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1.
Clin Sci (Lond) ; 134(2): 239-259, 2020 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-31943002

RESUMO

Mitochondrial stress has been widely observed in diabetic kidney disease (DKD). Cyclophilin D (CypD) is a functional component of the mitochondrial permeability transition pore (mPTP) which allows the exchange of ions and solutes between the mitochondrial matrix to induce mitochondrial swelling and activation of cell death pathways. CypD has been successfully targeted in other disease contexts to improve mitochondrial function and reduced pathology. Two approaches were used to elucidate the role of CypD and the mPTP in DKD. Firstly, mice with a deletion of the gene encoding CypD (Ppif-/-) were rendered diabetic with streptozotocin (STZ) and followed for 24 weeks. Secondly, Alisporivir, a CypD inhibitor was administered to the db/db mouse model (5 mg/kg/day oral gavage for 16 weeks). Ppif-/- mice were not protected against diabetes-induced albuminuria and had greater glomerulosclerosis than their WT diabetic littermates. Renal hyperfiltration was lower in diabetic Ppif-/- as compared with WT mice. Similarly, Alisporivir did not improve renal function nor pathology in db/db mice as assessed by no change in albuminuria, KIM-1 excretion and glomerulosclerosis. Db/db mice exhibited changes in mitochondrial function, including elevated respiratory control ratio (RCR), reduced mitochondrial H2O2 generation and increased proximal tubular mitochondrial volume, but these were unaffected by Alisporivir treatment. Taken together, these studies indicate that CypD has a complex role in DKD and direct targeting of this component of the mPTP will likely not improve renal outcomes.


Assuntos
/metabolismo , Diabetes Mellitus Experimental/metabolismo , Nefropatias/metabolismo , Proteínas de Transporte da Membrana Mitocondrial/metabolismo , Albuminúria/genética , Albuminúria/metabolismo , Animais , /genética , Ciclosporina/farmacologia , Diabetes Mellitus Experimental/genética , Nefropatias Diabéticas/genética , Nefropatias Diabéticas/metabolismo , Peróxido de Hidrogênio/metabolismo , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Nefropatias/genética , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Proteínas de Transporte da Membrana Mitocondrial/genética , ATPases Translocadoras de Prótons/metabolismo
2.
Medicine (Baltimore) ; 99(1): e18596, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31895808

RESUMO

Diabetic kidney disease (DKD) is a leading cause of end-stage renal disease. Because the molecular mechanisms of DKD are not fully understood, exploration of hub genes and the mechanisms underlying this disease are essential for elucidating the pathogenesis and progression of DKD. Accordingly, in this study, we performed an analysis of gene expression in DKD. The differentially expressed genes (DEGs) included 39 upregulated genes and 113 downregulated genes in the GSE30528 dataset and 127 upregulated genes and 18 downregulated genes in the GSE30529 dataset. Additionally, functional analyses were performed to determine the roles of DEGs using glomeruli samples from patients with DKD and healthy controls from the GSE30528 dataset and using tubule samples from patients with DKD and healthy controls from the GSE30529 dataset. These DEGs were enriched in pathways such as the Wnt signaling pathway, metabolic pathways, and the mammalian target of rapamycin signaling pathway in the GSE30528 dataset and the longevity regulating pathway and Ras signaling pathway in the GSE30529 dataset. Moreover, a protein-protein interaction network was constructed using the identified DEGs, and hub gene analysis was performed. Furthermore, correlation analyses between key genes and pathological characteristics of DKD indicated that CCR4, NTNG1, HGF and ISL1 are related to DKD, and NTNG1 and HGF may server as diagnostic biomarkers in DKD using the receiver-operator characteristic (ROC) curve. Collectively, our findings established 2 reliable biomarkers for DKD.


Assuntos
Nefropatias Diabéticas/metabolismo , Fator de Crescimento de Hepatócito/metabolismo , Rim/metabolismo , Netrinas/metabolismo , Biomarcadores/metabolismo , Estudos de Casos e Controles , Proteínas Ligadas por GPI/metabolismo , Humanos
3.
Life Sci ; 238: 116965, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31629762

RESUMO

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


Assuntos
Antioxidantes/farmacologia , Diabetes Mellitus Experimental/complicações , Nefropatias Diabéticas/prevenção & controle , Regulação da Expressão Gênica/efeitos dos fármacos , Propionatos/farmacologia , Receptor 4 Toll-Like/metabolismo , Animais , Glicemia/metabolismo , Creatinina/sangue , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/patologia , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Receptor 4 Toll-Like/genética
4.
EBioMedicine ; 47: 446-456, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31542391

