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1.
DNA Cell Biol ; 38(10): 1134-1142, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31433203

RESUMO

Diabetes mellitus is a complicated metabolic disease characterized by hyperglycemia. Diabetic nephropathy (DN) is a progressive kidney disease, which results in mortality in diabetic patients. The present study was designed to investigate the effect of applying spironolactone (S), captopril (C), and their combination (S+C) on some renal performance indices and microRNAs' (miRNAs) expression. A total of 35 two-month-old male Wistar rats were provided for the study. Intraperitoneal injection of freshly dissolved streptozotocin (60 mg/kg) in cold citrate buffer was used to induce diabetes. Blood samples were examined through calorimetry to assess serum concentrations of glucose, blood urea nitrogen (BUN), and creatinine. To measure the microalbuminuria and transforming growth factor-ß (TGF-ß) levels and to evaluate the miRNAs expression levels of the kidney tissue, the ELISA method and the real-time PCR were used. The obtained results serve as in vivo evidence for the positive relationship between miR-192 and TGF-ß levels in the DN rats. A significant increase and decrease were found for miR-29a/b/c and the miR-192 expression of DN after treatment with S, C, and S+C. TGF-ß levels and microalbuminuria of diabetic rats also increased. The results obtained from this research study suggest that S, C, and S + C can improve DN by targeting miR-192 and miR-29 family and changing their expression. These findings suggest that miR-192 and miRs-29a/b/c can be potential targets for DN remediation.


Assuntos
Captopril/farmacologia , Diabetes Mellitus Experimental/tratamento farmacológico , Nefropatias Diabéticas/tratamento farmacológico , Regulação da Expressão Gênica/efeitos dos fármacos , Hiperglicemia/tratamento farmacológico , Hipoglicemiantes/farmacologia , Espironolactona/farmacologia , Animais , Anti-Hipertensivos/farmacologia , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Nitrogênio da Ureia Sanguínea , Creatinina/sangue , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/patologia , Nefropatias Diabéticas/induzido quimicamente , Nefropatias Diabéticas/genética , Nefropatias Diabéticas/patologia , Diuréticos/farmacologia , Combinação de Medicamentos , Reposicionamento de Medicamentos , Hiperglicemia/induzido quimicamente , Hiperglicemia/genética , Hiperglicemia/patologia , Masculino , MicroRNAs/genética , MicroRNAs/metabolismo , Ratos , Ratos Wistar , Estreptozocina/administração & dosagem , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismo , Resultado do Tratamento
2.
Life Sci ; 234: 116738, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31398418

RESUMO

AIMS: Oxidative stress has been linked to the development and progression of diabetic nephropathy (DN). The present study evaluated whether the dipeptidyl peptidase-4 inhibitor sitagliptin attenuates glomerular lesions and oxidative stress evoked by chronic hyperglycemia, by a mechanism independent of insulin secretion and glycemia normalization. MAIN METHODS: A rat model of DN caused by streptozotocin injection was established and the effects of sitagliptin (5 mg/kg/day) were evaluated after two weeks of treatment. KEY FINDINGS: Sitagliptin treatment did not change body weight, glycemic and lipid profiles. However, histopathological observation revealed that sitagliptin attenuates diabetes-induced glomerular lesions on diabetic rats. Sitagliptin also ameliorated the increase in DPP-4 content and promoted the stabilization of GLP-1 in the diabetic kidney. Furthermore, sitagliptin treatment significantly attenuated the increase of free-radical formation and the decrease of antioxidant defenses, attenuating therefore the oxidative stress in the kidneys of diabetic animals. SIGNIFICANCE: The results suggest that sitagliptin treatment alleviates kidney oxidative stress in type 1 diabetic rats, which could play a key role in reducing the progression of DN.


Assuntos
Diabetes Mellitus Tipo 1/tratamento farmacológico , Nefropatias Diabéticas/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Glomérulos Renais/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Fosfato de Sitagliptina/uso terapêutico , Animais , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/patologia , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/patologia , Inibidores da Dipeptidil Peptidase IV/farmacologia , Glomérulos Renais/metabolismo , Glomérulos Renais/patologia , Masculino , Ratos , Ratos Wistar , Fosfato de Sitagliptina/farmacologia
3.
Life Sci ; 234: 116755, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31415769

