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1.
Phytomedicine ; 78: 153314, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32882582

RESUMO

BACKGROUND: Sarsasapogenin (Sar) shows good effects on diabetic nephropathy (DN) through inhibition of the NLRP3 inflammasome, yet the potential mechanism is not well known. PURPOSE: This study was designed to explore the regulation of thrombin and/or its receptor protease-activated receptor 1 (PAR-1) on the NLRP3 inflammasome and NF-κB signaling in DN condition, and further expounded the molecular mechanism of Sar on DN. METHODS: Streptozotocin-induced diabetic rats were treated by gavage with Sar (0, 20 and 60 mg/kg) for consecutive 10 weeks. Then urine and serum were collected for protein excretion, creatinine, urea nitrogen, and uric acid assay reflecting renal functions, renal tissue sections for periodic acid-Schiff staining and ki67 expression reflecting cell proliferation, and renal cortex for the NLRP3 inflammasome and NF-κB signaling as well as thrombin/PAR-1 signaling. High glucose-cultured human mesangial cells (HMCs) were used to further investigate the effects and mechanisms of Sar. RESULTS: Sar markedly ameliorated the renal functions and mesangial cell proliferation in diabetic rats, and suppressed activation of the NLRP3 inflammasome and NF-κB in renal cortex. Moreover, Sar remarkably down-regulated PAR-1 in protein and mRNA levels but didn't affect thrombin activity in kidney, although thrombin activity was significantly decreased in the renal cortex of diabetic rats. Meanwhile, high glucose induced activation of the NLRP3 inflammasome and NF-κB, and increased PAR-1 expression while didn't change thrombin activity in HMCs; however, Sar co-treatment ameliorated all the above indices. Further studies demonstrated that PAR-1 knockdown attenuated activation of the NLRP3 inflammasome and NF-κB, and Sar addition strengthened these effects in high glucose-cultured HMCs. CONCLUSION: Sar relieved DN in rat through inhibition of the NLRP3 inflammasome and NF-κB by down-regulating PAR-1 in kidney.


Assuntos
Nefropatias Diabéticas/tratamento farmacológico , Células Mesangiais/efeitos dos fármacos , Receptor PAR-1/metabolismo , Espirostanos/farmacologia , Animais , Glicemia/metabolismo , Células Cultivadas , Diabetes Mellitus Experimental/metabolismo , Nefropatias Diabéticas/metabolismo , Regulação para Baixo/efeitos dos fármacos , Humanos , Inflamassomos/efeitos dos fármacos , Rim/efeitos dos fármacos , Rim/metabolismo , Masculino , Células Mesangiais/metabolismo , NF-kappa B/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Nefrite/tratamento farmacológico , Nefrite/metabolismo , Ratos Sprague-Dawley , Receptor PAR-1/genética , Trombina/metabolismo
2.
Am J Physiol Renal Physiol ; 319(4): F571-F578, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32830537

RESUMO

(Pro)renin receptor [(P)RR] has multiple functions, but its regulation and role in the pathogenesis in glomerulonephritis (GN) are poorly defined. The aims of the present study were to determine the effects of direct renin inhibition (DRI) and demonstrate the role of (P)RR on the progression of crescentic GN. The anti-glomerular basement membrane nephritis rat model developed progressive proteinuria (83.64 ± 10.49 mg/day) and glomerular crescent formation (percent glomerular crescent: 62.1 ± 2.3%) accompanied by increased macrophage infiltration and glomerular expression of monocyte chemoattractant protein (MCP)-1, (P)RR, phospho-extracellular signal-regulated kinase (ERK)1/2, Wnt4, and active ß-catenin. Treatment with DRI ameliorated proteinuria (20.33 ± 5.88 mg/day) and markedly reduced glomerular crescent formation (20.9 ± 2.6%), induction of macrophage infiltration, (P)RR, phospho-ERK1/2, Wnt4, and active ß-catenin. Furthermore, primary cultured parietal epithelial cells stimulated by recombinant prorenin showed significant increases in cell proliferation. Notably, while the ERK1/2 inhibitor PD98059 or (P)RR-specific siRNA treatment abolished the elevation in cell proliferation, DRI treatment did not abrogate this elevation. Moreover, cultured mesangial cells showed an increase in prorenin-induced MCP-1 expression. Interestingly, (P)RR or Wnt4-specific siRNA treatment or the ß-catenin antagonist XAV939 inhibited the elevation of MCP-1 expression, whereas DRI did not. These results suggest that (P)RR regulates glomerular crescent formation via the ERK1/2 signaling and Wnt/ß-catenin pathways during the course of anti-glomerular basement membrane nephritis and that DRI mitigates the progression of crescentic GN through the reduction of (P)RR expression but not inhibition of prorenin binding to (P)RR.


Assuntos
Proliferação de Células , Glomerulonefrite/enzimologia , Células Mesangiais/enzimologia , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Receptores de Superfície Celular/metabolismo , Via de Sinalização Wnt , Amidas/farmacologia , Animais , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Modelos Animais de Doenças , Fumaratos/farmacologia , Glomerulonefrite/patologia , Glomerulonefrite/prevenção & controle , Masculino , Células Mesangiais/efeitos dos fármacos , Células Mesangiais/patologia , Fosforilação , Ratos Endogâmicos WKY , Via de Sinalização Wnt/efeitos dos fármacos , Proteína Wnt4/metabolismo , beta Catenina/metabolismo
3.
Am J Physiol Renal Physiol ; 319(3): F458-F468, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32715762

