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1.
Medicine (Baltimore) ; 99(38): e22278, 2020 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-32957381

RESUMO

BACKGROUND: Diabetic nephropathy (DN) is a multifactorial disease with gene-environment interaction resulting in progressive renal function damage. Multiple studies have assessed the association between matrix metalloproteinase-9 (MMP-9) gene promoter polymorphism and DN susceptibility. However, the results are inconclusive. In the present study, we will conduct a meta-analysis to further examine this relationship more precisely. METHODS: Electronic databases (Pubmed, Web of Science, Embase, Google Scholar, Wanfang, China Biological Medicine and China National Knowledge Infrastructure) will be used to search clinical case-control studies about MMP-9 polymorphism and DN published until 18 August 2020. The language will be restricted to Chinese and English. Two reviewers will take charge of completing the selection of study, the extraction of data as well as the assessment of study quality independently. The Newcastle-Ottawa Scale will be used to evaluate the study quality. We will evaluate the association under 5 genetic models. Fixed-effects or random-effects models will be used to calculate the effect sizes of odds ratio and 95% confidence intervals. Afterwards, subgroup analysis will be conducted in terms of the ethnicity and genotyping method. Additionally, sensitivity analysis will be performed via sequentially omitting each of the included studies one at a time. The funnel plots, Egger regression test, and Begg rank correlation test will be used to test the potential publication bias. All the statistical analyses will be performed using Review Manager 5.3 and Stata 12.0. RESULTS: This protocol reported according to the Preferred Reporting ltems for Systematic Reviews and Meta-Analyses Protocols (PRISMA-P) statement. This study will provide a better understanding of the association between MMP-9 polymorphisms and DN risk. CONCLUSION: Publishing this protocol will minimize the potential bias related to data mining, thus contributing to generation of reliable evidence. OSF REGISTRATION NUMBER: DOI 10.17605/OSF.IO/H5FS4.


Assuntos
Nefropatias Diabéticas/genética , Metaloproteinase 9 da Matriz/genética , Metanálise como Assunto , Polimorfismo Genético , Revisões Sistemáticas como Assunto , Nefropatias Diabéticas/enzimologia , Predisposição Genética para Doença , Humanos , Regiões Promotoras Genéticas/genética , Fatores de Risco
2.
Medicine (Baltimore) ; 99(35): e21558, 2020 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-32871871

RESUMO

BACKGROUND: As indicated by numerous studies, there exists a relationship between the polymorphism of methylenetetrahydrofolate reductase (MTHFR) and susceptibility to diabetic nephropathy (DN) in various populations; nonetheless, the findings remain inconsistent. Therefore, we carried out a meta-analysis to determine the relationship between the MTHFR gene polymorphism and DN susceptibility. MATERIALS AND METHOD: Related studies were identified from PubMed, Cochrane Library, EMBASE, and the China National Knowledge Infrastructure database (time period: from building the library to October 2019). The strength of the association was examined using odds ratios (ORs) with 95% confidence intervals (95% CIs). RESULTS: The findings illustrated that the C677T gene polymorphism was significantly associated with an enhanced susceptibility to DN compared to that with diabetes mellitus in allelic (OR = 1.64, 95% CI = 1.34-2.00, P < .001), dominant (OR = 1.85, 95% CI = 1.40-2.46, P < .001), codominant (heterozygote: OR = 1.67, 95% CI = 1.27-2.21, P < .001; homozygote: OR = 2.55, 95% CI = 1.82-3.57, P < .001), and recessive (OR = 1.89, 95% CI = 1.50-2.38, P < .001) models of the overall population. Moreover, as compared with the healthy controls, a significantly augmented susceptibility to DN was found in all 5 genetic comparison models (allelic: OR = 2.06, 95% CI = 1.58-2.67, P < .001; dominant: OR = 2.52, 95% CI = 1.73-3.69, P < .001; codominant: OR = 3.78, 95% CI = 2.50-5.70, P < .001; recessive: OR = 2.41, 95% CI = 1.96-2.97, P < .001). Furthermore, stratifying data by ethnicity revealed substantially augmented vulnerability to DN in not only Caucasian but also Asian populations. CONCLUSION: The present study suggests that the C677T polymorphism was associated with an augmented susceptibility to DN.


Assuntos
Diabetes Mellitus Tipo 2/complicações , Nefropatias Diabéticas/epidemiologia , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Polimorfismo de Nucleotídeo Único/genética , Alelos , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , China/epidemiologia , Diabetes Mellitus Tipo 2/genética , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/genética , Grupo com Ancestrais do Continente Europeu/genética , Predisposição Genética para Doença , Humanos , Fatores de Risco
3.
Gene ; 763: 145066, 2020 Dec 30.
Artigo em Inglês | MEDLINE | ID: mdl-32827686

RESUMO

Diabetes is characterized by changed homeostasis of blood glucose levels, which is associated with various complications, including cardiomyopathy, atherosclerosis, endothelial dysfunction, nephropathy, retinopathy and neuropathy. In recent years, accumulative evidence has demonstrated that circular RNAs are identified as a novel type of noncoding RNAs (ncRNAs) involving in the regulation of various physiological processes and pathologic conditions. Specifically, the emergence of complications response to diabetes is finely controlled by a complex gene regulatory network in which circular RNAs play a critical role. Recently, circular RNAs are emerging as messengers that could influence cellular functions under diabetic conditions. Dysregulation of circular RNAs has been closely linked to the pathophysiology of diabetes-related complications. In this review, we aimed to summarize the current progression and underlying mechanisms of circular RNA in the development of diabetes-related complications. We will also provide an overview of circular RNA-regulated cell communications in different types of cells that have been linked to diabetic complications. We anticipated that the completion of this review will provide potential clues for developing novel circular RNAs-based biomarkers or therapeutic targets for diabetes and its associated complications.


