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1.
Life Sci ; 242: 117248, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31899224

RESUMO

Diabetic nephropathy is the most common long-term complication of diabetes mellitus. The Methylglyoxal (MGO) production is mainly by metabolic pathways, such as lipolysis and glycolysis, its increases in the DM enhances oxidative stress and plays a crucial role in the diabetic nephrotic pathogenesis. Phosphocreatine (PCr) can improve lipopolysaccharide, ox-LDL-induced atherosclerosis, and alleviate vascular endothelial cell injury in diabetes. The aim of our present study is to examine the potential role of phosphocreatine (PCr) as a molecule protects against diabetes-induced Kidney Injury in-vitro and in-vivo through ERK/Nrf2/HO-1 signaling pathway. NRK-52E cells treatment with PCr obviously suppressed MGO-induced change of viability, apoptosis, coupled with decreased Bax/Bcl-2ratio, casapse-9 and caspase-3expressions. We determined the generation of reactive oxygen species (ROS) using membrane permeable fluorescent probe DCFH-DA as well as intracellular calcium by flow cytometry. ERK, Nrf2 and HO-1 expressions were determined by Western blot. PCr pretreatment significantly returned the oxidative stress enzymes to normal condition in-vitro and in-vivo. PCr pretreatment significantly reduced apoptosis, calcium and ROS production, induced by MGO, in NRK-52E cells. Moreover, pretreatment with PCr significantly inhibited cleaved caspase-3, cleaved caspase-9 and p-ERK expressions, while increased Nrf-2 and HO-1 expressions. Furthermore, PCr pretreatment significantly decreased p-ERK expression of MGO-induced injury in NRK-52E cells transfected with p-ERK cDNA. In conclusion, the renal protective effect of PCr in-vitro and in-vivo depends on suppressing apoptosis and ROS generation through ERK mediated Nrf-2/HO-1 pathway, suggesting that PCr may be a novel therapeutic candidate for the diabetic nephropathy treatment.


Assuntos
Nefropatias Diabéticas/prevenção & controle , Heme Oxigenase (Desciclizante)/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/metabolismo , Fosfocreatina/uso terapêutico , Animais , Apoptose/efeitos dos fármacos , Western Blotting , Cálcio/metabolismo , Linhagem Celular , Diabetes Mellitus Experimental/complicações , Citometria de Fluxo , Imunofluorescência , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo
2.
Life Sci ; 238: 116965, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31629762

RESUMO

AIMS: Diabetic nephropathy (DN) is responsible for the occurrence of 30-47% of the incident cases of end-stage renal disease (ESRD) worldwide. DN is a chronic inflammatory disorder, which results from hyperglycemia-induced alterations and leads to renal fibrosis and ESRD. Toll like receptor-4 (TLR-4) participates in regulation of inflammatory response through controlling of innate immune system. P-Coumaric Acid (P-CA) is a natural hydroxycinnamic acid derivative and is widely present in vegetables, fruits, mushrooms and cereals. This study aimed to explore the renoprotective effect of P-CA, as anti-inflammatory and antioxidant natural compound, against experimental DN. METHODS: DN was induced by single intraperitoneal injection of streptozotocin (45 mg/kg) in rats. In kidney homogenate, levels of TLR-4, interleukin-6 (IL-6) and transforming growth factor ß1 (TGFß1) were measured using ELISA technique. Also, kidney collagen content was determined colorimetrically. KEY FINDINGS: Oral administration of P-CA (100 mg/kg) for 8 weeks significantly alleviated the DN. P-CA significantly reduced serum concentrations of glucose, creatinine, blood urea nitrogen (BUN) and reduced protein content in urine. Also, P-CA significantly increased superoxide dismutase (SOD) activity and significantly reduced kidney contents of malondialdehyde (MDA), TLR-4, IL-6, TGFß1 and collagen when compared with DN group. Moreover, P-CA significantly improved DN-induced histopathological abnormalities. SIGNIFICANCE: P-CA confers protection against the progression of DN. This renoprotective effect can be attributed to its ability to decrease the generation of inflammatory and fibrotic cytokines in addition to restoring oxidant/antioxidant balance through its ability to down-regulate TLR-4 activation.


Assuntos
Antioxidantes/farmacologia , Diabetes Mellitus Experimental/complicações , Nefropatias Diabéticas/prevenção & controle , Regulação da Expressão Gênica/efeitos dos fármacos , Propionatos/farmacologia , Receptor 4 Toll-Like/metabolismo , Animais , Glicemia/metabolismo , Creatinina/sangue , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/patologia , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Receptor 4 Toll-Like/genética
3.
Life Sci ; 237: 116950, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31605709

RESUMO

C-peptide is a small peptide connecting two chains of proinsulin molecule and is dissociated before the release of insulin. It is secreted in an equimolar amount to insulin from the pancreatic beta-cells into the circulation. Recent evidence demonstrates that it has other physiologic activities beyond its structural function. C-peptide modulates intracellular signaling pathways in various pathophysiologic states and, could potentially be a new therapeutic target for different disorders including diabetic complications. There is growing evidence that c-peptide has modulatory effects on the molecular mechanisms involved in the development of diabetic nephropathy. Although we have little direct evidence, pharmacological properties of c-peptide suggest that it can provide potent renoprotective effects especially, in a c-peptide deficient milieu as in type 1 diabetes mellitus. In this review, we describe possible molecular mechanisms by which c-peptide may improve renal efficiency in a diabetic milieu.


