Complex-I-linked mitochondrial respiration was increased in the kidney of Akita mice which was unaffected by MitoGamide. Exploratory studies using transcriptomics identified that MitoGamide induced changes to olfactory signaling, immune system, respiratory electron transport, and post-translational protein modification pathways. These findings indicate that targeting methylglyoxal within the mitochondria using MitoGamide is not a valid therapeutic approach for DKD and that other mitochondrial targets or processes upstream should be the focus of therapy.


Assuntos
Benzamidas/uso terapêutico , Complicações do Diabetes/prevenção & controle , Diabetes Mellitus Experimental/complicações , Nefropatias/prevenção & controle , Mitocôndrias/efeitos dos fármacos , Aldeído Pirúvico/metabolismo , Animais , Modelos Animais de Doenças , Masculino , Camundongos , Camundongos Endogâmicos C57BL
11.
Sci Adv ; 7(14)2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33789895

RESUMO

Intake of processed foods has increased markedly over the past decades, coinciding with increased microvascular diseases such as chronic kidney disease (CKD) and diabetes. Here, we show in rodent models that long-term consumption of a processed diet drives intestinal barrier permeability and an increased risk of CKD. Inhibition of the advanced glycation pathway, which generates Maillard reaction products within foods upon thermal processing, reversed kidney injury. Consequently, a processed diet leads to innate immune complement activation and local kidney inflammation and injury via the potent proinflammatory effector molecule complement 5a (C5a). In a mouse model of diabetes, a high resistant starch fiber diet maintained gut barrier integrity and decreased severity of kidney injury via suppression of complement. These results demonstrate mechanisms by which processed foods cause inflammation that leads to chronic disease.

12.
Ren Fail ; 43(1): 477-487, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33685340

RESUMO

AIMS: Chronic kidney disease (CKD) and diabetes mellitus increase atherosclerotic cardiovascular diseases (ASCVD) risk. However, the association between renal outcome of diabetic kidney disease (DKD) and ASCVD risk is unclear. METHODS: This retrospective study enrolled 218 type 2 diabetic patients with biopsy-proven DKD, and without known cardiovascular diseases. Baseline characteristics were obtained and the 10-year ASCVD risk score was calculated using the Pooled Cohort Equation (PCE). Renal outcome was defined as progression to end-stage renal disease (ESRD). The association between ASCVD risk and renal function and outcome was analyzed with logistic regression and Cox analysis. RESULTS: Among all patients, the median 10-year ASCVD risk score was 14.1%. The median of ASCVD risk score in CKD stage 1, 2, 3, and 4 was 10.9%, 12.3%, 16.5%, and 14.8%, respectively (p = 0.268). Compared with patients with lower ASCVD risk (<14.1%), those with higher ASCVD risk had lower eGFR, higher systolic blood pressure, and more severe renal interstitial inflammation. High ASCVD risk (>14.1%) was an independent indicator of renal dysfunction in multivariable-adjusted logistic analysis (OR, 3.997; 95%CI, 1.385-11.530; p = 0.010), though failed to be an independent risk factor for ESRD in patients with DKD in univariate and multivariate Cox analysis. CONCLUSIONS: DKD patients even in CKD stage 1 had comparable ASCVD risk score to patients in CKD stage 2, 3, and 4. Higher ASCVD risk indicated severe renal insufficiency, while no prognostic value of ASVCD risk for renal outcome was observed, which implied macroangiopathy and microangiopathy in patients with DKD were related, but relatively independent.


Assuntos
Doenças Cardiovasculares/epidemiologia , Diabetes Mellitus Tipo 2/complicações , Nefropatias Diabéticas/complicações , Falência Renal Crônica/epidemiologia , Aterosclerose/epidemiologia , Aterosclerose/etiologia , Doenças Cardiovasculares/etiologia , China/epidemiologia , Nefropatias Diabéticas/patologia , Progressão da Doença , Feminino , Taxa de Filtração Glomerular , Humanos , Falência Renal Crônica/etiologia , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Índice de Gravidade de Doença
13.
Aging (Albany NY) ; 13(6): 8146-8154, 2021 03 03.
Artigo em Inglês | MEDLINE | ID: mdl-33686955