Assuntos
Angiopatias Diabéticas/metabolismo , Nefropatias Diabéticas/metabolismo , Neuropatias Diabéticas/metabolismo , RNA Circular/metabolismo , Animais , Biomarcadores/metabolismo , Angiopatias Diabéticas/genética , Angiopatias Diabéticas/patologia , Angiopatias Diabéticas/terapia , Nefropatias Diabéticas/genética , Nefropatias Diabéticas/patologia , Nefropatias Diabéticas/terapia , Neuropatias Diabéticas/genética , Neuropatias Diabéticas/patologia , Neuropatias Diabéticas/terapia , Terapia Genética/métodos , Humanos , Ilhotas Pancreáticas/metabolismo , RNA Circular/genética
4.
Gene ; 758: 144952, 2020 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-32683074

RESUMO

Diabetic nephropathy (DN) as one of the most frequent microvascular complications of diabetic patients causes chronic renal failure and end-stage renal disease. Noncoding RNAs including circular RNAs (circRNAs) and micro RNAs (miRNAs) were widely reported to play a critical role in numerous human diseases including DN. This research was designed to investigate the role of circ_0000064 in diabetic nephropathy progression. The results showed that circ_0000064 significantly promoted mesangial cells proliferation and aggravated fibrosis in DN. In the subsequent mechanism investigation, we found that circ_0000064 was involved in this process by targeting micro RNA miR-143. The inhibition of miR-143 significantly reverses the effect of circ_0000064 silencing on DN. In conclusion, we demonstrated the regulatory role of circ_0000064 in DN and clarified that circ_0000064 play a role in DN via targeting miR-143. Circ_0000064 and miR-143 also showed the potential as a biomarker for DN.


Assuntos
Nefropatias Diabéticas/genética , Fibrose/genética , Células Mesangiais/patologia , MicroRNAs/genética , RNA Circular/genética , Animais , Proliferação de Células/genética , Complicações do Diabetes/genética , Complicações do Diabetes/patologia , Diabetes Mellitus/patologia , Fibrose/patologia , Humanos , Camundongos
5.
Vasc Health Risk Manag ; 16: 241-248, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32606720

RESUMO

Aim: Type 2 diabetes (T2D), as a major cause of morbidity and mortality, is predicted to have a prevalence of 629 million by 2045. As diabetic patients show considerable inter-individual variation in response to antidiabetic treatment, this study aimed to investigate the gene polymorphism of cytochrome P450 as well as the effectiveness and safety of glibenclamide and gliclazide for different genotypes of CYP2C9. Besides, the chronic side effects of T2D including retinal microvasculature complications or retinopathy and renal dysfunction due to nephropathy in different genotypes were considered. Patients and Methods: The participants including 80 T2D patients treated with glibenclamide or gliclazide were recruited from university hospitals of Ahvaz Jundishpur University of Medical Sciences, Ahvaz, in the southwest of Iran. Blood samples were collected from the patients at 2.5h after the morning dose of glibenclamide and 12h after the last dose of gliclazide. Genotyping from the extracted DNA was, then, performed using PCR-RFLP. The plasma level of glibenclamide and gliclazide was, in turn, measured by the reverse-phase high-pressure liquid chromatography. Results: The results showed that the wild-type allele, i.e., CYP2C9*1, occurred in the highest frequency (0.8), while the frequency rates of the mutant allele, i.e., CYP2C9*2 and CYP2C9*3, were 0.15 and 0.05, respectively. Moreover, no significant association was found between any of the genotypes as well as the clinical and biochemical characteristics of the patients. The findings also showed that the plasma level of sulfonylureas (i.e., glibenclamide and gliclazide) was the highest in the patients with the CYP2C9*3 allele. It was also found that 75.9% of the patients with variant genotypes had experienced hypoglycemia events. Furthermore, in the absence of wild type allele, a significant increase was observed in retinopathy (p=0.039) and nephropathy (p=0.05). Conclusion: The findings can provide guidelines for the optimal management of the treatment protocols with sulfonylurea intended to control the T2D complications.