Assuntos
Peptídeo C/uso terapêutico , Complicações do Diabetes/prevenção & controle , Diabetes Mellitus Tipo 1/complicações , Nefropatias Diabéticas/prevenção & controle , Animais , Complicações do Diabetes/etiologia , Nefropatias Diabéticas/etiologia , Humanos
4.
Diabetes Res Clin Pract ; 155: 107807, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31394129

RESUMO

AIM: This study examined the association among the onset of diabetic kidney disease (DKD), blood glucose levels (HbA1C), and body mass index (BMI) in Japanese patients with type 2 diabetes mellitus. METHODS: Patients eligible for this study included those with type 2 diabetes who visited the outpatient clinic at Kawasaki Medical School Hospital between 2000 and 2018 and were followed up for more than two years. The Cox proportional hazards model was used in four categories of subjects: at the beginning of the follow-up period, "controlled" or "uncontrolled" glycemic control based on HbA1c and "overweight" or "non-overweight" based on BMI. RESULTS: After dividing the participants into four categories according to HbA1c (lower than 7.0% (C) or higher (U)), and BMI (25 kg/m2 or higher (O) or lower (N)), hazard ratios for groups CO, UN, and UO were 1.40 (95% CI 1.03-1.90, P = 0.030), 1.40 (1.04-1.88, P = 0.027), and 1.54 (1.12-2.11, P = 0.008), respectively, compared with the CN reference group, after adjustment was made for age, sex, duration of diabetes, and medication for hypertension or dyslipidemia. CONCLUSION: Maintenance of both an HbA1c level lower than 7.0% and a BMI lower than 25 kg/m2 was important for the prevention of DKD in Japanese patients with type 2 diabetes mellitus. Both factors had a similar effect on DKD in this study.


Assuntos
Índice de Massa Corporal , Nefropatias Diabéticas/diagnóstico , Nefropatias Diabéticas/prevenção & controle , Hemoglobina A Glicada/análise , Diabetes Mellitus Tipo 2/sangue , Nefropatias Diabéticas/patologia , Feminino , Humanos , Japão , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Pacientes Ambulatoriais , Estudos Retrospectivos
5.
Int J Mol Sci ; 20(14)2019 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-31295940

RESUMO

Diabetic kidney disease (DKD) remains the leading cause of end-stage renal disease (ESRD) and is therefore a major burden on the healthcare system. Patients with DKD are highly susceptible to developing cardiovascular disease, which contributes to increased morbidity and mortality rates. While progress has been made to inhibit the acceleration of DKD, current standards of care reduce but do not eliminate the risk of DKD. There is growing appreciation for the role of inflammation in modulating the process of DKD. The focus of this review is on providing an overview of the current status of knowledge regarding the pathologic roles of inflammation in the development of DKD. Finally, we summarize recent therapeutic advances to prevent DKD, with a focus on the anti-inflammatory effects of newly developed agents.


Assuntos
Nefropatias Diabéticas/etiologia , Suscetibilidade a Doenças , Inflamação/complicações , Animais , Biomarcadores , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/prevenção & controle , Nefropatias Diabéticas/terapia , Humanos , Mediadores da Inflamação/metabolismo , Transdução de Sinais
6.
Kidney Blood Press Res ; 44(4): 449-456, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31291624

RESUMO

BACKGROUND: This review considers anew the etiology of the cardio-renal protective effect of sodium-glucose cotransporter 2 (SGLT2) inhibitors by extending the discussion to renal congestion, inherent in diabetic kidney disease (DKD) even at an early stage of nephropathy in which heart failure (HF) or salt and water accumulation is asymptomatic. SUMMARY: The interstitial fluid (IF) space of the kidney space plays a crucial role for tubulointerstitial inflammation, renal hypoxia, and ischemic injury, which often leads to renal progression. In DKD, as a result of hyperglycemic milieu, excessive salt and water can be accumulated in the IF space, creating renal congestion. I hypothesize that SGLT2 inhibitors cause a shift in extracellular water from the IF space to the intravascular space to compensate for the SGLT2 inhibitor-induced hypovolemia. This decrease in IF volume ameliorates the IF space milieu and may reduce inflammation, hypoxia, and ischemic injury. Message: The present review proposes a novel theory; unlike other hypoglycemic agents or diuretics, SGLT2 inhibitor could protect DKD from failing by improving latent renal congestion even without symptomatic HF.