RESUMO

Several studies show that patients with early-onset diabetes have higher risk of diabetic complications than those diagnosed in middle age. However, whether early-onset of type 2 diabetes mellitus (T2DM) is a risk factor for diabetic nephropathy (DN) progression remains unclear, especially a lack of data in biopsy-confirmed cohort. In This study, we enrolled 257 patients with T2DM and biopsy-confirmed DN to investigate the role of early-onset T2DM in DN progression. Participants were divided into two groups according to the age of T2DM diagnosis: early-onset group (less than 40 years) and later-onset group (40 years or older). We found that patients with early-onset T2DM had higher glomerular grades and arteriolar hyalinosis scores than those in later-onset group. After adjusted for confounding factors, early-onset of T2DM remained an independent predictor of end-stage renal disease (ESRD) for patients with DN. In conclusion, although with the comparable renal function and proteinuria, patients with early-onset T2DM and DN had worse renal pathological changes than those with later-onset. Early-onset of T2DM might be an important predictor of ESRD for patients with DN, which called more attention to early supervision and prevention for patients with early-onset T2DM and DN.


Assuntos
Diabetes Mellitus Tipo 2/complicações , Nefropatias Diabéticas/patologia , Adulto , Idade de Início , Biópsia , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco
14.
Clin Kidney J ; 14(1): 226-236, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33564423

RESUMO

Background: Nephrotic-range proteinuria (NRP) is associated with rapid kidney function loss and increased cardiovascular (CV) disease risk. We assessed the effects of linagliptin (LINA) on CV and kidney outcomes in people with Type 2 diabetes (T2D) with or without NRP. Methods: Cardiovascular and renal microvascular outcome study with LINA randomized participants with T2D and CV disease and/or kidney disease to LINA 5 mg or placebo (PBO). The primary endpoint [time to first occurrence of 3-point major adverse cardiac events (3P-MACE)], and kidney outcomes, were evaluated by NRP status [urinary albumin:creatinine ratio (UACR) ≥2200 mg/g] at baseline (BL) in participants treated with one or more dose of study medication. Results: NRP was present in 646/6979 [9.3% (LINA/PBO n = 317/n = 329); median UACR 3486 (Q1: 2746/Q3: 4941) mg/g] participants, who compared with no-NRP were younger (62.3/66.1 years) and had lower estimated glomerular filtration rate (eGFR) (39.9/56.1 mL/min/1.73 m2). Over a median of 2.2 years, 3P-MACE occurred with a 2.0-fold higher rate in NRP versus no-NRP (PBO group), with a neutral LINA effect, regardless of NRP. The composite of time to renal death, end-stage kidney disease (ESKD) or decrease of ≥40 or ≥50% in eGFR, occurred with 12.3- and 13.6-fold higher rate with NRP (PBO group); evidence of heterogeneity of effects with LINA was observed for the former [NRP yes/no: hazard ratio 0.80 (0.63-1.01)/1.25 (1.02-1.54); P-interaction 0.005], but not the latter [0.83 (0.64-1.09)/1.17 (0.91-1.51), P-interaction 0.07]. No heterogeneity was observed for renal death or ESKD [0.88 (0.64-1.21)/0.94 (0.67-1.31), P-interaction 0.79]. Glycated haemoglobin A1c (HbA1c) was significantly reduced regardless of NRP, without increasing hypoglycaemia risk. Regression to normoalbuminuria [1.20 (1.07-1.34)] and reduction of UACR ≥50% [1.15 (1.07-1.25)] from BL, occurred more frequently with LINA, regardless of NRP status (P-interactions >0.05). Conclusions: Individuals with T2D and NRP have a high disease burden. LINA reduces their albuminuria burden and HbA1c, without affecting CV or kidney risk.