RESUMO

AIMS: Vitamin D and its receptor, vitamin D receptor (VDR), have renoprotection effect against diabetic nephropathy (DN). But the exact mechanism has not been fully elucidated. Epoxyeicosatrienoic acids (EETs) are cytochrome P450 (CYP) epoxygenase-derived metabolites of arachidonic acid, protecting against diabetes and DN. Herein, we hypothesized that activation of VDR attenuated high glucose-induced cellular injury in renal tubular epithelial cells partially through up-regulating CYP2J5 expression. MAIN METHODS: Streptozotocin (STZ) was injected to induce diabetic in wild type and Vdr-/- mice. The effects of VDR knockout and an activator of VDR, paricalcitol, on the renal injury were detected. In vitro, a murine kidney proximal tubule epithelial cell line BU.MPT induced by high glucose were treated with or without paricalcitol (30 mM) for 12 h or 24 h. KEY FINDINGS: The expression of CYP2J5 was significantly decreased both in wild type and Vdr-/- diabetic mice induced by STZ. The STZ-induced kidney architecture damage and apoptosis rate in Vdr-/- mice were more severe. In vitro, high glucose treatment strongly reduced the CYP2J5 expression and the synthesis of 14,15-EET in BU.MPT cells. Supplement of 14,15-EET significantly reduced the lactate dehydrogenase (LDH) release induced by high glucose in BU.MPT cells. Furthermore, treatment with paricalcitol attenuated cellular injury and restored the expression of CYP2J5 reduced by high glucose in BU.MPT cells. SIGNIFICANCE: We conclude that activation of VDR attenuates high glucose-induced cellular injury partially dependent on CYP2J5 in murine renal tubule epithelial cells and paricalcitol may represent a potential therapy for DN.


Assuntos
Sistema Enzimático do Citocromo P-450/genética , Diabetes Mellitus Experimental/complicações , Nefropatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/etiologia , Ergocalciferóis/farmacologia , Túbulos Renais Proximais/efeitos dos fármacos , Receptores de Calcitriol/agonistas , Animais , Linhagem Celular , Sistema Enzimático do Citocromo P-450/metabolismo , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/patologia , Nefropatias Diabéticas/genética , Nefropatias Diabéticas/patologia , Ergocalciferóis/uso terapêutico , Deleção de Genes , Regulação da Expressão Gênica/efeitos dos fármacos , Glucose/metabolismo , Túbulos Renais Proximais/metabolismo , Túbulos Renais Proximais/patologia , Masculino , Camundongos , Camundongos Knockout , Receptores de Calcitriol/genética , Receptores de Calcitriol/metabolismo
4.
Nat Commun ; 10(1): 2692, 2019 06 19.
Artigo em Inglês | MEDLINE | ID: mdl-31217420

RESUMO

Sphingomyelin phosphodiesterase acid-like 3b (SMPDL3b) is a lipid raft enzyme that regulates plasma membrane (PM) fluidity. Here we report that SMPDL3b excess, as observed in podocytes in diabetic kidney disease (DKD), impairs insulin receptor isoform B-dependent pro-survival insulin signaling by interfering with insulin receptor isoforms binding to caveolin-1 in the PM. SMPDL3b excess affects the production of active sphingolipids resulting in decreased ceramide-1-phosphate (C1P) content as observed in human podocytes in vitro and in kidney cortexes of diabetic db/db mice in vivo. Podocyte-specific Smpdl3b deficiency in db/db mice is sufficient to restore kidney cortex C1P content and to protect from DKD. Exogenous administration of C1P restores IR signaling in vitro and prevents established DKD progression in vivo. Taken together, we identify SMPDL3b as a modulator of insulin signaling and demonstrate that supplementation with exogenous C1P may represent a lipid therapeutic strategy to treat diabetic complications such as DKD.


Assuntos
Antígenos CD/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 3/metabolismo , Nefropatias Diabéticas/patologia , Insulina/metabolismo , Receptor de Insulina/metabolismo , Esfingomielina Fosfodiesterase/metabolismo , Animais , Caveolina 1/metabolismo , Linhagem Celular , Membrana Celular/metabolismo , Ceramidas/metabolismo , Ceramidas/uso terapêutico , Nucleotídeo Cíclico Fosfodiesterase do Tipo 3/genética , Nefropatias Diabéticas/tratamento farmacológico , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Camundongos , Camundongos Knockout , Podócitos/citologia , Podócitos/metabolismo , Isoformas de Proteínas/metabolismo , Transdução de Sinais , Resultado do Tratamento
5.
BMC Complement Altern Med ; 19(1): 118, 2019 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-31170978

RESUMO

BACKGROUND: Hirudin, an extract from Hirudo spp., is an anticoagulant used to treat a variety of renal diseases, including diabetic nephropathy (DN). Currently, hirudin has to be used at high dosages to treat DN because it poorly targets the kidneys, although at high dosages it can have severe side effects. Developing a targeted drug delivery system for hirudin, then, could boost its positive therapeutic effects while lowering the risk of side effects. Liposomes have been demonstrated to have significant renal targeting potential, but here we show that a hirudin-loaded liposome is an effective delivery method for patients with DN. METHOD: In this study, we prepared a hirudin/liposome complex and tested its efficacy by injecting it into a rat model. We then compared the renal accumulation of hirudin between complex-injected rat models and rat models that received injections of hirudin alone. We also investigated the mechanisms behind the complex's effects. RESULT: The hirudin/liposome complex increased the accumulation of hirudin in kidney tissues and relieved the renal injury in DN rat models. Moreover, the hirudin/liposome complex down-regulated the expression of TGF-ß1 and VEGF in the kidneys. CONCLUSION: We demonstrated that a hirudin/liposome complex can have a significant positive effect on DN. The mechanism may be that the complex inhibits the expression of VEGF and TGF-ß1.