RESUMO

The Wnt/ß-catenin signaling pathway is involved in production of the extracellular matrix (ECM) by mesangial cells (MCs). Recent studies by us and others have demonstrated that glucagon-like peptide-1 receptor agonists (GLP-1RAs) have protective effects against diabetic nephropathy. The purpose of the present study was to investigate whether the Wnt/ß-catenin signaling in MCs contributes to GLP-1RA-induced inhibition of ECM accumulation and mitigation of glomerular injury in diabetic nephropathy. In cultured human mesangial cells, liraglutide (a GLP-1RA) treatment significantly reduced high glucose (HG)-stimulated production of fibronectin, collagen type IV, and α-smooth muscle actin, and the liraglutide effects were significantly attenuated by XAV-939, a selective inhibitor of Wnt/ß-catenin signaling. Furthermore, HG treatment significantly decreased protein abundance of Wnt4, Wnt5a, phospho-glycogen synthase kinase-3ß, and ß-catenin. These HG effects on Wnt/ß-catenin signaling proteins were significantly blunted by liraglutide treatment. For in vivo experiments, we administered liraglutide (200 µg·kg-1·12 h-1) by subcutaneous injection to streptozocin-induced type 1 diabetic rats for 8 wk. Administration of liraglutide significantly improved elevated blood urine nitrogen, serum creatinine, and urinary albumin excretion rate and alleviated renal hypertrophy, mesangial expansion, and glomerular fibrosis in type 1 diabetic rats, whereas blood glucose level and body weight did not have significant changes. Consistent with the in vitro experiments, liraglutide treatment significantly reduced the diabetes-induced increases in glomerular fibronectin, collagen type IV, and α-smooth muscle actin and decreases in glomerular Wnt/ß-catenin signaling proteins. These results suggest that liraglutide alleviated glomerular ECM accumulation and renal injury in diabetic nephropathy by enhancing Wnt/ß-catenin signaling.


Assuntos
Proteínas da Matriz Extracelular/metabolismo , Liraglutida/farmacologia , Células Mesangiais/efeitos dos fármacos , Proteínas Wnt/metabolismo , beta Catenina/metabolismo , Animais , Diabetes Mellitus Experimental/complicações , Nefropatias Diabéticas , Proteínas da Matriz Extracelular/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Glucose/farmacologia , Humanos , Hipoglicemiantes/farmacologia , Masculino , Células Mesangiais/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais , Proteínas Wnt/genética , beta Catenina/genética
4.
Phytother Res ; 34(8): 2044-2052, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32155298

RESUMO

Oxidative stress plays an important role in diabetic nephropathy (DN), which is a diabetic complication. Ampelopsin (AMP) is a natural flavonoid that has been found to possess antidiabetic and antioxidative activities. However, the effect of AMP on DN remains unclear. In this study, we aimed to evaluate the protective effect of AMP on glomerular mesangial cells (MCs) exposed to high glucose (HG). We found that AMP improved HG-caused cell viability reduction in MCs. AMP significantly suppressed the intracellular ROS production and expression levels of ROS producing enzymes NADPH oxidase 2 (NOX2) and NOX4. Increased of NOX activity in HG-stimulated MCs was suppressed by AMP. Pretreatment with AMP inhibited extracellular matrix (ECM) accumulation in HG-stimulated MCs with decreased expression levels of fibronectin (FN) and collagen type IV (Col IV). Furthermore, AMP elevated the expression levels of nuclear Nrf2 and heme oxygenase-1 (HO-1), as well as increased the mRNA levels of Nrf2-driven genes NAD(P)H dehydrogenase quinone-1 (NQO-1) and HO-1 in HG-treated MCs. Knockdown of Nrf2 reversed the protective effects of AMP against HG-induced oxidative stress and EMC accumulation in MCs. In conclusion, these findings indicated that AMP protected MCs from HG-induced oxidative damage and ECM accumulation, which might be mediated by Nrf2/HO-1 pathway.


Assuntos
Nefropatias Diabéticas/tratamento farmacológico , Matriz Extracelular/efeitos dos fármacos , Flavonoides/uso terapêutico , Glucose/metabolismo , Células Mesangiais/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Nefropatias Diabéticas/patologia , Flavonoides/farmacologia , Humanos , Fator 2 Relacionado a NF-E2/metabolismo
5.
Med Sci Monit ; 26: e919399, 2020 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-32012145

RESUMO

BACKGROUND The aim of this study was to explore the effects of NADPH oxidase 5 (NOX5) in high glucose-stimulated human glomerular mesangial cells (HMCs). MATERIAL AND METHODS Cells were cultured under normal glucose (NG) or high glucose (HG) conditions. Then, NOX5 siRNA was transfected into HG-treated HMCs. A Cell Counting Kit-8 assay, colony formation assay and 5-ethynyl-20-deoxyuridine (EDU) incorporation assay were applied to measure cell proliferative ability. In addition, the levels of oxidative stress factors including reactive oxygen species (ROS), malonaldehyde (MDA), NADPH, superoxide dismutase (SOD), and glutathione peroxidase (GSH-PX), inflammatory cytokines including tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-6, IL-1ß, and monocyte chemoattractant protein-1 (MCP-1) in HMCs were detected by kits. Moreover, the expression of TLR4/NF-kappaB signaling and extracellular matrix (ECM) associated genes were evaluated by western blotting. RESULTS The results revealed that the NOX5 was overexpressed in HG-treated HMCs. Silencing of NOX5 decreased proliferation of HMCs induced by HG. And NOX5 silencing alleviated the production of MDA and NADPH accompanied by an increase of SOD and GSH-PX levels. Additionally, the contents of TNF-alpha, IL-6, IL-1ß, and MCP-1 were reduced after transfection with NOX5 siRNA. Furthermore, silencing of NOX5 deceased the expression of collagen I, collagen IV, TGF-ß1, and fibronectin induced by HG stimulation. TLR4, MyD88, and phospho-NF-kappaB p65 expression were downregulated notably in NOX5 silencing group. CONCLUSIONS Taken together, these findings demonstrated that inhibition of NOX5 attenuated HG-induced HMCs oxidative stress, inflammation, and ECM accumulation, suggesting that NOX5 may serve as a potential therapeutic target for diabetic nephropathy (DN) treatment.


