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1.
Zhongguo Ying Yong Sheng Li Xue Za Zhi ; 36(3): 207-210, 2020 May.
Artigo em Chinês | MEDLINE | ID: mdl-32981273

RESUMO

Objective: To observe the protective effects of exogenous spermine on renal fibrosis induced by diabetic nephropathy (DN) and to explore its mechanism.Methods: Twenty-four male C57 mice were randomly divided into control group, type 1 diabetes group (TID) and spermine pretreatment group (TID+Sp, n=8 in each group). TID mice were induced by STZ (60 mg/kg), and TID+Sp mice were pretreated with spermine (5 mg/(kg·d)) for 2 weeks before STZ injection. The mice were killed at the 12th week. The renal function was determined by serum creatinine and urea nitrogen. HE, PAS and Masson staining were used to evaluate renal tissue injury and fibrosis. The expressions of matrix metalloproteinase (MMP-2, MMP-9) and collagen IV (Coll-IV) in the kidney of mice were detected by Western blot. Results: Compared with the control group, the blood glucose (5.67±0.22 vs 28.40±0.57 mmol/L), creatinine (14.33±1.22 vs 30.67±4.73 µmol/L) and urea nitrogen (6.93±4.94 vs 22.00±1.04 mmol/L) in the T1D group were increased significantly (P<0.05), the glomerular basement membrane was thickened, the collagen was significantly increased, the expressions of MMP-2, MMP-9 and Coll-IV protein were increased (0.57±0.07 vs 1.06±0.20, 47.00±0.04 vs 1.29±0.09 and 0.42±0.16 vs 0.95±0.18,P<0.05). Exogenous spermine significantly alleviates the above-mentioned changes. Conclusion: Exogenous spermine pretreatment could significantly alleviate renal fibrosis in diabetic mice by regulating the balance between MMPs and collagen.


Assuntos
Diabetes Mellitus Experimental , Nefropatias Diabéticas , Espermina , Animais , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/patologia , Nefropatias Diabéticas/complicações , Nefropatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/patologia , Nefropatias Diabéticas/prevenção & controle , Fibrose/tratamento farmacológico , Regulação da Expressão Gênica/efeitos dos fármacos , Rim/patologia , Masculino , Camundongos , Distribuição Aleatória , Espermina/farmacologia , Espermina/uso terapêutico
2.
Life Sci ; 260: 118339, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-32841660

RESUMO

AIMS: To design and screen a potent GLP-1/GIP/Gcg receptors triagonist with therapeutic potential in rodent animals with diabetes and obesity. MAIN METHODS: First, we obtained a 12-mer dual GIP/Gcg receptor agonist from a large combinatorial peptide library via high-throughput screening technique and then fused to the Exendin (9-39) to generate a potent GLP-1/GIP/Gcg triagonist. Further site fatty chain modification was performed to improve the druggability via enhancing in vivo stability and cyclic half-life. In vitro signaling and functional assays in cell lines expressing each receptor and in vivo efficacy evaluation in rodent model animals with hyperglycemia and obesity were all carefully performed. KEY FINDINGS: We screened and obtained a potent GLP-1/GIP/Gcg triagonist, termed XFL0, which promotes in vitro GLP-1, GIP, Gcg receptor activation comparable to native GLP-1, GIP and glucagon, respectively. Site-specific fatty acid modification significantly enhanced plasma stability of XFL0 and exhibited no obvious impact on receptor activation. The selected XFL0 conjugates termed XFL6, showed glucose-dependent insulin secretion and improved glucose tolerance by acting on all GLP-1, GIP and Gcg receptors in gene-deficient mice of which the effects were all significantly greater than any single receptor agonist. After chronic treatment in rodent animals with diabetes and obesity, XFL6 potently decreased body weight and food intake, ameliorated the hyperglycemia and hemoglobin A1c levels as well as the lipid metabolism and diabetic nephropathy related disorders. SIGNIFICANCE: XFL6, as a novel GLP-1/GIP/Gcg receptor triagonist, held potential to deliver outstanding improvement in correcting hyperglycemia, obesity and diabetic nephropathy.


Assuntos
Nefropatias Diabéticas/prevenção & controle , Desenho de Fármacos , Polipeptídeo Inibidor Gástrico/agonistas , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Glucagon/agonistas , Hiperglicemia/prevenção & controle , Obesidade/prevenção & controle , Animais , Diabetes Mellitus Experimental/fisiopatologia , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/patologia , Polipeptídeo Inibidor Gástrico/fisiologia , Glucagon/fisiologia , Receptor do Peptídeo Semelhante ao Glucagon 1/fisiologia , Hiperglicemia/etiologia , Hiperglicemia/metabolismo , Hiperglicemia/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Obesidade/etiologia , Obesidade/metabolismo , Obesidade/patologia
3.
Nutr Metab Cardiovasc Dis ; 30(10): 1622-1632, 2020 09 24.
Artigo em Inglês | MEDLINE | ID: mdl-32631704