Assuntos
Nefropatias Diabéticas/tratamento farmacológico , Fibrinolíticos/administração & dosagem , Hirudinas/administração & dosagem , Animais , Glicemia , Diabetes Mellitus Experimental/complicações , Nefropatias Diabéticas/patologia , Avaliação Pré-Clínica de Medicamentos , Fibrinolíticos/farmacocinética , Hirudinas/farmacocinética , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Testes de Função Renal , Lipossomos , Masculino , Ratos Sprague-Dawley , Fator de Crescimento Transformador beta1/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo
6.
Medicine (Baltimore) ; 98(24): e15850, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31192915

RESUMO

BACKGROUND: The diabetic kidney disease (DKD) has become a seriously kidney disease that commonly caused by diabetes mellitus (DM). Oxidative stress response plays an essential role in the genesis and worsening of DKD and Coenzyme Q10 (CoQ10) has been reported the promising clinical effectiveness on DKD treatment. However, there is lack of relative evidence-based medical evidence currently. OBJECTIVE: The systematic review and meta-analysis was based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement, which conducted to evaluate the effectiveness of CoQ10 in combination with other western medicine for DKD therapy through the randomized controlled trials (RCTs) and experimental studies. METHODS: RCTs and experimental studies were searched based on standardized searching rules in 12 medical databases from the inception up to June 2018 and a total of 8 articles (4 RCTs and 4 experimental studies) were enrolled in the meta-analysis. RESULTS: The results revealed that CoQ10 combined with other western medicine show statistical differences in the laboratory parameters of fasting plasma glucose (FPG), Hemoglobin A1c (HbA1c), total cholesterol (TC), high density lipoprotein cholesterol (HDL-C), triglyceride (TG), and malondialdehyde (MDA) amelioration after DKD therapy compared with control group. However, LDL-C and Urea level for RCTs and Urine output and Glucose for experimental studies on DKD was not superior to control group. CONCLUSION: We need to make conclusion cautiously for the effectiveness of CoQ10 application on DKD therapy. More standard, multicenter, double-blind RCTs, and formal experimental studies of CoQ10 treatment for DKD were urgent to be conducted for more clinical evidence providing in the future. The underlying pharmacological mechanism of CoQ10 needs to be researched and revealed for its future application on DKD therapy.


Assuntos
Nefropatias Diabéticas/tratamento farmacológico , Ubiquinona/análogos & derivados , Vitaminas/uso terapêutico , Glicemia/metabolismo , Colesterol/metabolismo , Nefropatias Diabéticas/metabolismo , Medicina Baseada em Evidências , Hemoglobina A Glicada/metabolismo , Humanos , Estudos Multicêntricos como Assunto , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento , Ubiquinona/uso terapêutico
7.
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
8.
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
9.
Zhongguo Zhong Yao Za Zhi ; 44(8): 1660-1667, 2019 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-31090332

RESUMO

Buyang Huanwu Decoction(BHD) has the effect in benefiting Qi and activating blood circulation,and is the representative prescription for benefiting Qi and activating blood. At present,it is used for treatment of early diabetic nephropathy. However,its efficacy and safety remained to be verified. Therefore,this study aims to systematically evaluate the efficacy and safety of Buyang Huanwu Decoction for early-stage diabetic nephropathy. Data of randomized controlled trials(RCTs) of Buyang Huanwu Decoction for earlystage diabetic nephropathy were collected through the retrieval of electronic databases,including PubMed,EMbase,the Cochrane Library,CBM,CNKI,VIP and Wan Fang Data from inception to September 16,2018. Two reviewers independently screened out literatures,extracted data,and assessed the risk of bias. And then Meta-analysis was conducted by Rev Man 5. 3 software. A total of 15 RCTs involving 1 402 patients were included. The results of Meta-analysis indicated that Buyang Huanwu Decoction and conventional treatment group(combination treatment group) were superior to conventional treatment group in reducing 24 h urinary albumin excretion rates(MD =-40. 23,95% CI[-71. 25,-9. 21],P = 0. 01) and total cholesterol(MD =-0. 75,95% CI[-1. 02,-0. 48],P <0. 000 01). The effects of the two groups in reducing serum creatinine were similar(MD =-1. 48,95%CI[-4. 48,1. 53],P = 0. 34).However,the reduction of triglyceride was affected by the course of treatment. The effects were similar in less than or equal to eight weeks(MD =-0. 33,95%CI[-0. 97,0. 31],P = 0. 31),whereas the combination group was superior to the conventional treatment group in 12 weeks(MD =-0. 30,95%CI[-0. 58,-0. 22],P = 0. 03) and more than or equal to 16 weeks(MD =-0. 49,95% CI[-0. 9,-0. 08],P= 0. 02). There were no significant difference in adverse events between the two groups(OR= 1. 38,95%CI[0. 28,6. 8],P = 0. 69). The results showed that combination treatment group has a significantly higher efficacy on early diabetic nephropathy.The above conclusion shall be verified with more high-quality RCTs because of the low quality of the included studies.