Assuntos
Glicemia/efeitos dos fármacos , Citocromo P-450 CYP2C9/genética , Diabetes Mellitus Tipo 2/tratamento farmacológico , Nefropatias Diabéticas/genética , Retinopatia Diabética/genética , Gliclazida/uso terapêutico , Glibureto/uso terapêutico , Hipoglicemiantes/uso terapêutico , Variantes Farmacogenômicos , Biomarcadores/sangue , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/genética , Nefropatias Diabéticas/diagnóstico , Retinopatia Diabética/diagnóstico , Feminino , Frequência do Gene , Gliclazida/efeitos adversos , Gliclazida/sangue , Glibureto/efeitos adversos , Glibureto/sangue , Humanos , Hipoglicemia/induzido quimicamente , Hipoglicemia/genética , Hipoglicemiantes/efeitos adversos , Hipoglicemiantes/sangue , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Resultado do Tratamento
6.
Gene ; 761: 144971, 2020 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-32707301

RESUMO

Diabetic nephropathy (DN) is a serious microvascular complication of diabetes across the world. Recently, many circular RNAs (circRNAs) can exert a crucial role in DN progression. Our investigation was designed to study whether circ_0123996 was associated with DN and aimed to find out the underlying mechanisms. We observed that circ_0123996 expression was significantly increased in Type 2 diabetes (T2D) with DN in comparison to those patients without DN. Consistently, circ_0123996 was also obviously elevated in DN mice models and high glucose (HG)-incubated MMCs. Then, it was proved transfection of circ_0123996 siRNA in mice mesangial cells (MMCs) restrained MMCs proliferation greatly. In addition, it was demonstrated that decrease of circ_0123996 alleviated fibrosis-related protein expression including FN and Col-4 in MMCs. Next, it was confirmed by our study that circ_0123996 can serve as a sponge for miR-149-5p. miR-149-5p has been identified in several diseases including diabetes. At present, we observed that miR-149-5p was decreased in DN. Overexpression of miR-149-5p greatly repressed the effect of circ_0123996 on MMCs. BTB and CNC homology 1 (Bach1) is reported in various disease including some vascular diseases.Here, Bach1 was confirmed as a target of miR-149-5p. Circ_0123996 upregulated Bach1 expression and restrained MMCs proliferation and fibrosis through sponging miR-149-5p. Thus, it was revealed that circ_0123996 was involved in DN via sponging miR-149-5p and modulating Bach1 expression.


Assuntos
Fatores de Transcrição de Zíper de Leucina Básica/biossíntese , Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Nefropatias Diabéticas/metabolismo , MicroRNAs/metabolismo , RNA Circular/metabolismo , Adulto , Animais , Apoptose/fisiologia , Fatores de Transcrição de Zíper de Leucina Básica/genética , Estudos de Casos e Controles , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Nefropatias Diabéticas/genética , Modelos Animais de Doenças , Progressão da Doença , Feminino , Fibrose/genética , Fibrose/metabolismo , Humanos , Masculino , Células Mesangiais/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Pessoa de Meia-Idade , RNA Circular/genética
7.
Nat Rev Nephrol ; 16(7): 377-390, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32398868

RESUMO

Diabetes is one of the fastest growing diseases worldwide, projected to affect 693 million adults by 2045. Devastating macrovascular complications (cardiovascular disease) and microvascular complications (such as diabetic kidney disease, diabetic retinopathy and neuropathy) lead to increased mortality, blindness, kidney failure and an overall decreased quality of life in individuals with diabetes. Clinical risk factors and glycaemic control alone cannot predict the development of vascular complications; numerous genetic studies have demonstrated a clear genetic component to both diabetes and its complications. Early research aimed at identifying genetic determinants of diabetes complications relied on familial linkage analysis suited to strong-effect loci, candidate gene studies prone to false positives, and underpowered genome-wide association studies limited by sample size. The explosion of new genomic datasets, both in terms of biobanks and aggregation of worldwide cohorts, has more than doubled the number of genetic discoveries for both diabetes and diabetes complications. We focus herein on genetic discoveries for diabetes and diabetes complications, empowered primarily through genome-wide association studies, and emphasize the gaps in research for taking genomic discovery to the next level.


Assuntos
Complicações do Diabetes/genética , Diabetes Mellitus Tipo 2/genética , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/genética , Complicações do Diabetes/etiologia , Diabetes Mellitus Tipo 2/complicações , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/genética , Neuropatias Diabéticas/etiologia , Neuropatias Diabéticas/genética , Retinopatia Diabética/etiologia , Retinopatia Diabética/genética , Humanos
8.
Gene ; 747: 144661, 2020 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-32275999

RESUMO

Recently, increasing evidence has reported that circRNAs are non-coding RNAs and they bind with the corresponding miRNAs to modulate the target genes. However, the detailed role of circRNAs in the pathogenesis of DN still remains poorly known. Currently, we aimed to study how circ_0000285 functions in DN development. We found that circ_0000285 was significantly increased in DN mice models and mouse podocytes incubated with HG. Then, circ_0000285 was overexpressed in mouse podocytes and we observed that overexpression of circ_0000285 promoted podocytes injury. Moreover, miR-654-3p was precited as a target of circ_0000285. It was shown that circ_0000285 was strongly pulled down by circ_0000285 specific probe and circ_0000285 specific probe was used to successfully enrich miR-654-3p. In addition, we reported that miR-654-3p was obviously down-regulated in DN. Inhibitors of miR-654-3p greatly reversed the effects of circ_0000285 siRNA on podocytes injury. Moreover, the inflammation release was restrained by loss of circ_0000285, while induced by miR-654-3p inhibitors. IL-6, L-1ß and TNF-α level was remarkably depressed by the knockdown of circ_0000285 and miR-654-3p inhibitors induced that. Furthermore, MAPK6 was confirmed as a direct downstream target of miR-654-3p. As shown, MAPK6 was markedly suppressed by circ_0000285 siRNA, which was rescued by the decrease of miR-654-3p. These findings revealed that circ_0000285 promoted podocyte injury via sponging miR-654-3p and activating MAPK6 in DN.