Assuntos
Matriz Extracelular/metabolismo , Glucose/toxicidade , Inflamação/patologia , Células Mesangiais/enzimologia , Células Mesangiais/patologia , NADPH Oxidase 5/antagonistas & inibidores , Estresse Oxidativo , Proliferação de Células/efeitos dos fármacos , Citocinas/metabolismo , Matriz Extracelular/efeitos dos fármacos , Inativação Gênica , Glutationa Peroxidase/metabolismo , Humanos , Mediadores da Inflamação/metabolismo , Malondialdeído/metabolismo , Células Mesangiais/efeitos dos fármacos , NADP/metabolismo , NADPH Oxidase 5/genética , NADPH Oxidase 5/metabolismo , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Superóxido Dismutase/metabolismo , Receptor 4 Toll-Like/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/genética
6.
Eur J Pharmacol ; 873: 172955, 2020 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-32001218

RESUMO

Glomerular mesangial matrix expansion and cell autophagy are the most important factors in the development of kidney damage under diabetic conditions. The activation of AMPK might be an important treatment target for diabetic nephropathy. Berberine has multiple effects on all types of diabetic complications as an activator of AMPK. However, the poor bioavailability of berberine limits its clinical applications. Huang-Gui Solid Dispersion (HGSD), a new formulation of berberine developed in our lab, has 4-fold greater bioavailability than berberine. However, its therapeutic application and mechanism still need to be explored. In the present study, the effect of HGSD on kidney function in type 2 diabetic rats and db/db mice was investigated. The results demonstrated that HGSD improved kidney function in these two animal models, decreased the glomerular volume and increased autophagy. Meanwhile, AMPK phosphorylation levels and autophagy-related protein expression were significantly increased, and extracellular matrix protein deposition-related protein expression was decreased after treatment. The present study indicated that HGSD protected against diabetic kidney dysfunction by inhibiting glomerular mesangial matrix expansion and activating autophagy. The mechanism of HGSD in the treatment of diabetic nephropathy might be connected to the activation of AMPK phosphorylation.


Assuntos
Autofagia/efeitos dos fármacos , Berberina/farmacologia , Nefropatias Diabéticas/tratamento farmacológico , Células Mesangiais/efeitos dos fármacos , Proteínas Quinases Ativadas por AMP/efeitos dos fármacos , Animais , Berberina/farmacocinética , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/complicações , Nefropatias Diabéticas/patologia , Composição de Medicamentos , Ativação Enzimática/efeitos dos fármacos , Proteínas da Matriz Extracelular/metabolismo , Teste de Tolerância a Glucose , Testes de Função Renal , Masculino , Fosforilação , Ratos , Ratos Wistar
7.
Proc Natl Acad Sci U S A ; 117(10): 5409-5419, 2020 03 10.
Artigo em Inglês | MEDLINE | ID: mdl-32094169

RESUMO

Type III IFN lambdas (IFN-λ) have recently been described as important mediators of immune responses at barrier surfaces. However, their role in autoimmune diseases such as systemic lupus erythematosus (SLE), a condition characterized by aberrant type I IFN signaling, has not been determined. Here, we identify a nonredundant role for IFN-λ in immune dysregulation and tissue inflammation in a model of TLR7-induced lupus. IFN-λ protein is increased in murine lupus and IFN-λ receptor (Ifnlr1) deficiency significantly reduces immune cell activation and associated organ damage in the skin and kidneys without effects on autoantibody production. Single-cell RNA sequencing in mouse spleen and human peripheral blood revealed that only mouse neutrophils and human B cells are directly responsive to this cytokine. Rather, IFN-λ activates keratinocytes and mesangial cells to produce chemokines that induce immune cell recruitment and promote tissue inflammation. These data provide insights into the immunobiology of SLE and identify type III IFNs as important factors for tissue-specific pathology in this disease.


Assuntos
Interferons/fisiologia , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/patologia , Animais , Linfócitos B/imunologia , Linhagem Celular , Deleção de Genes , Humanos , Imiquimode/farmacologia , Inflamação/imunologia , Inflamação/patologia , Indutores de Interferon/farmacologia , Interferon Tipo I/fisiologia , Interferons/farmacologia , Queratinócitos/efeitos dos fármacos , Queratinócitos/imunologia , Queratinócitos/patologia , Células Mesangiais/efeitos dos fármacos , Células Mesangiais/imunologia , Células Mesangiais/patologia , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Receptores de Interferon/genética , Transdução de Sinais , Receptor 7 Toll-Like/agonistas , Receptor 7 Toll-Like/fisiologia
8.
Molecules ; 25(4)2020 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-32059523

RESUMO

Hyperglycemia is a strong risk factor for chronic complications of diabetes. Hyperglycemic conditions foster not only the production of reactive oxygen species (ROS), but also the consumption of antioxidants, leading to oxidative stress and promoting the occurrence and progression of complications. During our continuous search for antioxidant constituents from the pericarp of Toona sinensis (A. Juss.) Roem, we isolated two previously unreported apotirucallane-type triterpenoids, toonasinensin A (1) and toonasinensin B (2), together with five known apotirucallane-type triterpenoids (3-7) and two known cycloartane-type triterpenoids (8-9) from the pericarp. Compounds 8-9 were obtained from T. sinensis for the first time. Their structures were characterized based on interpretation of spectroscopic data (1D, 2D NMR, high-resolution electrospray ionization mass spectra, HR-ESI-MS) and comparison to previous reports. Compounds (2, 4, 6, 7, and 9) were able to inhibit proliferation against rat glomerular mesangial cells (GMCs) cultured under high-glucose conditions within a concentration of 80 µM. Compounds (2, 6, and 7) were tested for antioxidant activity attributable to superoxide dismutase (SOD), malondialdehyde (MDA), and ROS in vitro, and the results showed that compounds (2, 6, and 7) could significantly increase the levels of SOD and reduce the levels of MDA and ROS. The current studies showed that apotirucallane-type triterpenoids (2, 6, and 7) might have the antioxidant effects against diabetic nephropathy.