15.
Sci Rep ; 11(1): 4658, 2021 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-33633132

RESUMO

Few histological prognostic indicators for end-stage renal disease (ESRD) have been validated in diabetic patients. This biopsy-based study aimed to identify nephropathological risk factors for ESRD in Chinese patients with type 2 diabetes. Histological features of 322 Chinese type 2 diabetic patients with biopsy-confirmed diabetic nephropathy (DN) were retrospectively analysed. Cox proportional hazards analysis was used to estimate the hazard ratio (HR) for ESRD. Single glomerular proteomics and immunohistochemistry were used to identify differentially expressed proteins and enriched pathways in glomeruli. During the median follow-up period of 24 months, 144 (45%) patients progressed to ESRD. In multivariable models, the Renal Pathology Society classification failed to predict ESRD, although the solidified glomerulosclerosis (score 1: HR 1.65, 95% confidence interval [CI] 1.04-2.60; score 2: HR 2.48, 95% CI 1.40-4.37) and extracapillary hypercellularity (HR 2.68, 95% CI 1.55-4.62) were identified as independent risk factors. Additionally, single glomerular proteomics, combined with immunohistochemistry, revealed that complement C9 and apolipoprotein E were highly expressed in solidified glomerulosclerosis. Therefore, solidified glomerulosclerosis and extracapillary hypercellularity predict diabetic ESRD in Chinese patients. Single glomerular proteomics identified solidified glomerulosclerosis as a unique pathological change that may be associated with complement overactivation and abnormal lipid metabolism.

16.
NPJ Regen Med ; 6(1): 7, 2021 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-33580013

RESUMO

The role of DNA methylation in ß-cell neogenesis is poorly understood. We report that during the process of induced cell reprogramming, methylation content of the Ngn3 and Sox11 genes are diminished. These findings emphasise DNA methylation is a barrier in ß-cell regeneration in adulthood, a well described pathophysiological phenomenon of major significance in explaining ß-cell deficiency in diabetes in the adult pancreas.

17.
Kidney Int Rep ; 6(2): 284-295, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33615053

RESUMO

Introduction: Several circulating markers, including autoantibodies to erythropoietin receptor (anti-EPOR antibodies), have been identified as useful biomarkers in predicting diabetic kidney disease progression. However, a direct comparison of their utility is lacking. We aimed to validate and to compare the prognostic value of anti-EPOR antibodies with that of other known biomarkers, using the ADVANCE trial and its long-term follow-up, ADVANCE-ON, cohorts. Methods: In this nested case-control study from the ADVANCE trial cohort, we included 165 case participants who had the composite kidney outcome (renal replacement therapy, renal death, or doubling of serum creatinine to ≥200 µmol/l) and 330 matched controls. We compared the associations of baseline plasma levels of anti-EPOR antibodies, tumor necrosis factor receptor (TNFR)-1 and -2, and bone morphogenetic protein (BMP)-7 with kidney outcomes. Results: Cases had higher baseline plasma levels of anti-EPOR antibodies than controls (median 1.7 vs. 0.6 enzyme-linked immunosorbent assay unit, P < 0.001). Higher levels of anti-EPOR antibodies were associated with an increased risk of kidney outcome (odds ratio 2.16 [95% confidence interval 1.51, 3.08], per 1 SD of log-transformed levels) after adjusting for conventional markers. Elevated circulating TNFR1 and TNFR2 levels, and lower BMP-7 levels at baseline, were associated with poor kidney outcome (odds ratios 2.06 [1.29, 3.30], 1.66 [1.13, 2.43], and 0.45 [0.32, 0.65], respectively). The addition of anti-EPOR antibodies into the model improved the prediction of kidney outcome, regardless of other biomarkers. Conclusion: Anti-EPOR antibodies provide a promising biomarker, as with TNFR1, TNFR2, and BMP-7, in predicting kidney disease progression in people with type 2 diabetes mellitus.