RESUMO

AIMS: Sodium-glucose co-transporter-2 inhibitors (SGLT2i) have been proven to lead to relevant cardiovascular benefits, regardless of glycemic control function. SGLT2i have on the one hand led to reduction in cardiovascular events such as heart failure and on the other hand to renal protection. Blood pressure reduction and kidney function play a central role in these outcomes. This focused review describes the main mechanisms and clinical aspects of SGLT2i. DATA SYNTHESIS: These drugs act on the proximal renal tubule and behave as diuretics with a "hybrid" mechanism, as they can favour both natriuresis and enhanced diuresis due to an osmotic effect dependent on glycosuria, resulting in blood pressure decrease. The exclusive peculiarity of these "diuretics", which distinguishes them from loop and thiazide diuretics, lies also in the activation of the tubule-glomerular feedback. CONCLUSIONS: This mechanism, resulting in modulation of arterioles' tone and renin secretion, contributes to the favorable outcomes, suggesting a wider use of SGLT2i in internal medicine, nephrology and cardiology.


Assuntos
Glicemia/efeitos dos fármacos , Doenças Cardiovasculares/prevenção & controle , Diabetes Mellitus Tipo 2/tratamento farmacológico , Nefropatias Diabéticas/prevenção & controle , Diuréticos/uso terapêutico , Túbulos Renais Proximais/efeitos dos fármacos , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Biomarcadores/sangue , Glicemia/metabolismo , Pressão Sanguínea/efeitos dos fármacos , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/mortalidade , Doenças Cardiovasculares/fisiopatologia , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/mortalidade , Diabetes Mellitus Tipo 2/fisiopatologia , Nefropatias Diabéticas/sangue , Nefropatias Diabéticas/mortalidade , Nefropatias Diabéticas/fisiopatologia , Diuréticos/efeitos adversos , Humanos , Túbulos Renais Proximais/metabolismo , Túbulos Renais Proximais/fisiopatologia , Fatores de Proteção , Fatores de Risco , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos , Resultado do Tratamento
4.
N Engl J Med ; 382(26): 2493-2503, 2020 06 25.
Artigo em Inglês | MEDLINE | ID: mdl-32579810

RESUMO

BACKGROUND: Higher serum urate levels are associated with an increased risk of diabetic kidney disease. Lowering of the serum urate level with allopurinol may slow the decrease in the glomerular filtration rate (GFR) in persons with type 1 diabetes and early-to-moderate diabetic kidney disease. METHODS: In a double-blind trial, we randomly assigned participants with type 1 diabetes, a serum urate level of at least 4.5 mg per deciliter, an estimated GFR of 40.0 to 99.9 ml per minute per 1.73 m2 of body-surface area, and evidence of diabetic kidney disease to receive allopurinol or placebo. The primary outcome was the baseline-adjusted GFR, as measured with iohexol, after 3 years plus a 2-month washout period. Secondary outcomes included the decrease in the iohexol-based GFR per year and the urinary albumin excretion rate after washout. Safety was also assessed. RESULTS: A total of 267 patients were assigned to receive allopurinol and 263 to receive placebo. The mean age was 51.1 years, the mean duration of diabetes 34.6 years, and the mean glycated hemoglobin level 8.2%. The mean baseline iohexol-based GFR was 68.7 ml per minute per 1.73 m2 in the allopurinol group and 67.3 ml per minute per 1.73 m2 in the placebo group. During the intervention period, the mean serum urate level decreased from 6.1 to 3.9 mg per deciliter with allopurinol and remained at 6.1 mg per deciliter with placebo. After washout, the between-group difference in the mean iohexol-based GFR was 0.001 ml per minute per 1.73 m2 (95% confidence interval [CI], -1.9 to 1.9; P = 0.99). The mean decrease in the iohexol-based GFR was -3.0 ml per minute per 1.73 m2 per year with allopurinol and -2.5 ml per minute per 1.73 m2 per year with placebo (between-group difference, -0.6 ml per minute per 1.73 m2 per year; 95% CI, -1.5 to 0.4). The mean urinary albumin excretion rate after washout was 40% (95% CI, 0 to 80) higher with allopurinol than with placebo. The frequency of serious adverse events was similar in the two groups. CONCLUSIONS: We found no evidence of clinically meaningful benefits of serum urate reduction with allopurinol on kidney outcomes among patients with type 1 diabetes and early-to-moderate diabetic kidney disease. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; PERL ClinicalTrials.gov number, NCT02017171.).