Assuntos
Nefropatias Diabéticas/tratamento farmacológico , Meliaceae/química , Triterpenos/farmacologia , Animais , Técnicas de Cultura de Células , Nefropatias Diabéticas/induzido quimicamente , Nefropatias Diabéticas/patologia , Glucose/toxicidade , Humanos , Células Mesangiais/efeitos dos fármacos , Células Mesangiais/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos , Espécies Reativas de Oxigênio , Superóxido Dismutase/metabolismo , Triterpenos/química , Triterpenos/isolamento & purificação
9.
EBioMedicine ; 51: 102582, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31901873

RESUMO

BACKGROUND: Mesangial collagen synthesis in renal glomeruli contributes to the pathogenesis of diabetic nephropathy (DN) which is one of the most serious complications of diabetes mellitus. However, the underlying mechanism of mesangial collagen synthesis is largely unknown. METHODS: The differential expression of CHOP and TRIM13 which is a well-defined E3 ubiquitin ligase was compared in renal biopsy samples from DN/normal renal tissues, in isolated glomeruli of diabetic/control mice, as well as in high glucose (HG) or TGF-ß1-stimulated renal mesangial cells. Then the relationship between TRIM13 and CHOP was explored using the ubiquitination assay. FINDINGS: We found that the expression of TRIM13 was downregulated in renal biopsies, isolated glomeruli of diabetic mice, and HG/TGF-ß1-stimulated renal mesangial cells, while the expression of CHOP was upregulated. An increased level of TRIM13 promoter methylation contributed to the deregulation of TRIM13 in renal glomeruli of DN. The ubiquitination assay confirmed that TRIM13 promoted ubiquitination and degradation of CHOP. Meanwhile, overexpressing TRIM13 attenuated DN-induced collagen synthesis and restored renal function in vitro and in vivo via downregulating CHOP. INTERPRETATION: Our findings demonstrated that overexpressed TRIM13 suppresses mesangial collagen synthesis in DN by promoting ubiquitination of CHOP, suggesting TRIM13 as a potential therapeutic target in treating DN.


Assuntos
Colágeno/biossíntese , Metilação de DNA/genética , Proteínas de Ligação a DNA/genética , Nefropatias Diabéticas/genética , Células Mesangiais/metabolismo , Fator de Transcrição CHOP/metabolismo , Proteínas com Motivo Tripartido/genética , Proteínas Supressoras de Tumor/genética , Ubiquitina-Proteína Ligases/genética , Ubiquitinação , Animais , Biópsia , Linhagem Celular , Metilação de DNA/efeitos dos fármacos , Proteínas de Ligação a DNA/metabolismo , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/patologia , Nefropatias Diabéticas/fisiopatologia , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/genética , Glucose/toxicidade , Humanos , Testes de Função Renal , Células Mesangiais/efeitos dos fármacos , Células Mesangiais/patologia , Camundongos Endogâmicos C57BL , Proteólise/efeitos dos fármacos , Proteínas com Motivo Tripartido/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitinação/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/genética
10.
Biochem Biophys Res Commun ; 521(4): 984-990, 2020 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-31727371

RESUMO

Diabetic nephropathy (DN) is among the common complications of diabetes and is a major cause of end-stage kidney disease. Emerging data indicate that renal inflammation is involved in DN progression and aggravation. Still, the exact cellular mechanisms remain unclear. Dysregulated expression of microRNAs (miRNAs) is associated with multiple diseases, including DN. The relationship between miRNAs and inflammation in DN is also unexplored. Here, we evaluated the role of miR-485 in mediating the response of human mesangial cells (HMCs) to a high glucose (HG) concentration, and the potential underlying mechanism. We found that miR-485 expression is significantly decreased in HG-stimulated HMCs. Overexpression of miR-485 suppressed HG-induced proliferation of HMCs. Lower production of proinflammatory cytokines (i.e., TNF-α, IL-1ß, and IL-6) was observed in miR-485-overexpressing HMCs. Overexpression of miR-485 markedly suppressed the overexpression of extracellular-matrix proteins, e.g., collagen IV (Col IV) and fibronectin (FN), in HG-stimulated HMCs. Furthermore, miR-485 suppressed the expression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 5 (NOX5), restrained the HG-induced HMC proliferation, downregulated the expression of proinflammatory cytokines, and inhibited the production of extracellular-matrix proteins in HMCs. These results provide new insights into the involvement of the miR-485-NOX5 signaling pathway in DN progression.


Assuntos
Nefropatias Diabéticas/genética , Inflamação/genética , Inflamação/patologia , Células Mesangiais/metabolismo , Células Mesangiais/patologia , MicroRNAs/metabolismo , Modelos Biológicos , NADPH Oxidase 5/metabolismo , Sequência de Bases , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Nefropatias Diabéticas/patologia , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/genética , Matriz Extracelular/efeitos dos fármacos , Matriz Extracelular/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Glucose/toxicidade , Células HEK293 , Humanos , Células Mesangiais/efeitos dos fármacos , MicroRNAs/genética , Estresse Oxidativo/efeitos dos fármacos
11.
Chem Biol Interact ; 316: 108921, 2020 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-31838053