18.
Int Urol Nephrol ; 53(6): 1161-1170, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33389518

RESUMO

PURPOSE: The older population has increased sharply in China. However, renal clinical and histopathological data in this population are lacking. This study investigated the clinicopathologic features and the related risk factors for long-term renal survival in older patients with diabetic nephropathy (DN). METHODS: In this retrospective observational study, 74 older patients (≥ 60 years old) with type 2 diabetes mellitus and biopsy-proven DN from 2007 to 2019 were included. Clinical data were extracted from electronic records. Renal biopsy specimens were semiquantitatively evaluated using the Renal Pathology Society (RPS) classification system. Cox proportional hazard analysis was used to estimate hazard ratios (HRs) for progression to end-stage renal disease (ESRD). RESULTS: During the median follow-up period of 22 months, 24 (32%) older patients progressed to ESRD. Older patients who progressed to ESRD had poorer renal function, lower hemoglobin and albumin concentrations, more severe glomerular lesions, and higher percentages of Kimmelstiel-Wilson lesions than those who did not progress to ESRD. After adjusting for age, sex, baseline renal function, and pathological parameters, multivariate Cox proportional hazard analysis showed that RPS glomerular classification (HR 2.49, 95% confidence interval [CI] 1.03-6.04), estimated glomerular filtration rate (eGFR) (HR 0.76, 95% CI 0.58-0.99), and proteinuria (HR 3.85, 95% CI 1.44-10.27) were independent risk factors for progression to ESRD. CONCLUSION: Lower eGFR, heavier proteinuria, and more severe RPS glomerular lesions were associated with ESRD in older patients with type 2 diabetes mellitus and DN.


Assuntos
Nefropatias Diabéticas/diagnóstico , Fatores Etários , Idoso , Biópsia , Diabetes Mellitus Tipo 2/complicações , Nefropatias Diabéticas/etiologia , Progressão da Doença , Feminino , Humanos , Falência Renal Crônica/etiologia , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos
19.
Arterioscler Thromb Vasc Biol ; 41(3): 1167-1178, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33441028

RESUMO

OBJECTIVE: People with diabetes are at a significantly higher risk of cardiovascular disease, in part, due to accelerated atherosclerosis. Diabetic subjects have increased number of platelets that are activated, more reactive, and respond suboptimally to antiplatelet therapies. We hypothesized that reducing platelet numbers by inducing their premature apoptotic death would decrease atherosclerosis. Approach and Results: This was achieved by targeting the antiapoptotic protein Bcl-xL (B-cell lymphoma-extra large; which is essential for platelet viability) via distinct genetic and pharmacological approaches. In the former, we transplanted bone marrow from mice carrying the Tyr15 to Cys loss of function allele of Bcl-x (known as Bcl-xPlt20) or wild-type littermate controls into atherosclerotic-prone Ldlr+/- mice made diabetic with streptozotocin and fed a Western diet. Reduced Bcl-xL function in hematopoietic cells significantly decreased platelet numbers, exclusive of other hematologic changes. This led to a significant reduction in atherosclerotic lesion formation in Bcl-xPlt20 bone marrow transplanted Ldlr+/- mice. To assess the potential therapeutic relevance of reducing platelets in atherosclerosis, we next targeted Bcl-xL with a pharmacological strategy. This was achieved by low-dose administration of the BH3 (B-cell lymphoma-2 homology domain 3) mimetic, ABT-737 triweekly, in diabetic Apoe-/- mice for the final 6 weeks of a 12-week study. ABT-737 normalized platelet numbers along with platelet and leukocyte activation to that of nondiabetic controls, significantly reducing atherosclerosis while promoting a more stable plaque phenotype. CONCLUSIONS: These studies suggest that selectively reducing circulating platelets, by targeting Bcl-xL to promote platelet apoptosis, can reduce atherosclerosis and lower cardiovascular disease risk in diabetes. Graphic Abstract: A graphic abstract is available for this article.


Assuntos
Aterosclerose/sangue , Aterosclerose/complicações , Plaquetas/patologia , Angiopatias Diabéticas/sangue , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Aterosclerose/prevenção & controle , Compostos de Bifenilo/administração & dosagem , Plaquetas/efeitos dos fármacos , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/complicações , Feminino , Humanos , Leucócitos/patologia , Leucócitos/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Nitrofenóis/administração & dosagem , Piperazinas/administração & dosagem , Contagem de Plaquetas , Receptores de LDL/deficiência , Receptores de LDL/genética , Fatores de Risco , Sulfonamidas/administração & dosagem
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