Assuntos
Nefropatias Diabéticas/tratamento farmacológico , Medicamentos de Ervas Chinesas/uso terapêutico , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto
10.
Chem Biol Interact ; 310: 108665, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31125535

RESUMO

Diabetes mellitus (DM) is metabolism related problems that share the phenotype of hyperglycemia, which is triggered by a complicated interaction of hereditary and environmental elements. It is the main reason for end-stage renal disease (ESRD), amputations of the traumatic lower extremity, and grown-up visual impairment. It additionally inclines to neurodegenerative and cardiovascular sicknesses. With an expanding rate around the world, DM may be the main motive of morbidity and mortality within the foreseeable future. The objective of treatment for DM is to inhibit mortality and difficulties through normalizing blood glucose stage. Genistein, a naturally available soy isoflavone, is accounted for to have various medical advantages credited to numerous natural capacities. In the course of recent years, various examinations have shown that genistein has hostile to diabetic impacts, specifically, direct consequences for ß-cell expansion, glucose-triggered insulin discharge, and safety towards apoptosis, unbiased of its functions as an estrogen receptor agonist, cancer prevention agent, or tyrosine kinase inhibitor. The present evaluation emphases on the promising molecular and biochemical paths associated with DM complications and, specifically, the multi-target method of genistein in diminishing diabetic neuropathy, nephropathy, and retinopathy.


Assuntos
Complicações do Diabetes/tratamento farmacológico , Diabetes Mellitus/tratamento farmacológico , Genisteína/uso terapêutico , Estresse Oxidativo/efeitos dos fármacos , Animais , Complicações do Diabetes/metabolismo , Diabetes Mellitus/metabolismo , Nefropatias Diabéticas/tratamento farmacológico , Neuropatias Diabéticas/tratamento farmacológico , Retinopatia Diabética/tratamento farmacológico , Genisteína/farmacologia , Humanos
11.
Chem Biol Interact ; 307: 116-124, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31063766

RESUMO

Naringenin is a flavanone compound found in citrus fruits. Recent researches showed that naringenin has many potentially pharmacological effects. However, the therapeutic effect and the potential mechanism of naringenin on diabetic nephropathy (DN) remain to be elucidated. DN model was established by a high-fat diet combined with streptozotocin (STZ), which was confirmed by the levels of fasting blood glucose (FBG, more than 11.1 mmol/L) and urinary albumin (10 times higher than the normal mice). After 5 weeks of STZ injection, the DN was developed in model mice. Then naringenin (25 or 75 mg/kg·d) were supplemented for 4 weeks. At the end of the experiment, the injury of the renal function and structure was deteriorated. Concomitantly, peroxisome proliferators-activated receptors (PPARs) protein expression was down-regulated, and CYP4A expression and 20-hydroxyeicosatetraenoic acid (20-HETE) level were reduced in DN mice. Naringenin administration improved the renal damage of DN mice, and up-regulated PPARs expression, increased CYP4A-20-HETE level. Consistent with the results of in vivo, glucose at 30 mmol/L (high glucose, HG) significantly induced cell proliferation and hypertrophy in NRK-52E cells, following the reductive PPARs protein expression and the downward CYP4A-20-HETE level. Naringenin (0.01, 0.1, 1 µmol/L) reversed these changes induced by HG in a dose-dependent manner. HET0016, a selective inhibitor of 20-HETE synthase, partially blocked the effects of naringenin. In conclusion, naringenin has a therapeutic effect on DN, which may be, at least partly, related to the activation of CYP4A-20-HETE and the up-regulation of PPARs.