RESUMO

BACKGROUND: Senescent cells, which can release factors that cause inflammation and dysfunction, the senescence-associated secretory phenotype (SASP), accumulate with ageing and at etiological sites in multiple chronic diseases. Senolytics, including the combination of Dasatinib and Quercetin (D + Q), selectively eliminate senescent cells by transiently disabling pro-survival networks that defend them against their own apoptotic environment. In the first clinical trial of senolytics, D + Q improved physical function in patients with idiopathic pulmonary fibrosis (IPF), a fatal senescence-associated disease, but to date, no peer-reviewed study has directly demonstrated that senolytics decrease senescent cells in humans. METHODS: In an open label Phase 1 pilot study, we administered 3 days of oral D 100 mg and Q 1000 mg to subjects with diabetic kidney disease (N = 9; 68·7 ±â€¯3·1 years old; 2 female; BMI:33·9 ±â€¯2·3 kg/m2; eGFR:27·0 ±â€¯2·1 mL/min/1·73m2). Adipose tissue, skin biopsies, and blood were collected before and 11 days after completing senolytic treatment. Senescent cell and macrophage/Langerhans cell markers and circulating SASP factors were assayed. FINDINGS: D + Q reduced adipose tissue senescent cell burden within 11 days, with decreases in p16INK4A-and p21CIP1-expressing cells, cells with senescence-associated ß-galactosidase activity, and adipocyte progenitors with limited replicative potential. Adipose tissue macrophages, which are attracted, anchored, and activated by senescent cells, and crown-like structures were decreased. Skin epidermal p16INK4A+ and p21CIP1+ cells were reduced, as were circulating SASP factors, including IL-1α, IL-6, and MMPs-9 and -12. INTERPRETATION: "Hit-and-run" treatment with senolytics, which in the case of D + Q have elimination half-lives <11 h, significantly decreases senescent cell burden in humans. FUND: NIH and Foundations. ClinicalTrials.gov Identifier: NCT02848131. Senescence, Frailty, and Mesenchymal Stem Cell Functionality in Chronic Kidney Disease: Effect of Senolytic Agents.


Assuntos
Senescência Celular/efeitos dos fármacos , Dasatinibe/farmacologia , Nefropatias Diabéticas/metabolismo , Quercetina/farmacologia , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Idoso , Biomarcadores , Biópsia , Ensaios Clínicos Fase I como Assunto , Dasatinibe/uso terapêutico , Nefropatias Diabéticas/diagnóstico , Nefropatias Diabéticas/tratamento farmacológico , Quimioterapia Combinada , Feminino , Humanos , Imuno-Histoquímica , Testes de Função Renal , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Pessoa de Meia-Idade , Quercetina/uso terapêutico
5.
Comput Biol Chem ; 83: 107115, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31561072

RESUMO

Diabetic nephropathy (DN) is one of the common diabetic complications, but the mechanisms are still largely unknown. In this study, we constructed a DN related protein-protein interaction network (DNPPIN) on the basis of RNA-seq analysis of renal cortices of DN and normal mice, and the STRING database. We analyzed DNPPIN in detail revealing nine critical proteins which are central in DNPPIN, and contained in one network module which is functionally enriched in ribosome, nucleic acid binding and metabolic process. Overall, this study identified nine critical and functionally associated protein-coding genes concerning DN. These genes could be a starting point of future research towards the goal of elucidating the mechanisms of DN pathogenesis and progression.


Assuntos
Nefropatias Diabéticas/genética , Redes Reguladoras de Genes , Proteínas/genética , Animais , Bases de Dados de Proteínas , Nefropatias Diabéticas/metabolismo , Masculino , Camundongos , Camundongos Obesos , Ligação Proteica , Mapas de Interação de Proteínas , Proteínas/química
6.
Drug Deliv ; 26(1): 849-859, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31524015