Assuntos
Nefropatias Diabéticas/genética , Nefropatias Diabéticas/patologia , MicroRNAs/metabolismo , Proteína Quinase 6 Ativada por Mitógeno/metabolismo , Podócitos/patologia , RNA Circular/metabolismo , Animais , Sequência de Bases , Citocinas/metabolismo , Progressão da Doença , Regulação da Expressão Gênica , Mediadores da Inflamação/metabolismo , Masculino , Camundongos , MicroRNAs/genética , Proteína Quinase 6 Ativada por Mitógeno/genética , Podócitos/metabolismo , RNA Circular/genética
9.
Braz J Med Biol Res ; 53(4): e9288, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32294702

RESUMO

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


Assuntos
Proteína Morfogenética Óssea 7/metabolismo , Nefropatias Diabéticas/metabolismo , Transição Epitelial-Mesenquimal/fisiologia , RNA Longo não Codificante/fisiologia , Homeobox 1 de Ligação a E-box em Dedo de Zinco/metabolismo , Células Cultivadas , Nefropatias Diabéticas/genética , Regulação para Baixo , Humanos , MicroRNAs/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Regulação para Cima
10.
Life Sci ; 251: 117640, 2020 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-32259603

RESUMO

AIM: To evaluate the effects of P2X7 receptor blockade on renin-angiotensin system (RAS) in rats with diabetic nephropathy (DN). MAIN METHODS: Wistar rats were unilaterally nephrectomized and received streptozotocin for diabetes mellitus (DM) induction; control animals (CTL) received the drug vehicle. The animals were submitted to P2X7 receptor silencing, forming the group (DM + siRNA). The animals were placed in metabolic cages for data collection and evaluation of renal function; at the end of the protocol, the kidney was removed for analysis of P2X7, renin, angiotensin-converting enzyme (ACE), ACE2, angiotensin, thiobarbituric acid reactive substance levels (TBARS), nitric oxide (NO) and qualitative histological. KEY FINDINGS: The metabolic profile was attenuated in DM + siRNA vs. DM and there was a significant improvement in creatinine, urea and proteinuria levels in the same group. Renin expression was significantly decreased in DM + siRNA vs. DM. ACE and ACE2 were significantly reduced in DM + siRNA vs. DM. TBARS levels were decreased and NO showed an increase in DM + siRNA vs. DM, both significant. All histological alterations were improved in DM + siRNA vs. DM. SIGNIFICANCE: Data have shown that although silencing of the P2X7 receptor did not decrease fasting glucose, it promoted an improvement in the metabolic profile and a significant recovery of renal function, revealing a protective action by the inhibition of this receptor. This effect must have occurred due to the inhibition of RAS and the increase of NO, suggesting that the use of P2X7 receptors inhibitors could be used as adjuvant therapy against DN progression.


Assuntos
Diabetes Mellitus Experimental/terapia , Nefropatias Diabéticas/terapia , Inativação Gênica , Receptores Purinérgicos P2X7/genética , Sistema Renina-Angiotensina/genética , Animais , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/genética , Nefropatias Diabéticas/genética , Nefropatias Diabéticas/fisiopatologia , Masculino , Óxido Nítrico/metabolismo , RNA Interferente Pequeno/administração & dosagem , Ratos , Ratos Wistar , Estreptozocina
11.
Gene ; 741: 144551, 2020 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-32165305

RESUMO

BACKGROUND: Although the pathogenesis of diabetic nephropathy (DN) is multifactorial, and the precise mechanisms are unclear, there is a growing body of evidence suggesting that inflammatory processes and immune cells might be involved in the development and progression of DN. Leukotrienes (LTs) are a family of lipid mediators, which act as pro-inflammatory mediators. The study was designed to investigate the association between the polymorphism of the ALOX5 gene (rs12762303) and the ALOX5AP gene (rs3802278), and DN in patients with T2DM. METHODOLOGY: 651 subjects with diabetes mellitus type 2 (T2DM) were classified into two groups according to the presence of DN, and tested for ALOX5 and ALOX5AP gene polymorphisms using the KASPar genotyping chemistry with validated assay. Biochemical analyses were performed using standard biochemical methods. RESULTS: Logistic regression analysis demonstrated that the carriers of the CC genotype had a 3.14 higher risk for DN compared to TT genotype. Serum cystatin C was found to be statistically significantly higher in cases with DN in comparison with subjects without DN (p < 0.001). CONCLUSION: An association between the rs3803278 of the ALOX5AP gene and DN was found in Slovenian patients with T2DM. The rs3803278 CC allele appears to confer increased risk of DN possibly by increasing the production of LTs-potent drivers of inflammation.