Assuntos
Nefropatias Diabéticas/tratamento farmacológico , Flavanonas/uso terapêutico , Ácidos Hidroxieicosatetraenoicos/metabolismo , Receptores Ativados por Proliferador de Peroxissomo/metabolismo , Animais , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Citocromo P-450 CYP4A/metabolismo , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/patologia , Nefropatias Diabéticas/etiologia , Dieta Hiperlipídica , Feminino , Flavanonas/farmacologia , Glucose/farmacologia , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Camundongos , Ratos , Estreptozocina/toxicidade , Regulação para Cima/efeitos dos fármacos
12.
Int J Biol Macromol ; 132: 1001-1011, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-30946910

RESUMO

Dysbiosis of gut microbiota and low grade inflammation has gradually become a highly potential therapeutic agent for diabetic nephropathy (DN). It has been reported that a large number of polysaccharides have positive effects on DN, including Bupleurum polysaccharides. However, the mechanism remained unclear. This study selected two Bupleurum polysaccharides from different origins to investigate the potential relationship between kidney and gut. Diabetic mice model was established by streptozotocin (STZ, 100 mg/kg) and the treatment groups were treated with two Bupleurum polysaccharides (60 mg/kg) for 6 weeks, respectively. The results showed that the administration of Bupleurum polysaccharides ameliorated diabetic nephropathy induced by STZ. Blood glucose, blood creatinine and urine albumin were decreased after the oral administration of Bupleurum polysaccharides. And the dysbiosis of gut microbiota was modulated with higher diversity and gut protective microbiota. The gut barrier was also improved and the expression of inflammatory response both in kidney and colon was reduced. These results provided the evidence that modulating the gut microbiota and inflammation was involved in the effect of Bupleurum polysaccharides against diabetic nephropathy in mice and laid the foundation for the deeper, specific mechanism research on the interaction between kidney and gut.


Assuntos
Bupleurum/química , Nefropatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/microbiologia , Microbioma Gastrointestinal/efeitos dos fármacos , Polissacarídeos/farmacologia , Animais , Colo/efeitos dos fármacos , Colo/microbiologia , Colo/patologia , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/patologia , Glucose/metabolismo , Inflamação/tratamento farmacológico , Rim/efeitos dos fármacos , Rim/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Polissacarídeos/uso terapêutico
13.
Biomed Pharmacother ; 114: 108801, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30928803

RESUMO

BACKGROUND: Diabetic nephropathy (DN) is one of the most serious and dangerous chronic complications of diabetes mellitus.Panax notoginseng has been widely used with great efficacy in the long-term treatment of kidney disease. However, the mechanism by which it exerts its effects has not been fully elucidated. AIM: We sought to identify the major components ofPanax notoginseng that are effective in reducing the symptoms of DN in vitro and in vivo. METHODS: Inhibition of cell proliferation and collagen secretion were used to screen the ten most highly concentrated components ofPanax notoginseng. The STZ-induced DN rat model on a high-fat-high-glucose diet was used to investigate the renal protective effect of Panax notoginseng and dencichine and their underlying molecular mechanisms. RESULTS: Among the ten components analysed, dencichine (ß-N-oxalyl-L-α,ß-diaminopropionic acid) was the most protective against DN. Dencichine andPanax notoginseng attenuated glucose and lipid metabolic disorders in STZ-induced DN rats on a high-fat-high-glucose diet. In the untreated DN rats, we observed albuminuria, renal failure, and pathological changes. However, treatment with dencichine and Panax notoginseng alleviated these symptoms. We also observed that dencichine suppressed the expression of TGF-ß1 and Smad2/3, which mediates mesangial cell proliferation and extracellular matrix (ECM) accumulation in the glomerulus, and enhanced the expression of Smad7, the endogenous inhibitor of the TGF-ß1/Smad signalling pathway. CONCLUSION: From these results, we concluded that dencichine is the main compound inPanax notoginseng that is responsible for alleviating renal injury in the experimental DN model. Its mechanism may be related to the reduction of the deposition of ECM in glomeruli and inhibition of the epithelial mesenchymal transformation (EMT) by inhibition of the TGF-ß1/Smad signalling pathway.


Assuntos
Diamino Aminoácidos/farmacologia , Diabetes Mellitus Tipo 2/complicações , Nefropatias Diabéticas/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Cinuramina/farmacologia , Panax notoginseng/química , Animais , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Nefropatias Diabéticas/metabolismo , Matriz Extracelular/efeitos dos fármacos , Rim/efeitos dos fármacos , Rim/metabolismo , Masculino , Ratos , Ratos Sprague-Dawley , Transdução de Sinais , Proteínas Smad/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , beta-Alanina/análogos & derivados , beta-Alanina/farmacologia
14.
J Korean Med Sci ; 34(15): e117, 2019 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-31001934