RESUMO

Diabetic nephropathy (DN) is a serious complication of diabetes mellitus whose expand process is linked with the fibrosis, renal hypertrophy and inflammation. The current study was to formulate and optimize the nano-formulation of crocetin (CT-PLGA-NPs) against Streptozotocin-induced renal nephropathy in rats. Double emulsion evaporation technique was used for the preparation of CT-PLGA-NPs. CT-PLGA-NPs were scrutinized for polydispersity index, size, gastric stability, entrapment, drug-loading capacity and in-vitro drug release and in vivo preclinical study. Single intraperitoneal injection of streptozotocin (STZ) (55 mg/kg) and rats were divided into different group. Renal function and metabolic parameters of urine and serum were estimated. Fibrotic protein, renal pro-inflammatory cytokines and degree of renal damage expression were also determined. We also estimated the fibronectin, type IV collagen and transforming growth factor-ß1 for a possible mechanism of action. Crocetin supplement (10 mg/kg) and CT-PLGA-NPs exhibited the accumulation of the drug in kidney and liver of diabetic rats. Crocetin reduced the BGL and enhanced plasma insulin and body weight. Dose dependent treatment of crocetin significantly (p < .001) down-regulated the expression of renal tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin (IL)-1ß (IL-1ß) and Monocyte Chemoattractant Protein-1 (MCP-1). Crocetin significantly (p < .001) altered the expression of fibronectin, type IV collagen, and transforming growth factor-ß1 (TGF-1ß). Crocetin significantly (p < .001) down-regulated the protein kinase C activity and the expression of nuclear factor κB (NF-κB) p65 activity and protein production in renal tissue. On the basis of the available result, we can conclude that nano-formulation of crocetin could attenuate the diabetic nephropathy via antifibrotic and anti-inflammatory effect.


Assuntos
Biomarcadores/metabolismo , Carotenoides/administração & dosagem , Carotenoides/química , Nefropatias Diabéticas/tratamento farmacológico , Inflamação/tratamento farmacológico , Nanopartículas/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Citocinas/metabolismo , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Nefropatias Diabéticas/metabolismo , Regulação para Baixo/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Inflamação/metabolismo , Mediadores da Inflamação/metabolismo , Rim/efeitos dos fármacos , Rim/metabolismo , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Estreptozocina/farmacologia
7.
Chem Biol Interact ; 314: 108815, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31499054

RESUMO

Diabetic nephropathy (DN) is the one of the leading causes of end-stage renal disease (ESRD) in clinical. However, it is still lack of accurate biomarkers and effective methods for diagnosing and curing DN. Therefore, there is an urgent need to develop a definite strategy for the identification of reliable and versatile biomarkers for risk assessment of DN and search for therapeutic approaches that can effectively attenuate DN progression. Treatment with Gandi capsule (GDC) not only decreased the levels of urinary albumin excretion, but also increased the levels of estimated glomerular filtration rate (eGFR), indicating that it produces a renal protective effect on diabetic nephropathy. Based on metabolomics investigation including UHPLC-MS analysis and multivariate statistical analysis, sixteen disordered metabolites were screened out and considered as potential biomarkers corresponding to DN, which were mostly improved and partially returned to normalcy in GDC treatment group. Therefore, it was suggested that GDC was a promising therapeutic agent against DN. The underlying mechanisms of GDC attenuating the development of DN may be improving abnormal metabolic disorders by retrieving the imbalance of glycine metabolism, tryptophan metabolism, valine, leucine and isoleucine degradation, purine metabolism, nitrotoluene degradation, phenylalanine metabolism, fatty acid metabolism, tyrosine metabolism and bile acid metabolism pathways. The data obtained in this study may provide key clues to enhance our understanding of the metabolic mechanism of DN and shed new insights into the therapeutic mechanism of GDC.


Assuntos
Nefropatias Diabéticas/tratamento farmacológico , Medicamentos de Ervas Chinesas/uso terapêutico , Metabolômica , Substâncias Protetoras/uso terapêutico , Idoso , Biomarcadores/metabolismo , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/diagnóstico , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/patologia , Análise Discriminante , Feminino , Taxa de Filtração Glomerular , Humanos , Análise dos Mínimos Quadrados , Masculino , Pessoa de Meia-Idade , Substâncias Protetoras/química
8.
Life Sci ; 234: 116738, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31398418

RESUMO

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


Assuntos
Diabetes Mellitus Tipo 1/tratamento farmacológico , Nefropatias Diabéticas/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Glomérulos Renais/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Fosfato de Sitagliptina/uso terapêutico , Animais , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/patologia , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/patologia , Inibidores da Dipeptidil Peptidase IV/farmacologia , Glomérulos Renais/metabolismo , Glomérulos Renais/patologia , Masculino , Ratos , Ratos Wistar , Fosfato de Sitagliptina/farmacologia
9.
Diabetes Metab Syndr ; 13(4): 2661-2665, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31405691