RESUMO

Hyperproliferation and oxidative stress induced by hyperglycemia in mesangial cells plays crucial roles in the pathological process of diabetic nephropathy. Farrerol, isolated from rhododendron leaves, possesses broad anti-oxidative and anti-inflammatory properties towards several diseases, but its role in diabetic neuropathy remains unclear. The aim of this study was to evaluate the effects of farrerol in high glucose induced mesangial cell injury, and to explore underlying molecular mechanisms. Our results showed that high glucose in vitro conditions significantly stimulated cell proliferation, inflammatory cytokine secretion, extracellular matrix deposition, excessive oxidative stress, and NADPH oxidase activity in mesangial cells. Levels of NADPH oxidase 4 (Nox4) expression, ERK1/2 phosphorylation, and TGF-ß1/Smad2 activation were significantly induced by high glucose conditions in mesangial cells. Inversely, farrerol treatments at 40, 60, and 80 µM concentrations, dose-dependently alleviated this molecular damage by high glucose in mesangial cells. We also found that restoration of Nox4 expression abolished the protective effects of farrerol on high glucose-induced proliferation and reactive oxygen species generation. Furthermore, pretreatment with the Nox4 inhibitor diphenyliodonium or the ERK1/2 pathway inhibitor PD98059, displayed similar ameliorated effects of farrerol on high glucose-induced mesangial cell damage. Taken together, these data suggest that farrerol displays protective effects on high glucose induced mesangial cell injury, partly through the Nox4-mediated ROS/ERK1/2 signaling pathway. These observations may provide novel insights into the application of farrerol as a diabetic neuropathy treatment.


Assuntos
Cromonas/farmacologia , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , NADPH Oxidase 4/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Glucose/toxicidade , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Células Mesangiais/citologia , Células Mesangiais/efeitos dos fármacos , Células Mesangiais/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos , Fator de Crescimento Transformador beta/metabolismo
12.
Mol Cell Endocrinol ; 500: 110628, 2020 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-31647955

RESUMO

Metformin, as the basic pharmacological therapy and the first preventive drug in type 2 diabetes mellitus (T2DM), is proved to have potential protection in diabetic kidney disease (DKD). Here, we established a diabetic rat model induced by high-fat diet and low dose streptozotocin, and high glucose cultured rat mesangial cells (RMCs) pre-treated with metformin or transfected with AMPK, SIRT1 and FoxO1 small interfering RNA, and detected oxidative stress and autophagy related factors to explore the molecular mechanisms of metformin on DKD via adenosine monophosphate-activated protein kinase (AMPK)/silent mating type information regulation 2 homolog-1 (sirtuin-1, SIRT1)-Forkhead box protein O1 (FoxO1) pathway. We found that metformin effectively alleviated the disorders of glycolipid metabolism, renal function injury in diabetic rats, and relieved oxidative stress, enhanced autophagy and slowed down abnormal cell proliferation in high glucose cultured RMCs through AMPK/SIRT1-FoxO1 pathway, indicating the protective role of metformin against the pathological process of DKD.


Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Nefropatias Diabéticas/tratamento farmacológico , Metformina/administração & dosagem , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Autofagia , Células Cultivadas , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/induzido quimicamente , Diabetes Mellitus Tipo 2/metabolismo , Nefropatias Diabéticas/metabolismo , Dieta Hiperlipídica/efeitos adversos , Masculino , Células Mesangiais/citologia , Células Mesangiais/efeitos dos fármacos , Células Mesangiais/metabolismo , Metformina/farmacologia , Proteínas do Tecido Nervoso/metabolismo , Ratos , Sirtuína 1/metabolismo , Estreptozocina/efeitos adversos
13.
J Microbiol Immunol Infect ; 53(1): 23-32, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29657028

RESUMO

BACKGROUND: Renal disease is prevalent in gouty patients and monosodium urate (MSU) crystal deposition in the kidney can be detected in some gouty nephropathy patients. MSU crystals can induce inflammatory events, we investigated the MSU-induced expression of intercellular adhesion molecule (ICAM)-1 on human renal mesangial cells (HRMCs) and the involved signal transduction mechanisms. METHODS: The HRMCs cell line was purchased from ScienCell Research Laboratories. MSU crystals were made by dissolving uric acid in sodium hydroxide (NaOH) solution. The involvement of MAPKs, apoptosis-associated speck-like protein containing a CARD domain (ASC), and Toll-like receptor (TLR) was investigated using pharmacological inhibitors, transfection with short hairpin RNA (shRNA), or monoclonal antibodies. Protein expression was evaluated by Western blotting. The functional activity of ICAM-1 was evaluated with cell-cell adhesion assay and immunofluorescence analysis. RESULTS: MSU stimulation increased expression of ICAM-1 and adhesion between HRMCs and human monocytic THP-1 cells. The interaction between HRMCs and THP-1 was suppressed by ICAM-1 neutralizing antibodies. MSU stimulation induced activation of mitogen-activated protein kinases, including c-Jun N-terminal kinase (JNK), p38, and extracellular signal-regulated kinase (ERK), but only p38 was responsible for MSU-induced expression of ICAM-1 and cell-cell adhesion. ASC also play a role in MSU-induced effects. Pretreatment with monoclonal antibodies against toll-like receptor (TLR)2 or TLR4 reduced MSU-induced ICAM-1 expression, cell-cell adhesion, p38 phosphorylation but the reduction of ASC activation is insignificant. CONCLUSION: The MSU induced ICAM-1 expression on HRMCs and cell-cell adhesion involved TLR2/4-p38-ICAM1 pathway and TLR2/4 independent ASC-p38-ICAM1 axis. These findings might partly explain the mechanisms underlying gouty nephropathy.