Assuntos
Proteínas Ativadoras de 5-Lipoxigenase/genética , Araquidonato 5-Lipoxigenase/genética , Diabetes Mellitus Tipo 2/genética , Nefropatias Diabéticas/genética , Adulto , Alelos , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/patologia , Nefropatias Diabéticas/complicações , Nefropatias Diabéticas/patologia , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco
12.
Clin Sci (Lond) ; 134(7): 677-694, 2020 04 17.
Artigo em Inglês | MEDLINE | ID: mdl-32167139

RESUMO

Excessive mitochondrial fission has been identified as the central pathogenesis of diabetic kidney disease (DKD), but the precise mechanisms remain unclear. Disulfide-bond A oxidoreductase-like protein (DsbA-L) is highly expressed in mitochondria in tubular cells of the kidney, but its pathophysiological role in DKD is unknown. Our bioinformatics analysis showed that tubular DsbA-L mRNA levels were positively associated with eGFR but negatively associated with Scr and 24h-proteinuria in CKD patients. Furthermore, the genes that were coexpressed with DsbA-L were mainly enriched in mitochondria and were involved in oxidative phosphorylation. In vivo, knockout of DsbA-L exacerbated diabetic mice tubular cell mitochondrial fragmentation, oxidative stress and renal damage. In vitro, we found that DsbA-L was localized in the mitochondria of HK-2 cells. High glucose (HG, 30 mM) treatment decreased DsbA-L expression followed by increased mitochondrial ROS (mtROS) generation and mitochondrial fragmentation. In addition, DsbA-L knockdown exacerbated these abnormalities, but this effect was reversed by overexpression of DsbA-L. Mechanistically, under HG conditions, knockdown DsbA-L expression accentuated JNK phosphorylation in HK-2 cells. Furthermore, administration of a JNK inhibitor (SP600125) or the mtROS scavenger MitoQ significantly attenuated JNK activation and subsequent mitochondrial fragmentation in DsbA-L-knockdown HK-2 cells. Additionally, the down-regulation of DsbA-L also amplified the gene and protein expression of mitochondrial fission factor (MFF) via the JNK pathway, enhancing its ability to recruit DRP1 to mitochondria. Taken together, these results link DsbA-L to alterations in mitochondrial dynamics during tubular injury in the pathogenesis of DKD and unveil a novel mechanism by which DsbA-L modifies mtROS/JNK/MFF-related mitochondrial fission.


Assuntos
Diabetes Mellitus Experimental/enzimologia , Nefropatias Diabéticas/enzimologia , Glutationa Transferase/deficiência , Túbulos Renais/enzimologia , Mitocôndrias/enzimologia , Dinâmica Mitocondrial , Animais , Glicemia/metabolismo , Linhagem Celular , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/patologia , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/genética , Nefropatias Diabéticas/patologia , Glutationa Transferase/genética , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Túbulos Renais/ultraestrutura , Proteínas de Membrana/metabolismo , Camundongos Knockout , Mitocôndrias/ultraestrutura , Proteínas Mitocondriais/metabolismo , Estresse Oxidativo , Fosforilação , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais
13.
Am J Physiol Renal Physiol ; 318(4): F1030-F1040, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32150446

RESUMO

Manipulation of circulating histidine-containing dipeptides (HCD) has been shown to affect the development of diabetes and early-stage diabetic nephropathy (DN). The aim of the present study was to investigate whether such interventions, which potentially alter levels of circulating HCD, also affect the development of advanced-stage DN. Two interventions, aerobic exercise training and overexpression of the human carnosinase-1 (hCN1) enzyme, were tested. BTBR ob/ob mice were either subjected to aerobic exercise training (20 wk) or genetically manipulated to overexpress hCN1, and different diabetes- and DN-related markers were compared with control ob/ob and healthy (wild-type) mice. An acute exercise study was performed to elucidate the effect of obesity, acute running, and hCN1 overexpression on plasma HCD levels. Chronic aerobic exercise training did not affect the development of diabetes or DN, but hCN1 overexpression accelerated hyperlipidemia and aggravated the development of albuminuria, mesangial matrix expansion, and glomerular hypertrophy of ob/ob mice. In line, plasma, kidney, and muscle HCD were markedly lower in ob/ob versus wild-type mice, and plasma and kidney HCD in particular were lower in ob/ob hCN1 versus ob/ob mice but were unaffected by aerobic exercise. In conclusion, advanced glomerular damage is accelerated in mice overexpressing the hCN1 enzyme but not protected by chronic exercise training. Interestingly, we showed, for the first time, that the development of DN is closely linked to renal HCD availability. Further research will have to elucidate whether the stimulation of renal HCD levels can be a therapeutic strategy to reduce the risk for developing DN.


Assuntos
Nefropatias Diabéticas/enzimologia , Dipeptidases/biossíntese , Terapia por Exercício , Glomérulos Renais/enzimologia , Músculo Esquelético/enzimologia , Obesidade/enzimologia , Animais , Nefropatias Diabéticas/genética , Nefropatias Diabéticas/patologia , Dipeptidases/genética , Dipeptídeos/metabolismo , Modelos Animais de Doenças , Indução Enzimática , Histidina/análogos & derivados , Histidina/metabolismo , Humanos , Glomérulos Renais/patologia , Camundongos Transgênicos , Músculo Esquelético/patologia , Obesidade/complicações , Obesidade/genética , Obesidade/patologia , Fatores de Tempo
14.
Am J Physiol Renal Physiol ; 318(5): F1067-F1073, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32200667