Assuntos
Alopurinol/uso terapêutico , Diabetes Mellitus Tipo 1/tratamento farmacológico , Nefropatias Diabéticas/prevenção & controle , Inibidores Enzimáticos/uso terapêutico , Taxa de Filtração Glomerular/efeitos dos fármacos , Ácido Úrico/sangue , Xantina Oxidase/antagonistas & inibidores , Adulto , Idoso , Alopurinol/efeitos adversos , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/fisiopatologia , Método Duplo-Cego , Inibidores Enzimáticos/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Sistema Renina-Angiotensina , Falha de Tratamento
5.
Cardiovasc Diabetol ; 19(1): 98, 2020 06 26.
Artigo em Inglês | MEDLINE | ID: mdl-32590982

RESUMO

Sodium/glucose cotransporter-2 inhibitors (SGLT2i) are a new type of glucose-lowering drug that can reduce blood glucose by inhibiting its reabsorption in proximal tubules and by promoting urinary glucose excretion. SGLT2i are widely used in the clinical treatment of type 2 diabetes mellitus (T2DM). In recent studies, SGLT2i were found to not only reduce blood glucose but also protect the heart and kidney, which can significantly reduce cardiovascular events, delay the progression of renal failure, greatly improve the quality of life of patients, and reduce medical expenses for families and society. As adverse cardiac and renal events are the most common and serious complications of T2DM, it is very important to understand the cardio- and renoprotective mechanisms of SGLT2i. This article reviews the historical development, pharmacological mechanism, heart and kidney protection and safety of SGLT2i. The information presented provides a theoretical basis for the clinical prevention and treatment of diabetes and its complications and for the development of new glucose-lowering drugs.


Assuntos
Glicemia/efeitos dos fármacos , Doenças Cardiovasculares/prevenção & controle , Sistema Cardiovascular/efeitos dos fármacos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Nefropatias Diabéticas/prevenção & controle , Rim/efeitos dos fármacos , Insuficiência Renal/prevenção & controle , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Animais , Biomarcadores/sangue , Glicemia/metabolismo , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/fisiopatologia , Sistema Cardiovascular/fisiopatologia , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/epidemiologia , Nefropatias Diabéticas/diagnóstico , Nefropatias Diabéticas/epidemiologia , Nefropatias Diabéticas/fisiopatologia , Regulação para Baixo , Humanos , Rim/fisiopatologia , Insuficiência Renal/diagnóstico , Insuficiência Renal/epidemiologia , Insuficiência Renal/fisiopatologia , Medição de Risco , Fatores de Risco , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos , Resultado do Tratamento
6.
Life Sci ; 255: 117779, 2020 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-32417374

RESUMO

OBJECTIVE: Kidney is the most common location of microangiopathy in diabetic patients, and we designed this study to investigate the effects of hirudin on renal microangiopathy in STZ-induced diabetes rats and in vitro. METHODS: We established a diabetes model by intraperitoneal injection of STZ and administered hirudin daily by subcutaneous injection. HE staining was used to assess kidney pathological changes. Western blot and immunochemistry was used to detect the protein expression. Glomerular endothelial cells (GEC) in normal rats were assessed by cell scratch test for migration ability and tubule formation experiment for angiogenesis ability. RESULTS: Compared with DN rats without any treatment, the serum creatinine, serum Cys C, 24-hour urine protein of DN rats with hirudin treatment were significantly decrease, the kidney/body weight and glomerular area of DN rats with hirudin treatment were all significantly decrease, and also significant improvement in renal pathology revealed by HE staining in DN rats after treating with hirudin. Moreover, we also found that hirudin coun not only significantly increase the prothrombin time and aivated partial thromboplastin time in DN rats, but also significantly decrease the expression of VEGF and TM-1 protein in kidney tissues of DN rats. In vitro, we found that high glucose could promote the migration and angiogensis of GEC, and significantly increased the expression of VEGF and Ang protein, but significantly decreased the expression of THBS1 and Arg1 protein. More importantly was that hirudin could inhibit the migration and angiogensis of GEC, and reversed HG-induced the expression of VEGF, Ang, THBS1 and Arg1 protein in GEC. In addition, we also found that hirudin could not only decrease HG-enhanced the activity of RhoA in GEC, but also decrease HG-enhanced the expression of p-MYPT1/MYPT1, p-p38/p38 protein in GEC. CONCLUSION: Hirudin reduces nephropathy microangiopathy in STZ-induced diabetes, and might be related to hirudin inhibiting glomerular endothelial cell migration and angiogenesis through Rho-kinase and subsequent p38MAPK/NF-kB signaling pathway.


Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Angiopatias Diabéticas/prevenção & controle , Nefropatias Diabéticas/prevenção & controle , Hirudinas/farmacologia , Neovascularização Patológica/prevenção & controle , Animais , Movimento Celular/efeitos dos fármacos , Diabetes Mellitus Experimental/complicações , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Feminino , Glucose/metabolismo , Glomérulos Renais/metabolismo , Masculino , NF-kappa B/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Quinases Associadas a rho/metabolismo
7.
Am J Physiol Renal Physiol ; 318(5): F1295-F1305, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32249614