Assuntos
Adesão Celular/efeitos dos fármacos , Gota/complicações , Molécula 1 de Adesão Intercelular/genética , Nefropatias/fisiopatologia , Células Mesangiais/efeitos dos fármacos , Ácido Úrico/farmacologia , Linhagem Celular , Humanos , Rim/citologia , Células Mesangiais/fisiologia , Proteínas Quinases Ativadas por Mitógeno/genética , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Monócitos/metabolismo , Transdução de Sinais/genética , Células THP-1 , Receptor 2 Toll-Like/genética , Receptor 4 Toll-Like/genética
14.
Mar Drugs ; 17(12)2019 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-31842414

RESUMO

As one of the main marine carotenoids, fucoxanthin has strong antioxidant activity. FoxO3α, a member of the forkhead box O family of transcription factors, plays an important role in DN by regulating oxidative stress. The activity of FoxO3α is related to its phosphorylation and acetylation status, regulated by Akt and Sirt1, a lysine deacetylase. Our study aimed to investigate whether fucoxanthin could alleviate oxidative stress and fibrosis via FoxO3α in DN and whether Akt and Sirt1 were involved. We found that in GMCs cultured in HG, fucoxanthin treatment significantly reduced the expression of FN and collagen IV, as well as reactive oxygen species generation, suggesting that fucoxanthin is beneficial to alleviate both fibrosis and oxidative stress in DN. In addition, we found that fucoxanthin decreased the phosphorylation and acetylation level of FoxO3α, reversed the protein level of FoxO3α inhibited by HG, and then promoted the nuclear transport of FoxO3α. Besides, fucoxanthin promoted the expression of manganese superoxide dismutase, a downstream target of FoxO3α. Furthermore, we found that fucoxanthin reversed the activation of Akt and inhibition of Sirt1. However, the enhancement of fucoxanthin in FoxO3α expression and nuclear transport was significantly decreased by pretreatment with Akt activator SC79 or Sirt1 inhibitor EX527. In summary, our study explored fucoxanthin alleviated oxidative stress and fibrosis induced by HG through Akt/Sirt1/FoxO3α signaling in GMCs, suggesting fucoxanthin is a potential therapeutic strategy for DN.


Assuntos
Nefropatias Diabéticas/tratamento farmacológico , Células Mesangiais/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Xantofilas/farmacologia , Animais , Antioxidantes/farmacologia , Células Cultivadas , Nefropatias Diabéticas/patologia , Fibrose/tratamento farmacológico , Fibrose/patologia , Proteína Forkhead Box O3/metabolismo , Glucose/toxicidade , Células Mesangiais/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Sirtuína 1/metabolismo
15.
AAPS J ; 22(1): 8, 2019 12 05.
Artigo em Inglês | MEDLINE | ID: mdl-31807911

RESUMO

Moringa isothiocyanate (MIC-1) is a bioactive constituent found abundantly in Moringa oleifera which possesses antioxidant and anti-inflammation properties. However, epigenome and transcriptome effects of MIC-1 in kidney mesangial cells challenged with high glucose (HG), a pre-condition for diabetic nephropathy (DN) remain unknown. Herein, we examined the transcriptome gene expression and epigenome DNA methylation in mouse kidney mesangial cells (MES13) using next-generation sequencing (NGS) technology. After HG treatment, epigenome and transcriptome were significantly altered. More importantly, MIC-1 exposure reversed some of the changes caused by HG. Integrative analysis of RNA-Seq data identified 20 canonical pathways showing inverse correlations between HG and MIC-1. These pathways included GNRH signaling, P2Y purigenic receptor signaling pathway, calcium signaling, LPS/IL-1-mediated inhibition of RXR function, and oxidative ethanol degradation III. In terms of alteration of DNA methylation patterns, 173 differentially methylation regions (DMRs) between the HG group and low glucose (LG) group and 149 DMRs between the MIC-1 group and the HG group were found. Several HG related DMRs could be reversed by MIC-1 treatment. Integrative analysis of RNA-Seq and Methyl-Seq data yielded a subset of genes associated with HG and MIC-1, and the gene expression changes may be driven by promoter CpG status. These genes include Col4a2, Tceal3, Ret, and Agt. In summary, our study provides novel insights related to transcriptomic and epigenomic/CpG methylomic alterations in MES13 upon challenged by HG but importantly, MIC-1 treatment reverses some of the transcriptome and epigenome/CpG methylome. These results may provide potential molecular targets and therapeutic strategies for DN.


Assuntos
Nefropatias Diabéticas/tratamento farmacológico , Epigenoma/efeitos dos fármacos , Isotiocianatos/uso terapêutico , Células Mesangiais/efeitos dos fármacos , Ramnose/análogos & derivados , Transcriptoma/efeitos dos fármacos , Animais , Linhagem Celular , Avaliação Pré-Clínica de Medicamentos , Glucose , Isotiocianatos/farmacologia , Células Mesangiais/metabolismo , Camundongos , Moringa oleifera , Fitoterapia , Espécies Reativas de Oxigênio/metabolismo , Ramnose/farmacologia , Ramnose/uso terapêutico , Transdução de Sinais/efeitos dos fármacos
16.
Eur Rev Med Pharmacol Sci ; 23(20): 9099-9107, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31696501