RESUMO

BACKGROUND: Removal of uremic toxins such as indoxyl sulfate by AST-120 is known to improve renal function and delay the initiation of dialysis in patients with advanced chronic kidney disease. However, it is unclear whether the addition of AST-120 to conventional treatments is effective in delaying the progression of renal dysfunction in patients with diabetic nephropathy. METHODS: A total of 100 patients with type 2 diabetes and renal dysfunction (serum creatinine levels ranging from 1.5 to 3.0 mg/dL) were recruited from eight centers in Korea and treated with AST-120 (6 g/day) for 24 weeks. The primary endpoint was improvement in renal function measured as the gradient of the reciprocal serum creatinine level (1/sCr) over time (i.e., the ratio of 1/sCr time slope for post- to pre-AST-120 therapy). A response was defined as a ratio change of the regression coefficient of 1/sCr ≤ 0.90. RESULTS: Renal function improved in 80.3% of patients (61/76) after 24 weeks of AST-120 treatment. There were no differences between responder and non-responder groups in baseline characteristics except for diastolic blood pressure (73.5 ± 9.5 mmHg in the responder group vs. 79.3 ± 11.1 mmHg in the non-responder group; P = 0.046). Serum lipid peroxidation level decreased significantly in the responder group (from 2.25 ± 0.56 µol/L to 1.91 ± 0.72 µol/L; P = 0.002) but not in the non-responder group. CONCLUSION: The addition of AST-120 to conventional treatments may delay the progression of renal dysfunction in diabetic nephropathy. The antioxidant effect of AST-120 might contribute to improvement in renal function.


Assuntos
Carbono/uso terapêutico , Nefropatias Diabéticas/tratamento farmacológico , Óxidos/uso terapêutico , Substâncias Protetoras/uso terapêutico , Idoso , Pressão Sanguínea , Creatinina/sangue , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/patologia , Nefropatias Diabéticas/complicações , Nefropatias Diabéticas/patologia , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Humanos , Peroxidação de Lipídeos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Índice de Gravidade de Doença , Resultado do Tratamento
15.
BMC Complement Altern Med ; 19(1): 81, 2019 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-30943956

RESUMO

BACKGROUND: Diabetic nephropathy (DN) is a common complication of diabetes mellitus (DM) that imposes an enormous burden on the healthcare system. Although some studies show that traditional Chinese medicine (TCM) treatments confer a protective effect on DN, the long-term impact remains unclear. This study aims to examine end-stage renal disease (ESRD) and mortality rates among TCM users with DN. METHODS: A total of 125,490 patients with incident DN patients from 2004 to 2006 were identified from the National Health Insurance Research Database in Taiwan and followed until 2012. The landmark method was applied to avoid immortal time bias, and propensity score matching was used to select 1:1 baseline characteristics-matched cohort. The Kaplan-Meier method and competing-risk analysis were used to assess mortality and ESRD rates separately. RESULTS: Among all eligible subjects, about 60% of patients were classified as TCM users (65,812 TCM users and 41,482 nonusers). After 1:1 matching, the outcomes of 68,882 patients were analyzed. For the ESRD rate, the 8-year cumulative incidence was 14.5% for TCM users [95% confidence interval (CI): 13.9-15.0] and 16.6% for nonusers (95% CI: 16.0-17.2). For the mortality rate, the 8-year cumulative incidence was 33.8% for TCM users (95% CI: 33.1-34.6) and 49.2% for nonusers (95% CI: 48.5-49.9). After adjusting for confounding covariates, the cause-specific hazard ratio of ESRD was 0.81 (95% CI: 0.78-0.84), and the hazard ratio of mortality for TCM users was 0.48 (95% CI: 0.47-0.50). The cumulative incidence of mortality increased rapidly among TCM users with ESRD (56.8, 95% CI: 54.6-59.1) when compared with TCM users without ESRD (30.1, 95% CI: 29.4-30.9). In addition, TCM users who used TCM longer or initiated TCM treatments after being diagnosed with DN were associated with a lower risk of mortality. These results were consistent across sensitivity tests with different definitions of TCM users and inverse probability weighting of subjects. CONCLUSIONS: The lower ESRD and mortality rates among patients with incident DN correlates with the use of TCM treatments. Further studies about specific TCM modalities or medications for DN are still needed.


Assuntos
Nefropatias Diabéticas , Medicamentos de Ervas Chinesas/uso terapêutico , Falência Renal Crônica , Adulto , Estudos Transversais , Nefropatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/epidemiologia , Nefropatias Diabéticas/mortalidade , Feminino , Humanos , Estimativa de Kaplan-Meier , Falência Renal Crônica/tratamento farmacológico , Falência Renal Crônica/epidemiologia , Falência Renal Crônica/mortalidade , Masculino , Medicina Tradicional Chinesa , Pessoa de Meia-Idade , Taiwan/epidemiologia , Adulto Jovem
16.
Biomed Res Int ; 2019: 5280514, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31032350