Assuntos
Nefropatias Diabéticas/tratamento farmacológico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Animais , Nefropatias Diabéticas/patologia , Nefropatias Diabéticas/prevenção & controle , Deslocamentos de Líquidos Corporais/efeitos dos fármacos , Humanos , Substâncias Protetoras , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia
7.
Diabetes Res Clin Pract ; 155: 107775, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31271811

RESUMO

AIM: Diet plays an important role in the kidney health of individuals with type 1 diabetes. However, not much is known about dietary practices at different stages of diabetic nephropathy. We aimed at investigating food intake, dietary patterns, and nutrient intakes in individuals with type 1 diabetes differing in renal status. METHODS: Data were available from 1874 individuals with type 1 diabetes (45% men, age 48 ±â€¯13 years). Diet was assessed at the levels of food items and diet patterns (diet questionnaire), and energy and nutrient intakes (food record). Six groups were formed based on the eGFR or dialysis and transplantation status. RESULTS: Reductions in liquid-milk product and salt consumption, and increase in special diet adherence were observed at the early stages of eGFR decline. Reduced coffee consumption was observed after eGFR was <30 ml/min/1.73 m2. With advancing kidney failure, rye bread consumption decreased, but that of wheat bread increased. Compared to those with intact kidney function (the index group), the Fish and vegetable diet pattern scores were higher in individuals with mildly-to-severely decreased eGFR. Instead, the Sweet pattern scores were lower than in the index group in all other groups. Energy intake was lower in all groups compared to those with intact kidney function. Advancing kidney failure was associated with reductions in protein intake per body weight, and in the intakes of sodium, potassium, calcium, and phosphorus. CONCLUSIONS: Differences in the dietary intake are seen already at the early stages of kidney function decline.


Assuntos
Diabetes Mellitus Tipo 1/dietoterapia , Nefropatias Diabéticas/prevenção & controle , Dieta/estatística & dados numéricos , Taxa de Filtração Glomerular , Adulto , Idoso , Peso Corporal , Estudos Transversais , Laticínios , Diabetes Mellitus Tipo 1/epidemiologia , Ingestão de Energia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Diálise Renal , Verduras
8.
Lancet ; 394(10193): 131-138, Jul. 2019. gráfico, tabela
Artigo em Inglês | Sec. Est. Saúde SP, SESSP-IDPCPROD, Sec. Est. Saúde SP | ID: biblio-1046322

RESUMO

Background Two glucagon-like peptide-1 (GLP-1) receptor agonists reduced renal outcomes in people with type 2 diabetes at risk for cardiovascular disease. We assessed the long-term effect of the GLP-1 receptor agonist dulaglutide on renal outcomes in an exploratory analysis of the REWIND trial of the effect of dulaglutide on cardiovascular disease. Methods REWIND was a multicenter, randomized, double-blind, placebo-controlled trial at 371 sites in 24 countries. Men and women aged at least 50 years with type 2 diabetes who had either a previous cardiovascular event or cardiovascular risk factors were randomly assigned (1:1) to either weekly subcutaneous injection of dulaglutide (1·5 mg) or placebo and followed up at least every 6 months for outcomes. Urinary albumin-to-creatinine ratios (UACRs) and estimated glomerular filtration rates (eGFRs) were estimated from urine and serum values measured in local laboratories every 12 months. The primary outcome (first occurrence of the composite endpoint of non-fatal myocardial infarction, non-fatal stroke, or death from cardiovascular causes), secondary outcomes (including a composite microvascular outcome), and safety outcomes of this trial have been reported elsewhere. In this exploratory analysis, we investigate the renal component of the composite microvascular outcome, defined as the first occurrence of new macroalbuminuria (UACR >33·9 mg/mmol), a sustained decline in eGFR of 30% or more from baseline, or chronic renal replacement therapy. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01394952. Findings Between Aug 18, 2011, and Aug 14, 2013, 9901 participants were enrolled and randomly assigned to receive dulaglutide (n=4949) or placebo (n=4952). At baseline, 791 (7·9%) had macroalbuminuria and mean eGFR was 76·9 mL/min per 1·73 m² (SD 22·7). During a median follow-up of 5·4 years (IQR 5·1­5·9) comprising 51 820 person years, the renal outcome developed in 848 (17·1%) participants at an incidence rate of 3·5 per 100 person-years in the dulaglutide group and in 970 (19·6%) participants at an incidence rate of 4·1 per 100 person-years in the placebo group (hazard ratio [HR] 0·85, 95% CI 0·77­0·93; p=0·0004). The clearest effect was for new macroalbuminuria (HR 0·77, 95% CI 0·68­0·87; p<0·0001), with HRs of 0·89 (0·78­1·01; p=0·066) for sustained decline in eGFR of 30% or more and 0·75 (0·39­1·44; p=0·39) for chronic renal replacement therapy. (AU)


Assuntos
Masculino , Pessoa de Meia-Idade , Creatinina/urina , Diabetes Mellitus Tipo 2/tratamento farmacológico , Nefropatias Diabéticas/prevenção & controle , Albuminúria/prevenção & controle , Hipoglicemiantes/administração & dosagem
9.
J Pediatr Endocrinol Metab ; 32(7): 653-665, 2019 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-31194681

RESUMO

Diabetic nephropathy (DN) is considered as one of the most popular microvascular complications of diabetes and the leading cause of death among diabetic patients. Currently, even though safflower yellow (SY) is widely adapted in the clinical treatment of DN, no meta-analysis can guarantee the safety of this treatment. This paper aims to evaluate the dominant method of SY on DN disease. The reliable source of information for randomized controlled trials (RCTs) and clinical research is listed as follows: the Chinese Biomedical Literature database, Chongqing VIP, Embase, the Cochrane Library and the China Academic Journals Full-text Database (CNKI). The CNKI search included Chinese journal articles, the full-text of important conferences and dissertations up to March 30, 2017. We picked out some particularly influential outcome variables including urinary albumin excretion rate (UAER), fasting blood sugar (FBG), blood urea nitrogen (BUN) and high-sensitivity C-reactive protein (hs-CRP) in each extracted study. In total, 1289 participants were included in this meta-analysis. The efficacy of SY alone or combined with Western medicine in the treatment of DN was better with statistically significant factors (odds ratio [OR] = 3.6, 95% confidence interval [CI] [2.37, 5.47], p < 0.00001). We found that SY lessened the UAER, heightened the proportion of blood sugar and beneficially improved other detective indicators related to DN. Therefore, SY used alone or in combination with Western medicine was significantly more efficacious with lower toxicity than Western medicine alone.