RESUMO

Protease-activated receptors (PARs) are coagulation protease targets, and they increase expression of inflammatory cytokines and chemokines in various diseases. Of all PARs, previous reports have shown that PAR1 or PAR2 inhibition is protective against diabetic glomerular injury. However, how PAR1 and PAR2 cooperatively contribute to diabetic kidney disease (DKD) pathogenesis and whether dual blockade of PARs is more effective in DKD remain elusive. To address this issue, male type I diabetic Akita mice heterozygous for endothelial nitric oxide synthase were used as a model of DKD. Mice (4 mo old) were divided into four treatment groups and administered vehicle, PAR1 antagonist (E5555, 60 mg·kg-1·day-1), PAR2 antagonist (FSLLRY, 3 mg·kg-1·day-1), or E5555 + FSLLRY for 4 wk. The results showed that the urinary albumin creatinine ratio was significantly reduced when both PAR1 and PAR2 were blocked with E5555 + FSLLRY compared with the vehicle-treated group. Dual blockade of PAR1 and PAR2 by E5555 + FSLLRY additively ameliorated histological injury, including mesangial expansion, glomerular macrophage infiltration, and collagen type IV deposition. Marked reduction of inflammation- and fibrosis-related gene expression in the kidney was also observed. In vitro, PAR1 and PAR2 agonists additively increased mRNA expression of macrophage chemoattractant protein 1 or plasminogen activator inhibitor-1 in human endothelial cells. Changes induced by the PAR1 agonist were blocked by a NF-κB inhibitor, whereas those of the PAR2 agonist were blocked by MAPK and/or NF-κB inhibitors. These findings suggest that PAR1 and PAR2 additively contribute to DKD pathogenesis and that dual blockade of both could be a novel therapeutic option for treatment of patients with DKD.


Assuntos
Diabetes Mellitus Tipo 1/tratamento farmacológico , Nefropatias Diabéticas/prevenção & controle , Iminas/farmacologia , Rim/efeitos dos fármacos , Oligopeptídeos/farmacologia , Piridinas/farmacologia , Receptor PAR-1/antagonistas & inibidores , Receptor PAR-2/antagonistas & inibidores , Albuminúria/genética , Albuminúria/metabolismo , Albuminúria/prevenção & controle , Animais , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Colágeno Tipo IV/metabolismo , Citocinas/metabolismo , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/metabolismo , Nefropatias Diabéticas/genética , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/patologia , Modelos Animais de Doenças , Quimioterapia Combinada , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Fibrose , Humanos , Mediadores da Inflamação/metabolismo , Rim/metabolismo , Rim/patologia , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Óxido Nítrico Sintase Tipo III/deficiência , Óxido Nítrico Sintase Tipo III/genética , Receptor PAR-1/metabolismo , Receptor PAR-2/metabolismo , Transdução de Sinais
15.
Phytomedicine ; 69: 153192, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32200292

RESUMO

BACKGROUND: The epithelial-to-mesenchymal transition (EMT) of renal tubular epithelial cells is the main pathological alteration in diabetic nephropathy (DN). Traditional Chinese medicine (TCM) has been used for the treatment of DN in clinical practice and has been proven to be effective. PURPOSE: This aim of this study was to shed light on the efficacy of Shenxiao decoction (SXD) on the EMT of renal tubular epithelial cells and the molecular mechanisms of SXD in mice with DN, as well as on the high glucose (HG)- and TGF-ß1-induced EMT of NRK-52E and HK-2 cells. STUDY DESIGN AND METHODS: A bioinformatics and network pharmacology method were utilized to construct the active ingredient-target networks of SXD that were responsible for the beneficial effects against DN. The effects of RUNX3 were validated in HG- and TGF-ß1-induced EMT processes in NRK-52E and HK-2 cells. RESULTS: Bioinformatics analysis revealed that 122 matching targets were closely associated with the regulation of cell migration and the AGE-RAGE signaling pathway in diabetic complications. The results also revealed that, relative to the mice with DN, the mice in the treatment group had an improved general state and reduced blood glucose levels. The degradation of renal function was ameliorated by SXD. Moreover, the protective effects of SXD were also observed on renal structural changes. Furthermore, SXD suppressed the activation of the transforming growth factor (TGF)-ß1/Smad pathway and upregulated the RUNX3 and E-cadherin levels and downregulated the extracellular matrix (ECM) protein levels in mice with DN. SXD was further found to prevent the HG- and TGF-ß1-induced EMT processes in NRK-52E and HK-2 cells. Additionally, the overexpression of RUNX3 markedly inhibited the EMT and TGF-ß1/Smad pathway induced by HG and TGF-ß1 in NRK-52E and HK-2 cells. CONCLUSION: Taken together, these results suggest that SXD maybe alleviate EMT in DN via the inhibition of the TGF-ß1/Smad/RUNX3 signaling pathway under hyperglycemic conditions.