RESUMO

The study aims to investigate the effects of the alcohol extract of Coreopsis tinctoria Nutt (AC) on diabetic nephropathy (DN) mice. A total of 30 db/db (DN) mice were divided into 3 groups, which were treated with AC (300 mg/kg/day), metformin (180 mg/kg/day), or saline by gavage for 10 weeks. Ten db/m mice treated with saline were used as normal control (NC group). Body weight (BW) and fasting blood glucose (FBG), HbA1c, 24 h urinary albumin excretion (UAE), and renal pathological fibrosis were analyzed. Expression of miR-192, miR-200b, and proteins in the PTEN/PI3K/AKT pathway was analyzed by qPCR or western blot. The DN mice had significantly higher BW, FBG, and 24 h UAE, as well as more severe pathological fibrosis when compared with NC. Treatment of AC could decrease BW, FBG, and 24 h UAE and alleviated kidney damage. Compared with the NC group, expressions of miR-192 and miR-200b were increased, whereas their target proteins (ZEB2 and PTEN) were reduced in the kidneys of DN mice, which further modulated the expression of their downstream proteins PI3K p85α, P-AKT, P-smad3, and COL4 α1; these proteins were increased in the kidneys of DN mice. In contrast, AC treatment reversed the expression changes of these proteins. These findings demonstrate that AC may protect the kidneys of DN mice by decreasing miR-192 and miR-200b, which could further regulate their target gene expression and modulate the activity of the PTEN/PI3K/AKT pathway to reduce the degree of renal fibrosis.


Assuntos
Coreopsis/química , Diabetes Mellitus/tratamento farmacológico , Nefropatias Diabéticas/tratamento farmacológico , MicroRNAs/genética , Albuminúria/urina , Álcoois/química , Animais , Glicemia/isolamento & purificação , Diabetes Mellitus/genética , Diabetes Mellitus/patologia , Diabetes Mellitus/urina , Nefropatias Diabéticas/genética , Nefropatias Diabéticas/patologia , Nefropatias Diabéticas/urina , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Hemoglobina A Glicada/isolamento & purificação , Humanos , Rim/efeitos dos fármacos , Rim/fisiologia , Camundongos , Camundongos Endogâmicos NOD , PTEN Fosfo-Hidrolase/genética , Extratos Vegetais/administração & dosagem , Extratos Vegetais/química , Proteínas Proto-Oncogênicas c-akt/genética , Transdução de Sinais/efeitos dos fármacos , Homeobox 2 de Ligação a E-box com Dedos de Zinco/genética
17.
N Engl J Med ; 380(24): 2295-2306, 2019 06 13.
Artigo em Inglês | MEDLINE | ID: mdl-30990260

RESUMO

BACKGROUND: Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium-glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS: In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to <90 ml per minute per 1.73 m2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], >300 to 5000) and were treated with renin-angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73 m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS: The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P = 0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P<0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P = 0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P = 0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS: In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years. (Funded by Janssen Research and Development; CREDENCE ClinicalTrials.gov number, NCT02065791.).


Assuntos
Canagliflozina/uso terapêutico , Doenças Cardiovasculares/prevenção & controle , Diabetes Mellitus Tipo 2/tratamento farmacológico , Nefropatias Diabéticas/tratamento farmacológico , Falência Renal Crônica/prevenção & controle , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Idoso , Canagliflozina/efeitos adversos , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/mortalidade , Creatinina/sangue , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Nefropatias Diabéticas/complicações , Método Duplo-Cego , Feminino , Seguimentos , Taxa de Filtração Glomerular , Humanos , Falência Renal Crônica/epidemiologia , Masculino , Pessoa de Meia-Idade , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos
18.
Molecules ; 24(7)2019 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-30925713

RESUMO

Previous studies have shown that accumulation of advanced glycation end products (AGEs) can be the cause of diabetic nephropathy (DN) in diabetic patients. Dihydrochalcone 3'-O-ß-d-glucopyranosyl α,4,2',4',6'-pentahydroxy⁻dihydrochalcone (1) is a powerful antiglycation compound previously isolated from Eysenhardtia polystachya. The aim was to investigate whether (1) was able to protect against diabetic nephropathy in streptozotocin (STZ)-induced diabetic mice, which displayed renal dysfunction markers such as body weight, creatinine, uric acid, serum urea, total urinary protein, and urea nitrogen in the blood (BUN). In addition, pathological changes were evaluated including glycated hemoglobin (HbA1c), advanced glycation end products (AGEs) in the kidney, as well as in circulation level and pro-inflammatory markers ICAM-1 levels in diabetic mice. After 5 weeks, these elevated markers of dihydrochalcone treatment (25, 50 and 100 mg/kg) were significantly (p < 0.05) attenuated. In addition, they ameliorate the indices of renal inflammation as indicated by ICAM-1 markers. The kidney and circulatory AGEs levels in diabetic mice were significantly (p < 0.05) attenuated by (1) treatment. Histological analysis of kidney tissues showed an important recovery in its structure compared with the diabetic group. It was found that the compound (1) attenuated the renal damage in diabetic mice by inhibiting AGEs formation.