Assuntos
Chalcona/análogos & derivados , Diabetes Mellitus/fisiopatologia , Nefropatias Diabéticas/prevenção & controle , Chalcona/uso terapêutico , Nefropatias Diabéticas/epidemiologia , Humanos , Incidência , Prognóstico , Ensaios Clínicos Controlados Aleatórios como Assunto
10.
Dtsch Med Wochenschr ; 144(11): 710-714, 2019 06.
Artigo em Alemão | MEDLINE | ID: mdl-31163466

RESUMO

In diabetes, progression of cardio-renal disease is still the most important determinant of disease burden. Hence, the potential of glycaemic control is not the only measure any more to decide whether a new therapeutic approach is selected. Therapies with compelling cardiovascular and renal-protective effects are available. The two most promising new treatment concepts are sodium glucose co-transporter 2 (SGLT-2) inhibition and glucagon-like peptide-1 (GLP-1) receptor agonism. For both treatment concepts, prominent reductions in cardiovascular event rates and renal disease progression have been proven.To date, these beneficial effects appear to be more significant with SGLT-2 inhibitors than with GLP-1 receptor agonists, and further clinical trials with SGLT-2 inhibitors in patients with more advanced diabetic and non-diabetic kidney disease are currently underway. Furthermore, there are two new treatment concepts for attenuation of diabetic kidney disease progression close to finalization: selective antagonism of the mineralocorticoid receptor with finerenone and selective antagonism of the endothelin-1 receptor with atrasentan. Hence, in the near future, more treatment approaches might be available to face the major challenges in diabetes mellitus.


Assuntos
Diabetes Mellitus Tipo 2/complicações , Nefropatias Diabéticas , Atrasentana/uso terapêutico , Nefropatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/prevenção & controle , Antagonistas do Receptor de Endotelina A/uso terapêutico , Humanos , Hipoglicemiantes/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico
11.
Rev Med Suisse ; 15(653): 1106-1111, 2019 May 29.
Artigo em Francês | MEDLINE | ID: mdl-31148421

RESUMO

Diabetic nephropathy is a leading cause of chronic kidney disease and dialysis. We know that a good diabetes control slows the progression of kidney disease, but the risk of hypoglycemia is greater in patients with chronic kidney disease and contributes to their mortality. Chronic kidney disease and diabetes are major cardiovascular risk factors with additive effects. Decreasing cardiovascular mortality is a major aim in chronic kidney disease. The ideal antidiabetic molecule in these patients should reduce the risk of dialysis, reduce cardiovascular mortality and carry no risk of hypoglycaemia. This article aims to summarize for the general practician the nephrological implications of new antidiabetic drugs and their use in chronic kidney disease patients.


Assuntos
Diabetes Mellitus Tipo 2 , Nefropatias Diabéticas , Hipoglicemiantes , Falência Renal Crônica , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Nefropatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/prevenção & controle , Humanos , Hipoglicemiantes/uso terapêutico , Falência Renal Crônica/tratamento farmacológico , Falência Renal Crônica/prevenção & controle , Insuficiência Renal Crônica/tratamento farmacológico , Insuficiência Renal Crônica/prevenção & controle
12.
Lancet ; 394(10193): 131-138, 2019 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-31189509