Assuntos
Biologia Computacional/métodos , Nefropatias Diabéticas/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Animais , Subunidade alfa 3 de Fator de Ligação ao Core/genética , Subunidade alfa 3 de Fator de Ligação ao Core/metabolismo , Diabetes Mellitus Experimental/complicações , Nefropatias Diabéticas/genética , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/patologia , Regulação para Baixo/efeitos dos fármacos , Medicamentos de Ervas Chinesas/química , Células Epiteliais/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Hipoglicemiantes/farmacologia , Rim/efeitos dos fármacos , Rim/patologia , Masculino , Camundongos Endogâmicos C57BL , Mapas de Interação de Proteínas , Ratos , Proteínas Smad/genética , Proteínas Smad/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Fator de Crescimento Transformador beta/farmacologia , Regulação para Cima/efeitos dos fármacos
16.
Biol Pharm Bull ; 43(3): 558-564, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32115515

RESUMO

Diabetic kidney disease (DKD) is the leading cause of chronic kidney disease. Current therapies for DKD are insufficient. Therefore, there is an urgent need for identifying new therapies. An increasing number of micro RNAs (miRNAs) and long noncoding RNAs (lncRNAs) have been demonstrated to modulate the progression of diabetic kidney disease. Nevertheless, until now, there have been few reports evaluating the relevance of circular RNAs (circRNAs) in DKD. circRNAs have been reported to regulate the occurrence and development of multiple diseases. In this study, we intended to explore the circRNA expression profiles and determine the role of circRNA in DKD. We identified a series of dysregulated circRNAs in glucose-stressed HK-2 cells using circRNA microarray analysis. Among the candidate circRNAs, we found that circACTR2 was upregulated and may be involved in inflammation and pyroptosis. Knockdown of circACTR2 significantly decreased pyroptosis, interleukin (IL)-1ß release and collagen IV and fibronectin production, indicating the effective regulation by circACTR2 of cell death and inflammation. Overall, our study identified a new circRNA, circACTR2, that regulates high glucose-induced pyroptosis, inflammation and fibrosis in proximal tubular cells. The present study preliminarily explores the role of circRNAs in pyroptosis of tubular cells, and provides novel insight into the pathogenesis of DKD and new therapeutic strategies.


Assuntos
Nefropatias Diabéticas/genética , Nefropatias Diabéticas/metabolismo , Glucose/efeitos adversos , Piroptose/genética , Piroptose/fisiologia , RNA Circular/deficiência , RNA Circular/genética , Proteína 2 Relacionada a Actina , Linhagem Celular , Colágeno/metabolismo , Células Epiteliais , Fibronectinas/metabolismo , Fibrose/genética , Fibrose/metabolismo , Expressão Gênica , Humanos , Interleucina-1beta/metabolismo , Rim/metabolismo
17.
Biochim Biophys Acta Mol Basis Dis ; 1866(6): 165756, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32147421

RESUMO

The incidence of type 2 diabetes mellitus (T2DM) and diabetic kidney disease (DKD) has significantly increased worldwide in recent decades, and improved treatments for T2DM and DKD are urgently needed. The pathogenesis of aging-related disorders, such as T2DM and DKD, involves multiple mechanisms, including inflammation, autophagy impairment, and oxidative stress, which are closely associated with mitochondrial dysfunction. Therefore, mitochondrial quality control may be a novel therapeutic target for T2DM and DKD. Previous reports have shown that members of the mammalian Sirtuin family, SIRT 1-7, which are recognized as antiaging molecules, play a crucial role in the regulation of mitochondrial function and quality control through the modulation of oxidative stress, inflammation and autophagy. In this review, we summarized the research published in recent years to highlight the role of Sirtuins in mitochondrial quality control as a therapeutic target for T2DM and DKD.


Assuntos
Diabetes Mellitus Tipo 2/genética , Nefropatias Diabéticas/genética , Mitocôndrias/genética , Sirtuínas/genética , Envelhecimento/efeitos dos fármacos , Envelhecimento/genética , Envelhecimento/patologia , Animais , Autofagia/efeitos dos fármacos , Autofagia/genética , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/patologia , Nefropatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/patologia , Humanos , Mitocôndrias/efeitos dos fármacos
18.
Nat Rev Nephrol ; 16(6): 352-364, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32157251

RESUMO

Tonicity-responsive enhancer-binding protein (TonEBP), which is also known as nuclear factor of activated T cells 5 (NFAT5), was discovered 20 years ago as a transcriptional regulator of the cellular response to hypertonic (hyperosmotic salinity) stress in the renal medulla. Numerous studies since then have revealed that TonEBP is a pleiotropic stress protein that is involved in a range of immunometabolic diseases. Some of the single-nucleotide polymorphisms (SNPs) in TONEBP introns are cis-expression quantitative trait loci that affect TONEBP transcription. These SNPs are associated with increased risk of type 2 diabetes mellitus, diabetic nephropathy, inflammation, high blood pressure and abnormal plasma osmolality, indicating that variation in TONEBP expression might contribute to these phenotypes. In addition, functional studies have shown that TonEBP is involved in the pathogenesis of rheumatoid arthritis, atherosclerosis, diabetic nephropathy, acute kidney injury, hyperlipidaemia and insulin resistance, autoimmune diseases (including type 1 diabetes mellitus and multiple sclerosis), salt-sensitive hypertension and hepatocellular carcinoma. These pathological activities of TonEBP are in contrast to the protective actions of TonEBP in response to hypertonicity, bacterial infection and DNA damage induced by genotoxins. An emerging theme is that TonEBP is a stress protein that mediates the cellular response to a range of pathological insults, including excess caloric intake, inflammation and oxidative stress.