RESUMO

Podocyte loss and proteinuria are both key features of human diabetic nephropathy (DN). The leptin-deficient BTBR mouse strain with the ob/ob mutation develops progressive weight gain, type 2 diabetes, and diabetic nephropathy that has many features of advanced human DN, including increased mesangial matrix, mesangiolysis, podocyte loss, and proteinuria. Selective antagonism of the endothelin-1 type A receptor (ETAR) by atrasentan treatment in combination with renin-angiotensin-aldosterone system inhibition with losartan has been shown to have the therapeutic benefit of lowering proteinuria in patients with DN, but the underlying mechanism for this benefit is not well understood. Using a similar therapeutic approach in diabetic BTBR ob/ob mice, this treatment regimen significantly increased glomerular podocyte number compared with diabetic BTBR ob/ob controls and suggested that parietal epithelial cells were a source for podocyte restoration. Atrasentan treatment alone also increased podocyte number but to a lesser degree. Mice treated with atrasentan demonstrated a reduction in proteinuria, matching the functional improvement reported in humans. This is a first demonstration that treatment with the highly selective ETAR antagonist atrasentan can lead to restoration of the diminished podocyte number characteristic of DN in humans and thereby underlies the reduction in proteinuria in patients with diabetes undergoing similar treatment. The benefit of ETAR antagonism in DN extended to a decrease in mesangial matrix as measured by a reduction in accumulations of collagen type IV in both the atrasentan and atrasentan + losartan-treated groups compared with untreated controls.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Atrasentana/farmacologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Nefropatias Diabéticas/prevenção & controle , Antagonistas do Receptor de Endotelina A/farmacologia , Losartan/farmacologia , Podócitos/efeitos dos fármacos , Sistema Renina-Angiotensina/efeitos dos fármacos , Animais , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/patologia , Modelos Animais de Doenças , Quimioterapia Combinada , Feminino , Camundongos , Fosforilação , Podócitos/metabolismo , Podócitos/patologia , Proteinúria/metabolismo , Proteinúria/patologia , Proteinúria/prevenção & controle , Proteínas Quinases S6 Ribossômicas/metabolismo , Serina-Treonina Quinases TOR/metabolismo
8.
Diabetes Res Clin Pract ; 162: 108112, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32198123

RESUMO

Large cardiovascular outcome trials (CVOTs) have lent support to a cardiovascular protection with the use of SGLT2-inhibitors (SGLT2is) and GLP1-Receptor Agonists (GLP1-RAs) in subjects with type 2 diabetes. These two classes of novel glucose lowering agents have been shown to have a similar effect on the risk reduction of Major Adverse Cardiovascular Events (MACE: nonfatal myocardial infarction, nonfatal stroke, cardiovascular mortality). Nonetheless, they may not be simply interchangeable. Rather, careful evaluation of all the results of CVOTs leads identification of different effects that may allow profiling of the ideal individuals with T2DM who may benefit most from the use of one or the other class of agents. These differences include effect on heart failure, stroke and diabetic kidney disease that have prompt recent guidelines and recommendation for the treatment of type 2 diabetes to suggest the preferential use of SGLT2is in those with evidence of heart failure and impaired kidney function, while both SGLT2i and GLP1-RAs with proven effect could be use in those with prevalent atherosclerotic cardiovascular disease. This review discusses all these elements of differentiation along with others that in the future may help establishing the best cardiorenal benefit for individuals with T2DM.


Assuntos
Doenças Cardiovasculares/prevenção & controle , Diabetes Mellitus Tipo 2/tratamento farmacológico , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Hipoglicemiantes/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Aterosclerose/prevenção & controle , Diabetes Mellitus Tipo 2/mortalidade , Nefropatias Diabéticas/prevenção & controle , Insuficiência Cardíaca/prevenção & controle , Humanos , Hipoglicemiantes/farmacologia , Infarto do Miocárdio , Comportamento de Redução do Risco , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia
9.
Am J Physiol Renal Physiol ; 318(4): F1017-F1029, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32116017

RESUMO

Diabetic kidney disease is a worldwide epidemic, and therapies are incomplete. Clinical data suggest that improved renal outcomes by Na+-glucose cotransporter 2 inhibitor (SGLT2i) are partly beyond their antihyperglycemic effects; however, the mechanisms are still elusive. Here, we investigated the effect of the SGLT2i dapagliflozin (DAPA) in the prevention of elevated O-GlcNAcylation and tubular hypoxia as contributors of renal fibrosis. Type 1 diabetes was induced by streptozotocin in adult male Wistar rats. After the onset of diabetes, rats were treated for 6 wk with DAPA or DAPA combined with losartan (LOS). The effect of hyperglycemia was tested in HK-2 cells kept under normal or high glucose conditions. To test the effect of hypoxia, cells were kept in 1% O2 for 2 h. Cells were treated with DAPA or DAPA combined with LOS. DAPA slowed the loss of renal function, mitigated renal tubular injury markers (kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin), and reduced tubulointerstitial fibrosis. DAPA diminished high glucose-induced protein O-GlcNAcylation and moderated the tubular response to hypoxia through the hypoxia-inducible factor pathway. DAPA alone was as effective as combined treatment with LOS in all outcome parameters. These data highlight the role of ameliorated O-GlcNAcylation and diminished tubular hypoxia as important benefits of SGLT2i treatment. Our results support the link between glucose toxicity, tubular hypoxia, and fibrosis, a vicious trio that could be targeted by SGLT2i in kidney diseases of other origins as well.