RESUMO

OBJECTIVE: Gliclazide is one of the most widely used therapeutic drugs for diabetes. As a second-generation sulfonylurea oral hypoglycemic drug, it can lower blood glucose level and delay the occurrence and development of diabetic nephropathy (DN). However, the underlying mechanism remains unclear. Therefore, the aim of this study was to explore whether gliclazide had protective effects on high glucose and advanced glycation end products (AGEs)-induced injury of human mesangial cells (HMCs) and renal tubular epithelial cells. MATERIALS AND METHODS: HMC and renal tubular epithelial cell lines [human kidney 2 (HK-2)] were cultured in vitro. All cells were then divided into the follow groups: 1) blank control group (5.6 mmol/L glucose), 2) AGEs group [400 µg/mL AGE-bovine serum albumin (AGE-BSA)], 3) high glucose group (25 mmol/L glucose), 4) gliclazide + AGEs group (400 µg/mL AGE-BSA + 20 µmol/L gliclazide) and 5) gliclazide + high glucose group (25 mmol/L glucose + 20 µmol/L gliclazide). Cell counting kit-8 (CCK-8) assay was adopted to determine cell viability. Flow cytometry was used to detect cell apoptosis. The levels of malondialdehyde (MDA), superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) were measured as well. Furthermore, the mRNA expressions of receptor for AGE (RAGE), p22phox and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) were measured via fluorescence quantitative Real-time polymerase chain reaction (qRT-PCR). RESULTS: Compared with control group, significantly accelerated apoptosis of HMCs and HK-2, increased MDA level, decreased SOD and GSH-Px levels, and up-regulated mRNA expressions of RAGE, p22phox and NF-κB were observed in HMCs and HK-2 of high glucose group and AGEs group. Meanwhile, there were obviously alleviated apoptosis of HMCs and HK-2, decreased MDA level, increased SOD and GSH-Px levels, as well as down-regulated mRNA expressions of RAGE, p22phox and NF-κB in HMCs and HK-2 of gliclazide group compared with high glucose and AGEs group. Furthermore, significant correlations were found between the mRNA expression of RAGE and the apoptosis rate of HMCs and HK-2 (HMCs: r=0.701, p=0.004 and HK-2: r=0.633, p=0.011). CONCLUSIONS: Gliclazide has protective effects on high glucose and AGEs-induced damage of glomerular mesangial cells and renal tubular epithelial cells via inhibiting RAGE-NADPH oxidase-NF-kB pathway.


Assuntos
Gliclazida/farmacologia , Glucose/efeitos adversos , Produtos Finais de Glicação Avançada/efeitos adversos , Túbulos Renais/citologia , Células Mesangiais/citologia , Soroalbumina Bovina/efeitos adversos , Antígenos de Neoplasias/genética , Apoptose/efeitos dos fármacos , Células Cultivadas , Células Epiteliais/citologia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Túbulos Renais/efeitos dos fármacos , Túbulos Renais/metabolismo , Células Mesangiais/efeitos dos fármacos , Células Mesangiais/metabolismo , Proteínas Quinases Ativadas por Mitógeno/genética , NADPH Oxidases/genética , NF-kappa B/genética , Transdução de Sinais/efeitos dos fármacos
17.
Med Sci Monit ; 25: 8753-8763, 2019 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-31745068

RESUMO

BACKGROUND Zafirlukast is an antagonist of cysteinyl leukotriene receptor 1 (CysLTR1). Advanced glycation end-products (AGEs) are formed by the glycation of lipids and proteins in hyperglycemia, including diabetes mellitus. Zafirlukast has not previously been studied in diabetic nephropathy. This study aimed to investigate the effects of zafirlukast on rat renal mesangial cells cultured with AGEs in vitro. MATERIAL AND METHODS Mesangial cells were cultured in AGEs (0, 20, 50, 100 µg/ml), and with AGEs (100 µg/ml) and zafirlukast (2.5 µm, 5 µm, and 100 µm). An enzyme-linked immunoassay (ELISA) was used to measure the levels of tumor necrosis factor-alpha (TNF-alpha), interleukin-1ß (IL-1ß), IL-6, and monocyte chemoattractant protein-1 (MCP-1). Reactive oxygen species (ROS) were assessed by intracellular fluorescence measurement of 2'-7'-dichlorodihydrofluorescein diacetate (DCFH-DA), and detection kits were used to measure malondialdehyde (MDA), lactate dehydrogenase (LDH), glutathione peroxidase (GSH-Px), and superoxide dismutase (SOD). Cell apoptosis was assessed by flow cytometry, and Western blot was used to measure protein levels. RESULTS In mesangial cells cultured with AGEs, markers of inflammation, oxidative stress, and apoptosis and levels of CysLTR1 increased, and these effects were reduced by zafirlukast in a dose-dependent manner. The effects of zafirlukast as a CysLTR1 antagonist protected mesangial cells from the effects of AGE in vitro. CONCLUSIONS Zafirlukast, a CysLTR1 antagonist, reduced the levels of inflammatory cytokines, markers of oxidative stress, and cell apoptosis induced by AGE in mesangial cells in a dose-dependent way. Future in vivo studies are needed to investigate the potential role for zafirlukast in models of diabetic nephropathy.


Assuntos
Produtos Finais de Glicação Avançada/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Compostos de Tosil/farmacologia , Animais , Diabetes Mellitus Experimental/metabolismo , Nefropatias Diabéticas/metabolismo , Glutationa Peroxidase/metabolismo , Produtos Finais de Glicação Avançada/metabolismo , Inflamação/patologia , Malondialdeído/metabolismo , Células Mesangiais/efeitos dos fármacos , Ratos , Espécies Reativas de Oxigênio/metabolismo , Receptores de Leucotrienos/metabolismo , Superóxido Dismutase/metabolismo , Compostos de Tosil/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
18.
Kidney Blood Press Res ; 44(6): 1339-1351, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31661692

RESUMO

AIM: This study aimed to investigate the effect of norcantharidin (NCTD) on human mesangial cells (HMCs) apoptosis in vitro and further examine its molecular mechanism. METHODS: HMCs were divided into 5 groups: control group, 25% fetal bovine serum (FBS)-treated group, and NCTD groups (NCTD [2.5, 5 and 10 µg/mL] + 25% FBS, respectively). Cell proliferation was determined by MTT assay, while apoptosis was evaluated by Hoechest 33258 staining, the level of cytochrome c, immunohistochemistry, and apoptotic-related proteins/gene expression. RESULTS: Cell viability was inhibited in NCTD-treated HMCs in a dose-dependent manner. The number of apoptotic cells and the content of cytochrome c were significantly increased by NCTD treatment but that of mitochondrial membrane was decreased. Moreover, the expression of bcl-2 and caspase-3 was prompted by NCTD, but the expression of bax, MMP-2, and MMP-9 in 25% FBS-treated HMCs was inhibited. In addition, NCTD markedly unregulated the expression of apoptosis-related gene/protein, including p-Erk1/2, phosphorylated-Jun N-terminal kinase (JNK), p-p38, and p53. CONCLUSION: NCTD enhances 25% FBS-treated HMC apoptosis in vitro, and this effect may be attributed to the modulation of the ERK, JNK, and p38 mitogen-activated protein kinase signaling pathways.