RESUMO

AIM: diabetic patients are required for continuous monitoring programs hence continuous assessment of kidney function parameters is crucial. So, we aimed to determine the prevalence of Chronic Kidney Disease (CKD) and abnormal renal parameters, with poorly controlled type 2 diabetes mellitus pateints MATERIALS AND METHODS: A cross-sectional study was carried out at private health care centre. A total of 300 diabetic patients aged 18 years and above attended the clinic from February 2018 to Dec 2018 were included. Socio-demographic, clinical, and laboratory data were obtained from the medical records of patients. Statistical analysis was carried out using (SPSS, version 23). RESULTS: out of the 300 diabetes patients recruited 42% of patients with type 2 diabetes had abnormal Creatinine Serum levels and 22.3% had abnormal glomerular filtration rate (GFR). Abnormal albumin urine levels were found in 28.3% and 11.3% had abnormal creatinine in urine. Abnormal Albumin: Creatinine Ratios (Alb/Cr), were found in 23%. Of the total, 77% (n = 231) had normal Alb: Cr Ratio, 20% had risk of nephropathy and 9% had nephropathy. CONCLUSION: Current study revealed a high prevalence of abnormal renal parameters in patients with type 2 diabetes Mellitus. This necessitates the need for early and universal screening of renal functions. There is also an urgent demand for measures that target tight glycaemic, Vitamin D level and life style modifications is also required to all diabetic patients to achieve target value of HbA1C ≤ 7.


Assuntos
Biomarcadores/análise , Diabetes Mellitus Tipo 2/complicações , Nefropatias Diabéticas/epidemiologia , Insuficiência Renal Crônica/epidemiologia , Glicemia/análise , Estudos Transversais , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/patologia , Feminino , Seguimentos , Taxa de Filtração Glomerular , Hemoglobina A Glicada/análise , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Prognóstico , Insuficiência Renal Crônica/etiologia , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/patologia , Fatores de Risco , Emirados Árabes Unidos/epidemiologia
10.
BMC Complement Altern Med ; 19(1): 193, 2019 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-31362740

RESUMO

BACKGROUND: Wenshen Jianpi recipe (WSJPR), a blended traditional Chinese medicine, is considered to have the possible beneficial effect on the progression of diabetic nephropathy (DN). This present study was designed to elucidate this protective activity in a rat model with streptozotocin (STZ)-induced DN and to explore the possible underlying mechanism. METHODS: Adult Sprague Dawley (SD) rats were induced to develop DN through intraperitoneal injection of STZ (60 mg/kg). Animals were orally administered saline, WSJPR at 7.5, 15, 30 g/kg, and valsartan (25 mg/kg) daily for 8 weeks. Blood and 24-h urine samples of each rat were collected for biochemical examination at 2-week intervals. Microcirculatory blood flow in the renal cortex and hemorheology index were also measured. At the end of 8 weeks, all rats were sacrificed to obtain the kidney tissues for histological examination and reverse transcription polymerase chain reaction (RT-PCR) was used to analyze the transcriptional levels of nephrin and podocin genes. RESULTS: WSJPR could improve serum total protein (TP) and albumin (ALB), reduce the excretion rates of urine-TP (U-TP), urine-ALB (U-ALB) and urine urea nitrogen (UUN) (P < 0.05), although it did not significantly alter the hyperglycemia. In addition, treatment with WSJPR could strongly reduce blood flow, erythrocyte aggregation index, and ameliorate microcirculation. In histological measurement, WSJPR-treated rats showed a significant amelioration in glomerular hypertrophy and mesangial expansion. By RT-PCR, we found WSJPR up-regulated the nephrin and podocin expression at mRNA levels. CONCLUSION: This study suggested that WSJPR could effectively relieve renal damage and improve renal function of DN rats by ameliorating metabolism disorder and increasing the gene expression of nephrin and podocin, which might be a useful approach for the treatment of DN.