Assuntos
Compostos Benzidrílicos/farmacologia , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 1/tratamento farmacológico , Nefropatias Diabéticas/prevenção & controle , Glucosídeos/farmacologia , Glicosilação/efeitos dos fármacos , Túbulos Renais Proximais/efeitos dos fármacos , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Animais , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Hipóxia Celular , Linhagem Celular , Colágeno/metabolismo , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 1/induzido quimicamente , Diabetes Mellitus Tipo 1/metabolismo , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/patologia , Fibronectinas/metabolismo , Fibrose , Humanos , Túbulos Renais Proximais/metabolismo , Túbulos Renais Proximais/patologia , Masculino , Ratos Wistar , Estreptozocina
10.
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
11.
Intern Med ; 59(5): 601-609, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32115517

RESUMO

Objective To examine the add-on effects, compared to the existing antidiabetes treatment, of the sodium-glucose cotransporter 2 inhibitor ipragliflozin on glycemic control and the risk factors of cardiovascular disease (CVD) and chronic kidney disease (CKD) in patients with inadequately controlled type 2 diabetes. Methods This 12-week, randomized, open-label, active-controlled trial included 30 patients with type 2 diabetes who were randomized 1:1 to ipragliflozin and control groups (n=15 each). The ipragliflozin group received 50 mg of ipragliflozin once daily in addition to conventional therapy. The primary outcome was the change in hemoglobin A1c (HbA1c) from the baseline. Secondary outcomes were changes from the baseline in indices of glycemic control, uric acid (UA), renal function, and arterial stiffness. Results The patients' diminished estimated glomerular filtration rate (eGFR) was alleviated in the ipragliflozin group compared to the control group [difference between groups (Δ) =4.6 (95% confidence interval (CI): 1.5-7.7) mL/min/1.73 m2, p=0.006] prior to significant improvements in HbA1c and other parameters, including anthropometric indices and arterial stiffness. Furthermore, ipragliflozin add-on therapy resulted in a greater reduction in serum UA levels than control therapy [Δ=-52.3 (95% CI: -85.5-19.1) µmol/L, p=0.003]. The changes in the eGFR with ipragliflozin treatment were associated with ipragliflozin-mediated changes in the UA, even after adjusting for the age, sex, baseline HbA1c, baseline UA, and baseline eGFR (standardized regression coefficient=-0.535, p=0.010). Conclusion Ipragliflozin add-on therapy was associated with beneficial renal effects in parallel with reducing serum UA levels.


Assuntos
Diabetes Mellitus Tipo 2/prevenção & controle , Glucosídeos/administração & dosagem , Hipoglicemiantes/administração & dosagem , Insuficiência Renal Crônica/prevenção & controle , Inibidores do Transportador 2 de Sódio-Glicose/administração & dosagem , Tiofenos/administração & dosagem , Adulto , Idoso , Glicemia/efeitos dos fármacos , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/fisiopatologia , Angiopatias Diabéticas/sangue , Angiopatias Diabéticas/fisiopatologia , Angiopatias Diabéticas/prevenção & controle , Nefropatias Diabéticas/sangue , Nefropatias Diabéticas/fisiopatologia , Nefropatias Diabéticas/prevenção & controle , Esquema de Medicação , Quimioterapia Combinada , Feminino , Hemoglobina A Glicada/efeitos dos fármacos , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/fisiopatologia , Fatores de Risco , Resultado do Tratamento , Ácido Úrico/metabolismo , Adulto Jovem
12.
Oxid Med Cell Longev ; 2020: 6431517, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32215175

RESUMO

Diabetic kidney disease (DKD) has become the leading cause of end-stage renal disease worldwide. Renal tubular epithelial cell apoptosis and tubular atrophy have been recognized as indicators of the severity and progression of DKD, while the mechanism remains elusive. Tumor necrosis factor receptor-associated protein 1 (TRAP1) plays critical roles in apoptosis. The aim of this study was to investigate the protective role TRAP1 plays in DKD and to study the potential underlying mechanisms. TRAP1 expression was decreased, and mitochondria were injured in NRK-52e cells under high-glucose (HG) conditions. The overexpression of TRAP1 ameliorated HG-induced apoptosis, increased cell viability, maintained mitochondrial morphology, adenosine triphosphate (ATP) levels, and mitochondrial membrane potential (MMP), and buffered oxidative stress, whereas TRAP1 knockdown aggravated these effects. The protective effects of TRAP1 may be exerted via the inhibition of mitochondrial permeability transition pore (mPTP) opening, and the damage caused by TRAP1 knockdown can be partially reversed by treatment with the mPTP opening inhibitor cyclosporin A (CsA). In vivo, TRAP1 expression upregulation by AAV2/9 injection prevented renal dysfunction, ameliorated histopathological changes, maintained mitochondrial morphology and function, and reduced apoptosis and reactive oxygen species (ROS) in STZ-treated DKD rats. Thus, our results suggest that TRAP1 ameliorates diabetes-induced renal injury by preventing abnormal mPTP opening and maintaining mitochondrial structure and function, which may be treated as a potential target for DKD treatment.