Assuntos
Chalconas/uso terapêutico , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/tratamento farmacológico , Nefropatias Diabéticas/sangue , Nefropatias Diabéticas/tratamento farmacológico , Fabaceae/química , Produtos Finais de Glicação Avançada/sangue , Casca de Planta/química , Animais , Biomarcadores/metabolismo , Peso Corporal/efeitos dos fármacos , Chalconas/síntese química , Chalconas/química , Chalconas/farmacologia , Creatinina/sangue , Nefropatias Diabéticas/patologia , Ingestão de Líquidos , Comportamento Alimentar , Glucose/metabolismo , Hemoglobina A Glicada/metabolismo , Mediadores da Inflamação/metabolismo , Rim/efeitos dos fármacos , Rim/patologia , Masculino , Camundongos Endogâmicos C57BL , Niacinamida , Tamanho do Órgão/efeitos dos fármacos , Ratos , Estreptozocina , Ureia/sangue , Ácido Úrico/sangue , Urina
19.
Expert Opin Investig Drugs ; 28(4): 377-388, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30848158

RESUMO

INTRODUCTION: DPP-4 inhibitors have pleomorphic effects that extend beyond the anti-hyperglycemic labeled use of the drug. DPP-4 inhibitors have demonstrated promising renal protective effects in T2DM and T1DM and protective effects against immune destruction of pancreatic beta-cells in T1DM. AREAS COVERED: The efficacy of DPP-4 inhibitors in the treatment of diabetic kidney disease and possible adjunct with insulin in the treatment of T1DM to preserve beta-cell function. Pertinent literature was identified through Medline, PubMed and ClinicalTrials.gov (1997-November 2018) using the search terms T1DM, sitagliptin, vildagliptin, linagliptin, beta-cell function, diabetic nephropathy. Only articles are written in the English language, and clinical trials evaluating human subjects were used. EXPERT OPINION: DPP-4 inhibitors can be used safely in patients with diabetic kidney disease and do not appear to exacerbate existing diabetic nephropathy. Linagliptin reduces albuminuria and protects renal endothelium from the deleterious effects of hyperglycemia. The effects of DPP-4 inhibitors on preserving beta-cell function in certain subtypes of T1DM [e.g. Latent Autoimmune Diabetes in Adult (LADA) and Slowly Progressive Type 1 Diabetes (SPIDDM)] are encouraging and show promise.


Assuntos
Diabetes Mellitus Tipo 1/tratamento farmacológico , Nefropatias Diabéticas/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/farmacologia , Animais , Diabetes Mellitus Tipo 1/enzimologia , Diabetes Mellitus Tipo 1/fisiopatologia , Nefropatias Diabéticas/enzimologia , Nefropatias Diabéticas/fisiopatologia , Inibidores da Dipeptidil Peptidase IV/administração & dosagem , Humanos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/farmacologia , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo
20.
Nephrology (Carlton) ; 24(5): 497-503, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30848004

RESUMO

Beta2-adrenergic receptor (ß2 -AR) is a G-protein-coupled adrenergic receptor family member, whose clinical significance has been extensively investigated in lung, cardiovascular and muscular diseases, but its role in kidney biology remains understudied. In this review, we discuss some of the recent studies, where the effect of agonist/antagonist-mediated activation/inhibition of ß2 -AR on disease pathogenesis process was studied, and highlighted the role of ß2 -AR in kidney biology. The expression of ß2 -AR has been noted in many kidney subunits including proximal tubules, glomeruli and podocytes. In vivo studies have shown that in cultured proximal tubules ß2 -AR is involved in Na-ATPase activity and transcellular Na-transport through protein kinase-C activation; whereas in cultured podocytes, it was associated with depolarization of the membrane. The animal studies further revealed that ß2 -AR activation by short-acting ß2 agonists attenuated monocyte activation, pro-inflammatory and pro-fibrotic responses through ß-arrestin2 dependent NF-kB inactivation in diabetic kidney disease; in contrast, activation by long-acting ß2 agonists restored mitochondrial and renal function in the acute kidney injury mice models through PGC-1α dependent mitochondrial biogenesis. In conclusion, the activation of ß2 -AR may present a rapidly developing therapeutic target for renal diseases.


Assuntos
Lesão Renal Aguda/metabolismo , Nefropatias Diabéticas/metabolismo , Rim/metabolismo , Receptores Adrenérgicos beta 2/metabolismo , Lesão Renal Aguda/tratamento farmacológico , Lesão Renal Aguda/patologia , Lesão Renal Aguda/fisiopatologia , Agonistas de Receptores Adrenérgicos beta 2/uso terapêutico , Animais , Nefropatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/patologia , Nefropatias Diabéticas/fisiopatologia , Humanos , Rim/efeitos dos fármacos , Rim/patologia , Rim/fisiopatologia , Receptores Adrenérgicos beta 2/efeitos dos fármacos , Fármacos Renais/uso terapêutico , Transdução de Sinais
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