Assuntos
Doenças Autoimunes/metabolismo , Dano ao DNA/fisiologia , Fatores de Transcrição NFATC/metabolismo , Estresse Fisiológico/fisiologia , Artrite Reumatoide/metabolismo , Aterosclerose/metabolismo , Infecções Bacterianas/metabolismo , Carcinoma Hepatocelular/metabolismo , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Nefropatias Diabéticas/genética , Nefropatias Diabéticas/metabolismo , Proteínas de Choque Térmico , Humanos , Hiperlipidemias/metabolismo , Hipertensão/genética , Hipertensão/metabolismo , Resistência à Insulina , Neoplasias Hepáticas/metabolismo , Fatores de Transcrição NFATC/genética , Fatores de Transcrição NFATC/fisiologia , Obesidade/metabolismo , Estresse Oxidativo/fisiologia , Polimorfismo de Nucleotídeo Único , Estresse Salino/fisiologia , Viroses/metabolismo
19.
Am J Med Sci ; 359(2): 79-83, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32039769

RESUMO

BACKGROUND: The hexosamine biosynthesis pathway (HBP) is hypothesized to mediate many of the adverse effects of hyperglycemia. We have shown previously that increased flux through this pathway leads to induction of the growth factor transforming growth factor-α (TGF-α) and to insulin resistance in cultured cells and transgenic mice. TGF-ß is regulated by glucose and is involved in the development of diabetic nephropathy. We therefore hypothesized that the HBP was involved in the regulation of TGF-ß by glucose in rat vascular and kidney cells. METHODS: A plasmid containing the promoter region of TGF-ß1 cloned upstream of the firefly luciferase gene was electroporated into rat aortic smooth muscle, mesangial, and proximal tubule cells. Luciferase activity was measured in cellular extracts from cells cultured in varying concentrations of glucose and glucosamine. RESULTS: Glucose treatment of all cultured cells led to a time- and dose-dependent stimulation in TGF-ß1 transcriptional activity, with high (20 mM) glucose causing a 1.4- to 2.0-fold increase. Glucose stimulation did not occur until after 12 hours and disappeared after 72 hours of treatment. Glucosamine was more potent than glucose, with 3 mM stimulating up to a 4-fold increase in TGFß1-transcriptional activity. The stimulatory effect of glucosamine was also dose-dependent but was slower to develop and longer lasting than that of glucose. CONCLUSIONS: The metabolism of glucose through the HBP mediates extracellular matrix production, possibly via the stimulation of TGF-ß in kidney cells. Hexosamine metabolism therefore, may play a role in the development of diabetic nephropathy.


Assuntos
Nefropatias Diabéticas/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Glucose/farmacologia , Hexosaminas/biossíntese , Túbulos Renais Proximais/metabolismo , Células Mesangiais/metabolismo , Transcrição Genética/efeitos dos fármacos , Fator de Crescimento Transformador beta1/biossíntese , Animais , Nefropatias Diabéticas/genética , Nefropatias Diabéticas/patologia , Matriz Extracelular/genética , Matriz Extracelular/metabolismo , Matriz Extracelular/patologia , Glucose/metabolismo , Hexosaminas/genética , Humanos , Túbulos Renais Proximais/patologia , Células Mesangiais/patologia , Camundongos , Camundongos Transgênicos , Ratos , Fatores de Tempo , Fator de Crescimento Transformador beta1/genética
20.
Biomed Res Int ; 2020: 1360843, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32025515

RESUMO

Diabetic nephropathy (DN) is characterized by metabolic disorder and inflammation. However, the regulatory effects that long noncoding RNAs (lncRNAs) have on the pathogenesis of DN and on the efficacy of rosiglitazone treatment have yet to be clearly defined. Herein, we performed unbiased RNA sequencing to characterize the transcriptomic profiles in db/db diabetic mouse model with or without rosiglitazone treatment that served to improve the phenotypes of DN. Moreover, RNA-seq profiling revealed that the development of DN caused an upregulation in the expression of 1176 mRNAs and a downregulation in the expression of 1010 mRNAs compared to controls, with the expression of 251 mRNAs being returned to normal following treatment with rosiglitazone. Further, 88 upregulated and 68 downregulated lncRNAs were identified in db/db mice compared to controls, 10 of which had their normal expression restored following treatment with rosiglitazone. Bioinformatic analysis revealed that the primary pathways involved in the pathogenesis of DN, and subsequently in the therapeutic effects of PPARγ, are related to inflammatory and metabolic processes. From bioinformatics analysis, lncRNA-AI838599 emerged as a novel molecular mechanism for rosiglitazone treatment in DN through TNFα-NFκb pathway. These findings may indicate a new molecular regulatory approach for the development of DN therapeutic agents.


Assuntos
Nefropatias Diabéticas/genética , Hipoglicemiantes/uso terapêutico , RNA Longo não Codificante/genética , RNA Mensageiro/genética , Rosiglitazona/uso terapêutico , Animais , Biologia Computacional , Nefropatias Diabéticas/tratamento farmacológico , Modelos Animais de Doenças , Regulação para Baixo/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , PPAR gama/metabolismo , Análise de Sequência de RNA , Fator de Necrose Tumoral alfa/metabolismo , Regulação para Cima/efeitos dos fármacos
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