Assuntos
Nefropatias Diabéticas/prevenção & controle , Glucose/efeitos adversos , Proteínas de Choque Térmico HSP90/metabolismo , Mitocôndrias/patologia , Proteínas de Transporte da Membrana Mitocondrial/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Apoptose , Linhagem Celular , Sobrevivência Celular , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/patologia , Expressão Gênica , Glucose/metabolismo , Proteínas de Choque Térmico HSP90/genética , Masculino , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Ratos , Ratos Sprague-Dawley
13.
Nephrol Dial Transplant ; 35(Suppl 1): i24-i32, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-32003832

RESUMO

Diabetic kidney disease (DKD) is a common complication of type 1 diabetes (T1D) and a major risk factor for premature death from cardiovascular disease (CVD). Current treatments, such as control of hyperglycaemia and hypertension, are beneficial, but only partially protect against DKD. Finding new, safe and effective therapies to halt nephropathy progression has proven to be challenging. Sodium-glucose cotransporter 2 (SGLT2) inhibitors have demonstrated, in addition to glycaemic lowering, impressive protection against DKD and CVD progression in people with type 2 diabetes. Although these beneficial cardiorenal effects may also apply to people with T1D, supporting data are lacking. Furthermore, the increased rates of euglycaemic diabetic ketoacidosis may limit the use of this class in people with T1D. In this review we highlight the pathophysiology of DKD in T1D and the unmet need that exists. We further detail the beneficial and adverse effects of SGLT2 inhibitors based on their mechanism of action. Finally, we balance the effects in people with T1D and indicate future lines of research.


Assuntos
Diabetes Mellitus Tipo 1/tratamento farmacológico , Nefropatias Diabéticas/prevenção & controle , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Transportador 2 de Glucose-Sódio/química , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/patologia , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/patologia , Humanos , Prognóstico
14.
Nephrol Dial Transplant ; 35(Suppl 1): i13-i23, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-32003834

RESUMO

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have clearly demonstrated their beneficial effect in diabetic kidney disease (DKD) on top of the standard of care [blood glucose control, renin-angiotensin system blockade, smoking cessation and blood pressure (BP) control], even in patients with overt DKD. However, the indication of this drug class is still blood glucose lowering in type 2 diabetic patients with estimated glomerular filtration rate >45 mL/min/1.73 m2. Based on the new evidence, several scientific societies have emphasized the preferential prescription of SGLT2i for patients at risk of heart failure or kidney disease, but still within the limits set by health authorities. A rapid positioning of both the European Medicines Agency and the US Food and Drug Administration will allow patients with overt DKD to benefit from SGLT2i. Clinical experience suggests that SGLT2i safety management may in part mirror renin-angiotensin blockade safety management in patients with overt DKD. This review focuses on the rationale for an indication of SGTL2i in DKD. We further propose clinical steps for maximizing the safety of SGLT2i in DKD patients on other antidiabetic, BP or diuretic medication.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Nefropatias Diabéticas/prevenção & controle , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Transportador 2 de Glucose-Sódio/química , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/patologia , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/patologia , Humanos , Prognóstico
15.
Diabetes ; 69(3): 291-299, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32079705

RESUMO

The results of the Diabetes Control and Complications Trial (DCCT) have given rise to much encouragement in the battle to stave off the complications of type 1 diabetes, showing dramatic declines in the development of severe retinopathy, nephropathy, and neuropathy in those treated intensively compared with conventional therapy. Particularly encouraging has been the continuing difference between the two groups despite both having similar HbA1c (∼8%) since the end of DCCT, when 96% of participants entered the observational Epidemiology of Diabetes Interventions and Complications (EDIC) study. This continuing relative benefit has been termed "metabolic memory," which implies altered metabolic regulation. Based on evidence from both the Epidemiology of Diabetes Complications (EDC) prospective cohort study of childhood-onset type 1 diabetes and DCCT/EDIC, we show that the metabolic memory effect can be largely explained by lower cumulative glycemic exposure in the intensive therapy group, and, on average, the development of complications increases with greater glycemic exposure, irrespective of whether this results from a high exposure for a short time or a lower exposure for a longer time. Thus, there is no need for a concept like "metabolic memory" to explain these observations. Potential mechanisms explaining the cumulative glycemic effect are also briefly discussed.


Assuntos
Glicemia/metabolismo , Complicações do Diabetes/prevenção & controle , Diabetes Mellitus Tipo 1/tratamento farmacológico , Hemoglobina A Glicada/metabolismo , Hipoglicemiantes/uso terapêutico , Insulina/uso terapêutico , Estudos de Coortes , Complicações do Diabetes/metabolismo , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/metabolismo , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/prevenção & controle , Neuropatias Diabéticas/metabolismo , Neuropatias Diabéticas/prevenção & controle , Retinopatia Diabética/metabolismo , Retinopatia Diabética/prevenção & controle , Humanos , Planejamento de Assistência ao Paciente , Estudos Prospectivos , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Tempo
16.
Nephrol Dial Transplant ; 35(2): 274-282, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-32030417