RESUMO

BACKGROUND: Two glucagon-like peptide-1 (GLP-1) receptor agonists reduced renal outcomes in people with type 2 diabetes at risk for cardiovascular disease. We assessed the long-term effect of the GLP-1 receptor agonist dulaglutide on renal outcomes in an exploratory analysis of the REWIND trial of the effect of dulaglutide on cardiovascular disease. METHODS: REWIND was a multicentre, randomised, double-blind, placebo-controlled trial at 371 sites in 24 countries. Men and women aged at least 50 years with type 2 diabetes who had either a previous cardiovascular event or cardiovascular risk factors were randomly assigned (1:1) to either weekly subcutaneous injection of dulaglutide (1·5 mg) or placebo and followed up at least every 6 months for outcomes. Urinary albumin-to-creatinine ratios (UACRs) and estimated glomerular filtration rates (eGFRs) were estimated from urine and serum values measured in local laboratories every 12 months. The primary outcome (first occurrence of the composite endpoint of non-fatal myocardial infarction, non-fatal stroke, or death from cardiovascular causes), secondary outcomes (including a composite microvascular outcome), and safety outcomes of this trial have been reported elsewhere. In this exploratory analysis, we investigate the renal component of the composite microvascular outcome, defined as the first occurrence of new macroalbuminuria (UACR >33·9 mg/mmol), a sustained decline in eGFR of 30% or more from baseline, or chronic renal replacement therapy. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01394952. FINDINGS: Between Aug 18, 2011, and Aug 14, 2013, 9901 participants were enrolled and randomly assigned to receive dulaglutide (n=4949) or placebo (n=4952). At baseline, 791 (7·9%) had macroalbuminuria and mean eGFR was 76·9 mL/min per 1·73 m2 (SD 22·7). During a median follow-up of 5·4 years (IQR 5·1-5·9) comprising 51 820 person-years, the renal outcome developed in 848 (17·1%) participants at an incidence rate of 3·5 per 100 person-years in the dulaglutide group and in 970 (19·6%) participants at an incidence rate of 4·1 per 100 person-years in the placebo group (hazard ratio [HR] 0·85, 95% CI 0·77-0·93; p=0·0004). The clearest effect was for new macroalbuminuria (HR 0·77, 95% CI 0·68-0·87; p<0·0001), with HRs of 0·89 (0·78-1·01; p=0·066) for sustained decline in eGFR of 30% or more and 0·75 (0·39-1·44; p=0·39) for chronic renal replacement therapy. INTERPRETATION: Long-term use of dulaglutide was associated with reduced composite renal outcomes in people with type 2 diabetes. FUNDING: Eli Lilly and Company.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Nefropatias Diabéticas/prevenção & controle , Peptídeos Semelhantes ao Glucagon/análogos & derivados , Hipoglicemiantes/uso terapêutico , Fragmentos Fc das Imunoglobulinas/uso terapêutico , Proteínas Recombinantes de Fusão/uso terapêutico , Idoso , Albuminúria/prevenção & controle , Creatinina/urina , Método Duplo-Cego , Feminino , Taxa de Filtração Glomerular/efeitos dos fármacos , Peptídeos Semelhantes ao Glucagon/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade
13.
Environ Toxicol ; 34(7): 861-868, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31062909

RESUMO

Clinical studies have shown that hyperglycemia can induce early-stage diabetic nephropathy (DN). Furthermore, oxidative stress, tubular epithelial-mesenchymal transition and extracellular matrix accumulation promote the progression of DN to chronic kidney disease and tubulointerstitial fibrosis. It is necessary to initiate treatment at the early stages of DN or even during the early stages of diabetes. In this work, rats with streptozotocin (STZ)-induced diabetes mellitus (DM) presented early DN symptoms within 45 days, and collagen accumulation in the glomerulus of the rats was primarily mediated through the RhoA/ROCK pathway instead of the TGF-ß signaling pathway. Resveratrol (15 mg/kg/day) and ramipril (10 mg/kg/day) co-treatment of STZ-induced DN rats showed that glomerulosclerosis in early-stage DN was reversible (P < .05 compared with that in STZ-induced DM rats). The results of this study support early intervention in diabetes or DN as a more efficient therapeutic strategy.


Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Nefropatias Diabéticas/prevenção & controle , Glomerulosclerose Segmentar e Focal/prevenção & controle , Rim/efeitos dos fármacos , Ramipril/administração & dosagem , Resveratrol/administração & dosagem , Animais , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/metabolismo , Nefropatias Diabéticas/complicações , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/patologia , Progressão da Doença , Quimioterapia Combinada , Glomerulosclerose Segmentar e Focal/patologia , Rim/patologia , Masculino , Ratos , Ratos Sprague-Dawley , Índice de Gravidade de Doença , Transdução de Sinais/efeitos dos fármacos , Estreptozocina , Quinases Associadas a rho/metabolismo , Proteína rhoA de Ligação ao GTP/metabolismo
14.
Food Funct ; 10(5): 2970-2985, 2019 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-31074472

RESUMO

Obesity-related renal disease is related to caloric excess promoting deleterious cellular responses. However, a full understanding of the molecular mechanisms involved in progressive kidney disease, as well as a therapeutic strategy, is still absent. Fisetin (FIS), as a natural flavonoid, possesses various bioactivities in a number of disease models. However, its role in obesity-associated kidney injury is still unclear and requires elucidation. In our study, an obesity animal model was established using C57BL/6 mice fed with a normal chow diet (NCD) or high fat diet (HFD) for 16 weeks with or without FIS administration (20, 40 or 80 mg kg-1). Our results indicated that chronic HFD feeding led to a significant body weight gain in mice compared to the normal control group, accompanied by a marked insulin resistance and glucose intolerance, whereas FIS treatment exerted prominently protective effects. In addition, FIS significantly attenuated HFD-induced histological alterations in renal tissue samples. Moreover, FIS treatment down-regulated expression of kidney injury molecule-1 (KIM-1), and up-regulated nephrin and podocin expression levels in the kidneys of HFD-fed mice, improving their renal dysfunction. After HFD feeding, mice treated with FIS exhibited a decrease in phosphorylated IRS1Ser307, and an increase in phosphorylated glycogen synthase kinase 1 (IRS1Tyr608), AKT, forkhead box protein O1 (FOXO1) and glycogen synthase kinase (GSK)-3ß. Furthermore, FIS administration markedly restrained the inflammatory response in the kidneys of HFD-challenged mice, as evidenced by the reduced pro-inflammatory cytokines, tumor necrosis factor-α (TNF-α), interleukin 6 (IL-6), IL-1ß and IL-18, which was attributed to the blockage of nuclear factor κB (NF-κB) signaling. Importantly, FIS-treated obese mice exerted a remarkable decrease in RIP3 expressions in the kidneys compared to obese mice in the absence of FIS, along with an evident reduction in the NOD-like receptor protein 3 (NLRP3), an apoptosis-associated speck-like protein containing a Caspase recruitment domain (ASC) and Caspase-1. The protective effects of FIS against HFD-induced renal injury were verified in vitro using palmitate (PAL)-treated HK2 cells, an immortalized proximal tubule epithelial cell line from the adult human kidney. In summary, our results supported the notion that FIS functions as a promising agent to improve insulin resistance and inflammatory response against metabolic stress-induced renal injury.