Assuntos
Nefropatias Diabéticas/tratamento farmacológico , Medicamentos de Ervas Chinesas/administração & dosagem , Proteinúria/tratamento farmacológico , Animais , Nefropatias Diabéticas/genética , Nefropatias Diabéticas/metabolismo , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas/química , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Rim/efeitos dos fármacos , Rim/lesões , Rim/metabolismo , Masculino , Medicina Tradicional Chinesa , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Proteinúria/genética , Proteinúria/metabolismo , Ratos , Ratos Sprague-Dawley
11.
Life Sci ; 235: 116796, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31470003

RESUMO

AIM: Depressor arm of the renin-angiotensin system (RAS) exerts reno-protective effects in chronic kidney diseases like diabetic nephropathy. However, same is still elusive under AKI and hyperglycaemia comorbidity. Hence, the present study delineates the role of angiotensin-II type 2 receptor (AT2R) and angiotensin-converting enzyme 2 (ACE2) in AKI under normal and hyperglycaemia condition. METHODS: Non-diabetic (ND) and Streptozotocin-induced diabetes mellitus (DM) rats were subjected to ischemic renal injury (IRI). Rats underwent IRI were treated with an AT2R agonist, C21 (0.3 mg/kg/day, i.p.) or ACE2 activator, Dize, (5 mg/kg/day, p.o.) either alone or as combination therapy. Renal histopathology and immunohistochemistry, proximal tubular fraction isolation, ELISA, immunoblotting and qRT-PCR were performed for subsequent analysis. KEY FINDINGS: Rats subjected to IRI displayed an increase in plasma ACE, AT1R, AT2R, Ang II, and reduction in ACE2, Ang-(1-7) expressions, with augmented renal inflammation and apoptosis. These changes were more prominent in diabetic rats with IRI. Co-administration of C21 and Dize augmented ACE2, Ang-(1-7), AT2R and MasR expressions, and attenuated tubular injury in both DM and ND rats. CONCLUSION: We demonstrated that pharmacological activation of AT2R and ACE2 protects DM and ND rats from IRI by preventing oxidative stress, inflammation and apoptosis-mediated tubular damage.


Assuntos
Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Tipo 1/complicações , Nefropatias Diabéticas/etiologia , Peptidil Dipeptidase A/metabolismo , Receptor Tipo 2 de Angiotensina/metabolismo , Traumatismo por Reperfusão/fisiopatologia , Animais , Apoptose , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/patologia , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/patologia , Inflamação/etiologia , Inflamação/metabolismo , Inflamação/patologia , Masculino , Estresse Oxidativo , Peptidil Dipeptidase A/química , Ratos , Ratos Wistar , Receptor Tipo 2 de Angiotensina/química
12.
Molecules ; 24(15)2019 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-31390847

RESUMO

Diabetic kidney disease develops in approximately 40% of diabetic patients and is a major cause of chronic kidney diseases (CKD) and end stage kidney disease (ESKD) worldwide. Hydrogen sulfide (H2S), the third gasotransmitter after nitric oxide (NO) and carbon monoxide (CO), is synthesized in nearly all organs, including the kidney. Though studies on H2S regulation of renal physiology and pathophysiology are still in its infancy, emerging evidence shows that H2S production by renal cells is reduced under disease states and H2S donors ameliorate kidney injury. Specifically, aberrant H2S level is implicated in various renal pathological conditions including diabetic nephropathy. This review presents the roles of H2S in diabetic renal disease and the underlying mechanisms for the protective effects of H2S against diabetic renal damage. H2S may serve as fundamental strategies to treat diabetic kidney disease. These H2S treatment modalities include precursors for H2S synthesis, H2S donors, and natural plant-derived compounds. Despite accumulating evidence from experimental studies suggests the potential role of the H2S signaling pathway in the treatment of diabetic nephropathy, these results need further clinical translation. Expanding understanding of H2S in the kidney may be vital to translate H2S to be a novel therapy for diabetic renal disease.


Assuntos
Sulfeto de Hidrogênio/metabolismo , Animais , Nefropatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/patologia , Avaliação Pré-Clínica de Medicamentos , Fibrose , Humanos , Sulfeto de Hidrogênio/química , Sulfeto de Hidrogênio/farmacologia , Sulfeto de Hidrogênio/uso terapêutico , Glomérulos Renais/efeitos dos fármacos , Glomérulos Renais/metabolismo , Glomérulos Renais/patologia , Redes e Vias Metabólicas/efeitos dos fármacos , Óxido Nítrico/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Oxigênio/metabolismo , Podócitos/metabolismo , Podócitos/patologia , Sistema Renina-Angiotensina
13.
Int J Mol Sci ; 20(14)2019 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-31295940

RESUMO

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


Assuntos
Nefropatias Diabéticas/etiologia , Suscetibilidade a Doenças , Inflamação/complicações , Animais , Biomarcadores , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/prevenção & controle , Nefropatias Diabéticas/terapia , Humanos , Mediadores da Inflamação/metabolismo , Transdução de Sinais
14.
Folia Med (Plovdiv) ; 61(2): 249-257, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-31301655