Assuntos
Apoptose/efeitos dos fármacos , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Células Mesangiais/citologia , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/farmacologia , Humanos , Células Mesangiais/efeitos dos fármacos , Células Mesangiais/metabolismo
19.
Aging (Albany NY) ; 11(20): 8745-8759, 2019 10 20.
Artigo em Inglês | MEDLINE | ID: mdl-31631065

RESUMO

Diabetic nephropathy (DN) is one of the leading causes of end-stage renal diseases worldwide. This study is designed to investigate the underlying function and mechanism of a novel lncRNA GAS5 in the progression of DN. We found that lncRNA GAS5 expression level was decreased in type 2 diabetes (T2D) with DN compared with that in patients without DN. Moreover, lncRNA GAS5 expression level was negatively associated with the severity of DN-related complications. lncRNA GAS5 inhibited MCs proliferation and caused G0/1 phase arrest. lncRNA GAS5 overexpression alleviated the expression of fibrosis-related protein in mesangial cells (MCs). The dual-luciferase reporter assay and RNA binding protein immunoprecipitation (RIP) assay results revealed that lncRNA GAS5 functions as an endogenous sponge for miR-221 via both the directly targeting way and Ago2-dependent manner. Furthermore, SIRT1 was confirmed as a target gene of miR-221. lncRNA GAS5 upregulated SIRT1 expression and inhibited MCs proliferation and fibrosis by acting as an miR-221 sponge. Finally, we found that lncRNA GSA5 suppressed the development of DN in vivo. Thus, lncRNA GAS5 was involved in the progression of DN by sponging miR-221 and contributed to lncRNA-directed diagnostics and therapeutics in DN.


Assuntos
Nefropatias Diabéticas/metabolismo , Fibrose/metabolismo , MicroRNAs/metabolismo , RNA Longo não Codificante/metabolismo , Sirtuína 1/metabolismo , Envelhecimento , Animais , Proteínas Argonauta/genética , Proteínas Argonauta/metabolismo , Proliferação de Células , Diabetes Mellitus Experimental/complicações , Deleção de Genes , Regulação da Expressão Gênica/efeitos dos fármacos , Glucose/administração & dosagem , Glucose/farmacologia , Masculino , Células Mesangiais/efeitos dos fármacos , Células Mesangiais/fisiologia , Camundongos , MicroRNAs/genética , Células RAW 264.7 , RNA Longo não Codificante/genética , Ratos , Ratos Sprague-Dawley , Sirtuína 1/genética
20.
Ren Fail ; 41(1): 899-906, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31552773

RESUMO

Objective: To investigate effects of combination use of leflunomide and benazepril on diabetic nephropathy (DN) both in vivo and in vitro. Methods: The streptozotocin (STZ) induced Sprague-Dawley rats were treated with leflunomide (15 mg/kg/d), benazepril (15 mg/kg/d) or both the two drugs. Fasting blood glucose (FBG) and renal function indexes including blood urea nitrogen (BUN), serum creatinine (Scr), and proteinuria and kidney/body weight ratio (KW/BW) were measured. HE staining was used for histological analysis. The rat glomerular mesangial cells (RMCs) were treated with high-glucose (150 mg/ml) and the leflunomide and benazepril with both concentrations of 50 µmol/l were used to treat the high-glucose induced cells. TUNEL assay was used for measurement of cell apoptosis. Western blotting was conducted to determine expression of nuclear factor Kappa B (NF-κB), transforming growth factor-ß (TGF-ß) and transient receptor potential canonical 6 (TRPC6). Results: The body weight was significantly lower and all indexes of FBG, BUN, Scr, proteinuria and KW/BW ratio, GFR, as well as inflammatory factors TNF-α and IL-6 were significantly increased in the DN group after STZ treatment for 4 weeks. The treatment with leflunomide, benazepril or the both dramatically reduced the above effects induced by STZ, and the alteration was the most significant in the combination group. Treatment of leflunomide and benazepril significantly reduced expression levels of NF-κB, TGF-ß and TRPC6 in renal tissues of DN rats as well as in high-glucose induced RMCs. It was also observed leflunomide and benazepril reduced high-glucose induced cell apoptosis of RMCs. Conclusion: The combination use of leflunomide and benazepril could improve the renal function and reduce the renal injury of DN rats and could reduce the levels of NF-κb, TGF-ß and TRPC6 in both DN rats and high-glucose induced RMCs.


Assuntos
Apoptose/efeitos dos fármacos , Benzazepinas/farmacologia , Diabetes Mellitus Experimental/complicações , Nefropatias Diabéticas/tratamento farmacológico , Hiperglicemia/complicações , Leflunomida/farmacologia , Animais , Benzazepinas/uso terapêutico , Glicemia/análise , Linhagem Celular , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/induzido quimicamente , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/patologia , Sinergismo Farmacológico , Quimioterapia Combinada , Taxa de Filtração Glomerular/efeitos dos fármacos , Humanos , Hiperglicemia/sangue , Hiperglicemia/induzido quimicamente , Leflunomida/uso terapêutico , Masculino , Células Mesangiais/efeitos dos fármacos , Células Mesangiais/patologia , NF-kappa B/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Estreptozocina/toxicidade , Canais de Cátion TRPC/metabolismo , Fator de Crescimento Transformador beta/metabolismo
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