Assuntos
Nefropatias Diabéticas/prevenção & controle , Flavonoides/administração & dosagem , Resistência à Insulina , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Proteína Serina-Treonina Quinases de Interação com Receptores/imunologia , Animais , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/genética , Nefropatias Diabéticas/imunologia , Dieta Hiperlipídica/efeitos adversos , Proteína Forkhead Box O1/genética , Proteína Forkhead Box O1/imunologia , Receptor Celular 1 do Vírus da Hepatite A/genética , Receptor Celular 1 do Vírus da Hepatite A/imunologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína Serina-Treonina Quinases de Interação com Receptores/genética
15.
Front Biosci (Landmark Ed) ; 24: 1477-1486, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-31136992

RESUMO

Diabetic nephropathy (DN) is one of the most serious complications of diabetes mellitus, for which no effective treatment currently exists. We tested the hypothesis that Qi-dan-di-huang (QDDH) might have therapuetic effects in an experimental rat model of DN. The levels of I kappa KinaseAlpha and Beta, p-p65, p-IκB alpha, TGF-ß1 and Alpha-SMA were significantly increased in kidneys in DN. QDDH decoction only partially reversed the increased Ikappa KinaseAlpha/Beta, p-p65, p-IKappaB alpha, TGF-Beta1 and alpha-SMA in the kidneys in DN. However, treatment of diabetic rats with QDDH decoction significantly inhibited the production and release of inflammatory cytokines IL-6, IL-1 beta and TNF-alpha into the serum. QDDH decoction also significantly improved the physiologic and biochemical indicators of DN, reduced glycogen and protein deposition in DN and prevented renal fibrosis. Together, the data show that QDDH decoction exerts a protective effect on kidneys in diabetic rats and reverses the inflammatory milieu of the serum in DN.


Assuntos
Diabetes Mellitus Experimental/complicações , Nefropatias Diabéticas/prevenção & controle , Medicamentos de Ervas Chinesas/farmacologia , NF-kappa B/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Citocinas/sangue , Nefropatias Diabéticas/complicações , Nefropatias Diabéticas/metabolismo , Fibrose , Glicogênio/metabolismo , Humanos , Mediadores da Inflamação/sangue , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Masculino , Ratos Sprague-Dawley
16.
Lancet ; 393(10184): 1937-1947, 2019 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-30995972

RESUMO

BACKGROUND: Short-term treatment for people with type 2 diabetes using a low dose of the selective endothelin A receptor antagonist atrasentan reduces albuminuria without causing significant sodium retention. We report the long-term effects of treatment with atrasentan on major renal outcomes. METHODS: We did this double-blind, randomised, placebo-controlled trial at 689 sites in 41 countries. We enrolled adults aged 18-85 years with type 2 diabetes, estimated glomerular filtration rate (eGFR) 25-75 mL/min per 1·73 m2 of body surface area, and a urine albumin-to-creatinine ratio (UACR) of 300-5000 mg/g who had received maximum labelled or tolerated renin-angiotensin system inhibition for at least 4 weeks. Participants were given atrasentan 0·75 mg orally daily during an enrichment period before random group assignment. Those with a UACR decrease of at least 30% with no substantial fluid retention during the enrichment period (responders) were included in the double-blind treatment period. Responders were randomly assigned to receive either atrasentan 0·75 mg orally daily or placebo. All patients and investigators were masked to treatment assignment. The primary endpoint was a composite of doubling of serum creatinine (sustained for ≥30 days) or end-stage kidney disease (eGFR <15 mL/min per 1·73 m2 sustained for ≥90 days, chronic dialysis for ≥90 days, kidney transplantation, or death from kidney failure) in the intention-to-treat population of all responders. Safety was assessed in all patients who received at least one dose of their assigned study treatment. The study is registered with ClinicalTrials.gov, number NCT01858532. FINDINGS: Between May 17, 2013, and July 13, 2017, 11 087 patients were screened; 5117 entered the enrichment period, and 4711 completed the enrichment period. Of these, 2648 patients were responders and were randomly assigned to the atrasentan group (n=1325) or placebo group (n=1323). Median follow-up was 2·2 years (IQR 1·4-2·9). 79 (6·0%) of 1325 patients in the atrasentan group and 105 (7·9%) of 1323 in the placebo group had a primary composite renal endpoint event (hazard ratio [HR] 0·65 [95% CI 0·49-0·88]; p=0·0047). Fluid retention and anaemia adverse events, which have been previously attributed to endothelin receptor antagonists, were more frequent in the atrasentan group than in the placebo group. Hospital admission for heart failure occurred in 47 (3·5%) of 1325 patients in the atrasentan group and 34 (2·6%) of 1323 patients in the placebo group (HR 1·33 [95% CI 0·85-2·07]; p=0·208). 58 (4·4%) patients in the atrasentan group and 52 (3·9%) in the placebo group died (HR 1·09 [95% CI 0·75-1·59]; p=0·65). INTERPRETATION: Atrasentan reduced the risk of renal events in patients with diabetes and chronic kidney disease who were selected to optimise efficacy and safety. These data support a potential role for selective endothelin receptor antagonists in protecting renal function in patients with type 2 diabetes at high risk of developing end-stage kidney disease. FUNDING: AbbVie.