RESUMO

BACKGROUND: Recent cardiovascular outcome trials have shown that sodium-glucose co-transporter 2 (SGLT2) inhibitors slow the progression of chronic kidney disease (CKD) in patients with type 2 diabetes at high cardiovascular risk. Whether these benefits extend to CKD patients without type 2 diabetes or cardiovascular disease is unknown. The Dapagliflozin and Prevention of Adverse Outcomes in CKD (DAPA-CKD) trial (NCT03036150) will assess the effect of the SGLT2 inhibitor dapagliflozin on renal and cardiovascular events in a broad range of patients with CKD with and without diabetes. METHODS: DAPA-CKD is a randomized, double-blind, placebo-controlled, trial in which ∼4300 patients with CKD Stages 2-4 and elevated urinary albumin excretion will be enrolled. The vast majority will be receiving a maximum tolerated dose of a renin-angiotensin system inhibitor at enrolment. RESULTS: After a screening assessment, eligible patients with a urinary albumin:creatinine ratio ≥200 mg/g and estimated glomerular filtration rate (eGFR) between 25 and 75 mL/min/1.73 m2 are randomly assigned to placebo or dapagliflozin 10 mg/day. Enrolment is monitored to ensure that at least 30% of patients do not have diabetes and that no more than 10% have an eGFR >60 mL/min/1.73 m2. The primary endpoint is a composite of a sustained decline in eGFR of ≥50%, end-stage renal disease, renal death or cardiovascular death. The trial will conclude when 681 primary renal events have occurred, providing 90% power to detect a 22% relative risk reduction (α level of 0.05). CONCLUSION: DAPA-CKD will determine whether the SGLT2 inhibitor dapagliflozin, added to guideline-recommended therapies, safely reduces the rate of renal and cardiovascular events in patients across multiple CKD stages with and without diabetes.


Assuntos
Compostos Benzidrílicos/uso terapêutico , Doenças Cardiovasculares/prevenção & controle , Diabetes Mellitus Tipo 2/tratamento farmacológico , Nefropatias Diabéticas/prevenção & controle , Glucosídeos/uso terapêutico , Insuficiência Renal Crônica/prevenção & controle , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/patologia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/patologia , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/patologia , Método Duplo-Cego , Feminino , Taxa de Filtração Glomerular , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Insuficiência Renal Crônica/etiologia , Insuficiência Renal Crônica/patologia , Projetos de Pesquisa , Adulto Jovem
17.
Am J Physiol Renal Physiol ; 318(2): F509-F517, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31904280

RESUMO

Endothelial dysfunction, characterized by reduced bioavailability of nitric oxide and increased oxidative stress, is a hallmark characteristic in diabetes and diabetic nephropathy (DN). High levels of asymmetric dimethylarginine (ADMA) are observed in several diseases including DN and are a strong prognostic marker for cardiovascular events in patients with diabetes and end-stage renal disease. ADMA, an endogenous endothelial nitric oxide synthase (NOS3) inhibitor, is selectively metabolized by dimethylarginine dimethylaminohydrolase (DDAH). Low DDAH levels have been associated with cardiac and renal dysfunction, but its effects on DN are unknown. We hypothesized that enhanced renal DDAH-1 expression would improve DN by reducing ADMA and restoring NOS3 levels. DBA/2J mice injected with multiple low doses of vehicle or streptozotocin were subsequently injected intrarenally with adenovirus expressing DDAH-1 (Ad-h-DDAH-1) or vector control [Ad-green fluorescent protein (GFP)], and mice were followed for 6 wk. Diabetes was associated with increased kidney ADMA and reduced kidney DDAH activity and DDAH-1 expression but had no effect on kidney DDAH-2 expression. Ad-GFP-treated diabetic mice showed significant increases in albuminuria, histological changes, glomerular macrophage recruitment, inflammatory cytokine and fibrotic markers, kidney ADMA levels, and urinary thiobarbituric acid reactive substances excretion as an indicator of oxidative stress, along with a significant reduction in kidney DDAH activity and kidney NOS3 mRNA compared with normal mice. In contrast, Ad-h-DDAH-1 treatment of diabetic mice reversed these effects. These data indicate, for the first time, that DDAH-1 mediates renal tissue protection in DN via the ADMA-NOS3-interaction. Enhanced renal DDAH-1 activity could be a novel therapeutic tool for treating patients with diabetes.


Assuntos
Adenoviridae/genética , Amidoidrolases/biossíntese , Arginina/análogos & derivados , Diabetes Mellitus Experimental/terapia , Nefropatias Diabéticas/prevenção & controle , Terapia Genética , Vetores Genéticos , Rim/enzimologia , Albuminúria/enzimologia , Albuminúria/genética , Albuminúria/prevenção & controle , Amidoidrolases/genética , Animais , Arginina/metabolismo , Citocinas/genética , Citocinas/metabolismo , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/enzimologia , Diabetes Mellitus Experimental/genética , Nefropatias Diabéticas/enzimologia , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/genética , Fibrose , Mediadores da Inflamação/metabolismo , Rim/patologia , Masculino , Camundongos Endogâmicos DBA , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo III/genética , Óxido Nítrico Sintase Tipo III/metabolismo , Estresse Oxidativo , Transdução de Sinais , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismo
18.
Rev Assoc Med Bras (1992) ; 66Suppl 1(Suppl 1): s17-s24, 2020 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-31939531