Assuntos
Atrasentana/administração & dosagem , Creatinina/sangue , Diabetes Mellitus Tipo 2/tratamento farmacológico , Nefropatias Diabéticas/prevenção & controle , Antagonistas do Receptor de Endotelina A/administração & dosagem , Insuficiência Renal Crônica/prevenção & controle , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Atrasentana/uso terapêutico , Creatinina/urina , Nefropatias Diabéticas/sangue , Nefropatias Diabéticas/urina , Método Duplo-Cego , Antagonistas do Receptor de Endotelina A/uso terapêutico , Feminino , Taxa de Filtração Glomerular , Humanos , Masculino , Pessoa de Meia-Idade , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/urina , Albumina Sérica Humana/urina , Resultado do Tratamento , Adulto Jovem
17.
Biochim Biophys Acta Mol Cell Res ; 1866(8): 1272-1281, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30959066

RESUMO

Diabetic nephropathy (DN) is the leading cause of end stage renal disease, posing a severe threat to public health. Previous studies reported the protective role of sirtuin 1 (SIRT1) in DN, encouraging the investigation of more potent and specific SIRT1 activators. SRT2104 is a novel, first-in-class, highly selective small-molecule activator of SIRT1, with its effect and mechanism unknown on DN. To this end, streptozotocin-induced C57BL/6 wild-type (WT) diabetic mice were treated with SRT2104, for 24 weeks. To determine whether SRT2104 acted through inhibition of P53 - a substrate of SIRT1, the P53 activator nutlin3a was administered to the WT diabetic mice in the presence of SRT2104. In order to test whether nuclear factor erythroid 2-related factor 2 (NRF2) - the master of cellular antioxidants - mediated SIRT1 and P53's actions, WT and Nrf2 gene knockout (KO) diabetic mice were treated with SRT2104 or the P53 inhibitor pifithrin-α (PFT-α). In the WT mice, SRT2104 enhanced renal SIRT1 expression and activity, deacetylated P53, and activated NRF2 antioxidant signaling, providing remarkable protection against the DM-induced renal oxidative stress, inflammation, fibrosis, glomerular remodeling and albuminuria. These effects were completely abolished in the presence of nutlin3a. Deletion of the Nrf2 gene completely abrogated the efficacies of SRT2104 and PFT-α in elevating antioxidants and ameliorating DN, despite their abilities to activate SIRT1 and inhibit P53 in the Nrf2 KO mice. The present study reports the beneficial effects of SRT2104 on DN, uncovering a SIRT1/P53/NRF2 pathway that modulates the pathogenesis of DN.


Assuntos
Nefropatias Diabéticas/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Transdução de Sinais , Sirtuína 1/biossíntese , Proteína Supressora de Tumor p53/metabolismo , Animais , Nefropatias Diabéticas/genética , Nefropatias Diabéticas/patologia , Nefropatias Diabéticas/prevenção & controle , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Compostos Heterocíclicos com 2 Anéis/farmacologia , Camundongos , Camundongos Knockout , Fator 2 Relacionado a NF-E2/genética , Sirtuína 1/antagonistas & inibidores , Sirtuína 1/genética , Proteína Supressora de Tumor p53/genética
18.
J Food Sci ; 84(5): 1208-1215, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31012974

RESUMO

Type II diabetes (T2D) nephropathy, a major cause of end-stage kidney disease, progresses and develops from oxidative stress. Natural polyphenols can protect the kidney from diabetic nephropathy exerting antioxidant activities. The present approach enumerates the reno-protective and anti-apoptotic effects of mangosteen vinegar rind (MVR, a phenolic aqueous extract) against high-fat diet (5 g/day up to five weeks)-/streptozotocin (single ip, dose 30 mg/kgBW)-induced T2D nephropathy of albino mice. In vitro total phenolic content, 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) (ABTS) activity, 2,2-diphenyl-1-picrylhydrazyl (DPPH) antioxidant capacity, and α-amylase inhibition activity as antidiabetic assay of MVR were performed. In vivo mice body weight, oral glucose, and maltose tolerance test, metabolic parameters (plasma glucose, insulin level, omeostasis model assessment-estimated insulin resistance), biochemical parameters (kidney hypertrophy, blood urea nitrogen, creatinine), oxidative stress parameters (malondialdehyde, superoxide dismutase, catalase) were estimated in an intervention study. Additionally, renal morphology and early apoptosis were observed following the H & E staining and TUNEL assay of the tissue frozen section. We found that the aqueous extract of MVR possesses potent in vitro antioxidative and antidiabetic activities. Animal intervention results showed that MVR 100, 200 mg/kgBW, and Glibenclamide 60 mg/kgBW treatments significantly improved (P < 0.05) the abovementioned parameters compared to the diabetic control group. Furthermore, treatments also significantly restored (P < 0.05) kidney histological alterations and reduced cellular apoptosis compared to the diabetic control group. These findings concluded that MVR treatments significantly modulated the glucose intolerance, metabolic alterations, and oxidative stress-induced pathological alterations and cellular apoptosis of diabetic kidney. PRACTICAL APPLICATION: Garcinia mangostana, a polyphenol rich natural product, is obtained from the tropical rain forest area of Southeast Asian countries and processes diverse biological activities including antioxidant, anti-proliferative, anti-inflammatory, anti-carcinogenic, and so on. This research first time focuses on the nephro-protective and anti-apoptotic effects of mangosteen vinegar rind (MVR) from the mangosteen fruit pericarp. Our study provides the efficient data to prove the beneficial effect of MVR as a dietary supplement for the prevention and management of diabetic nephropathy.