RESUMO

Type 2 diabetes mellitus is an important public health problem, with a significant impact on cardiovascular morbidity and mortality and an important risk factor for chronic kidney disease. Various hypoglycemic therapies have proved to be beneficial to clinical outcomes, while others have failed to provide an improvement in cardiovascular and renal failure, only reducing blood glucose levels. Recently, sodium-glucose cotransporter-2 (SGLT2) inhibitors, represented by the empagliflozin, dapagliflozin, and canagliflozin, have been showing satisfactory and strong results in several clinical trials, especially regarding the reduction of cardiovascular mortality, reduction of hospitalization due to heart failure, reduction of albuminuria, and long-term maintenance of the glomerular filtration rate. The benefit from SGLT2 inhibitors stems from its main mechanism of action, which occurs in the proximal tubule of the nephron, causing glycosuria, and a consequent increase in natriuresis. This leads to increased sodium intake by the juxtaglomerular apparatus, activating the tubule glomerular-feedback and, finally, reducing intraglomerular hypertension, a frequent physiopathological condition in kidney disease caused by diabetes. In addition, this class of medication presents an appropriate safety profile, and its most frequently reported complication is an increase in the incidence of genital infections. Thus, these hypoglycemic agents gained space in practical recommendations for the management of type 2 diabetes mellitus and should be part of the initial therapeutic approach to provide, in addition to glycemic control, cardiovascular outcomes, and the renoprotection in the long term.


Assuntos
Doenças Cardiovasculares/prevenção & controle , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/farmacologia , Nefropatias/prevenção & controle , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Transportador 2 de Glucose-Sódio/farmacologia , Compostos Benzidrílicos/uso terapêutico , Canagliflozina/uso terapêutico , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/mortalidade , Diabetes Mellitus Tipo 2/complicações , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/prevenção & controle , Taxa de Filtração Glomerular , Glucose/metabolismo , Glucosídeos/uso terapêutico , Humanos , Hipoglicemiantes/uso terapêutico , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/fisiopatologia , Nefropatias/etiologia , Nefropatias/metabolismo , Transportador 2 de Glucose-Sódio/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico
19.
Am J Physiol Endocrinol Metab ; 318(3): E343-E356, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31891537

RESUMO

Diabetic nephropathy (DN) is one of the most important renal complications associated with diabetes, and the mechanisms are yet to be fully understood. To date, few studies have shown the antioxidant effects of 1α,25-dihydroxyvitamin-D3 [1,25(OH)2D3] on hyperglycemia-induced renal injury. The aim of the present study was to explore the potential mechanism by which 1,25(OH)2D3 reduced oxidative stress in diabetic rat kidneys. In this study, we established a vitamin D-deficient spontaneous diabetes model: 5-6 wk of age Zucker diabetic fatty (ZDF) rats were treated with or without 1,25(OH)2D3 for 7 wk, age-matched Zucker lean rats served as control. Results showed that ZDF rats treated with 1,25(OH)2D3 had decreased body mass, food intake, water intake, and urine volume. 1,25(OH)2D3 ameliorated urine glucose, blood glucose and abnormal glucose tolerance. Additionally, 1,25(OH)2D3 significantly lowered microalbuminuria, decreased the glomerular basement membrane thickness, and in some degree inhibited glomerular hypertrophy, mesangial expansion, and tubular dilatation. Furthermore, 1,25(OH)2D3 attenuated renal oxidative damage, as reflected by the levels of malondialdehyde, reduced glutathione, 4-hydroxynonenal, 8-hydroxy-2'-deoxyguanosine, and reactive oxygen species production, and notably inhibited poly(ADP-ribose) polymerase-1 (PARP1), activated sirtuin 1 (SIRT1), and decreased the expression of NADPH oxidase 4 (NOX4). Of interest, the abovementioned proteins could be involved in the antioxidant mechanism of 1,25(OH)2D3 in diabetic rat kidneys. Our study showed that oxidative stress might be a major contributor to DN pathogenesis and uncovered the antioxidant role of 1,25(OH)2D3 in diabetic nephropathy that was associated with the PARP1/SIRT1/ NOX4 pathway.


Assuntos
Calcitriol/farmacologia , Diabetes Mellitus Experimental/metabolismo , Nefropatias Diabéticas/prevenção & controle , NADPH Oxidase 4/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Poli(ADP-Ribose) Polimerase-1/metabolismo , Transdução de Sinais/efeitos dos fármacos , Sirtuína 1/metabolismo , Animais , Peso Corporal/efeitos dos fármacos , Diabetes Mellitus Experimental/genética , Ingestão de Líquidos/efeitos dos fármacos , Ingestão de Alimentos/efeitos dos fármacos , Glucose/metabolismo , Teste de Tolerância a Glucose , Masculino , Ratos , Ratos Zucker , Urodinâmica/efeitos dos fármacos
20.
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
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