Assuntos
Ácido Acético/farmacologia , Diabetes Mellitus Experimental/prevenção & controle , Nefropatias Diabéticas/prevenção & controle , Dieta Hiperlipídica/efeitos adversos , Garcinia mangostana/química , Extratos Vegetais/farmacologia , Animais , Apoptose/efeitos dos fármacos , Camundongos , Estreptozocina/efeitos adversos
19.
Postgrad Med ; 131(4): 251-260, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30929540

RESUMO

Chronic kidney disease (CKD) is a frequent complication of type 2 diabetes mellitus (T2DM) and is associated with poor clinical outcomes, including an increased risk of all-cause and cardiovascular mortality, as well as adverse economic and social effects. Slowing the development and progression of CKD remains an unmet clinical need in patients with T2DM. Sodium-glucose co-transporter 2 (SGLT2) inhibitors are widely used for the management of T2DM and have effects beyond glucose lowering that include cardiovascular benefits and potential renoprotective effects. Although the glucose-lowering efficacy of these agents is dependent on renal function, the cardiovascular and renal benefits of SGLT2 inhibition appear to be maintained to estimated glomerular filtration levels as low as 30 mL/min/1.73 m2. Clinical evidence has indicated that these agents can reduce the risk of development or worsening of albuminuria, a marker of renal damage, through a range of mechanisms. These include blood pressure lowering, reduction of intraglomerular pressure and hyperfiltration, modification of inflammatory processes, reduction of ischemia-related renal injury, and increases in glucagon levels. The blood pressure-lowering effect of SGLT2 inhibitors is maintained in people with CKD and could further contribute to reduced renal burden, as well as potentially offering synergistic effects with antihypertensive therapies in these patients. Several cardiovascular outcomes trials (CVOTs) have included renal endpoints, adding to the growing evidence of the potential renoprotective effects of these agents in patients with T2DM. Several ongoing dedicated renal outcomes trials will provide further guidance on the potential clinical role of SGLT2 inhibitors in slowing the development and progression of renal impairment in individuals with T2DM.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Cardiomiopatias Diabéticas/prevenção & controle , Nefropatias Diabéticas/prevenção & controle , Hipoglicemiantes/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Albuminúria/metabolismo , Glicemia , Pressão Sanguínea , Ensaios Clínicos como Assunto , Taxa de Filtração Glomerular , Hemoglobina A Glicada , Humanos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/efeitos adversos , Inibidores do Transportador 2 de Sódio-Glicose/administração & dosagem , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos
20.
Pharmazie ; 74(4): 239-242, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30940309

RESUMO

Diabetic nephropathy (DN) is a common cause of end-stage kidney disease (ESKD) all over the world. Sitagliptin, an inhibitor of DPP-IV plays a beneficial role in type 2 diabetic nephropathy. The purpose of this study was to explore the effect and mechanism of sitagliptin on renal injury in type 1 diabetic mice. Streptozotocin (STZ) induced type 1 diabetic mice were treated with oral administration of sitagliptin (15 mg/kg/ day) for 4 weeks. The results showed that sitagliptin treatment did not change the levels of blood glucose in STZ induced type 1 diabetic mice. Sitagliptin attenuates diabetic nephropathy by significantly inhibiting 24 h proteinuria, renal injury and fibrosis. Sitagliptin can inhibit the expression level of TGF-ß1 and the other related fibrosis factors in renal tissue of type 1 diabetic mice while delaying the progression of type 1 diabetic nephropathy. These results indicated that sitagliptin treatment is potentially a new strategy for treating type 1 diabetic nephropathy.


Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 1/tratamento farmacológico , Nefropatias Diabéticas/prevenção & controle , Inibidores da Dipeptidil Peptidase IV/farmacologia , Fosfato de Sitagliptina/farmacologia , Administração Oral , Animais , Glicemia/efeitos dos fármacos , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Tipo 1/complicações , Hipoglicemiantes/farmacologia , Masculino , Camundongos , Proteinúria/prevenção & controle , Transdução de Sinais/efeitos dos fármacos , Proteínas Smad/metabolismo , Estreptozocina , Fator de Crescimento Transformador beta1/genética
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