RESUMO

BACKGROUND: Diabetes mellitus (DM) leads to disruption of kidney function parameters (KFPs) which are markers of kidney diseases, especially nephropathy. Virgin coconut oil (VCO) has been implicated in playing a significant role in DM management. However, its role on KFPs in DM is scarce. AIM: To evaluate the kidney function parameters following VCO diet in diabetic rats. MATERIALS AND METHODS: Twenty-five (25) male rats of 150 - 200 g were divided into 5 groups (n=5): Non-diabetic control (Group 1), diabetes control (Group 2), diabetes + metformin (Group 3), diabetes + 10% VCO (Group 4) and diabetes + 20% VCO (Group 5). Apart from Group 1, other groups were given intraperitone-ally 50 mg/kg of streptozotocin to induce diabetes mellitus. After 72 hours, fasting hyperglycaemia was confirmed by glucose oxidase method. All the rats were fed normal rat chow for 8 weeks. At 8th week, serum and urine samples were analysed for biochemical analysis. After 8 weeks, Group 1 and Group 2 continued to be fed on normal rat chow while other groups were treated with diets (VCO) or drug (metformin) for 4 weeks. At 12th week, urine samples were collected for biochemical analysis, the rats were sacrificed, and blood samples were collected by cardiac puncture. RESULTS: There were significant differences in some KFPs in diabetes control (Group 2) compared to other experimental groups. However, there was no significant difference in glomerular filtration rate (GFR) and serum sodium in all the groups. CONCLUSION: VCO supplementary diet improved the altered KFPs and could be a therapy for kidney problems.


Assuntos
Óleo de Coco/farmacologia , Diabetes Mellitus Experimental/metabolismo , Nefropatias Diabéticas/metabolismo , Taxa de Filtração Glomerular/efeitos dos fármacos , Rim/efeitos dos fármacos , Animais , Nitrogênio da Ureia Sanguínea , Peso Corporal , Creatinina/metabolismo , Dieta , Hipoglicemiantes/farmacologia , Rim/metabolismo , Rim/patologia , Masculino , Metformina/farmacologia , Tamanho do Órgão/efeitos dos fármacos , Ratos , Albumina Sérica/efeitos dos fármacos
15.
Cells ; 8(7)2019 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-31262060

RESUMO

Diabetes-associated advanced glycation end-products (AGEs) can increase extracellular matrix (ECM) expression and induce renal fibrosis. Calbindin-D28k, which plays a role in calcium reabsorption in renal distal convoluted tubules, is increased in a diabetic kidney. The role of calbindin-D28k in diabetic nephropathy still remains unclear. Here, calbindin-D28k protein expression was unexpectedly induced in the renal tubules of db/db diabetic mice. AGEs induced the calbindin-D28k expression in human renal proximal tubule cells (HK2), but not in mesangial cells. AGEs induced the expression of fibrotic molecules, ECM proteins, epithelial-mesenchymal transition (EMT) markers, and endoplasmic reticulum (ER) stress-related molecules in HK2 cells, which could be inhibited by a receptor for AGE (RAGE) neutralizing antibody. Calbindin-D28k knockdown by siRNA transfection reduced the cell viability and obviously enhanced the protein expressions of fibrotic factors, EMT markers, and ER stress-related molecules in AGEs-treated HK2 cells. Chemical chaperone 4-Phenylbutyric acid counteracted the AGEs-induced ER stress and ECM and EMT markers expressions. Calbindin-D28k siRNA in vivo delivery could enhance renal fibrosis in db/db diabetic mice. These findings suggest that inducible calbindin-D28k protects against AGEs/RAGE axis-induced ER stress-activated ECM induction and cell injury in renal proximal tubule cells.


Assuntos
Calbindina 1/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Nefropatias Diabéticas/patologia , Produtos Finais de Glicação Avançada/metabolismo , Túbulos Renais Distais/patologia , Animais , Calbindina 1/genética , Diabetes Mellitus Tipo 2/complicações , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/metabolismo , Modelos Animais de Doenças , Retículo Endoplasmático/efeitos dos fármacos , Retículo Endoplasmático/patologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Fibrose , Técnicas de Silenciamento de Genes , Humanos , Túbulos Renais Distais/efeitos dos fármacos , Masculino , Células Mesangiais/metabolismo , Camundongos , Fenilbutiratos/farmacologia , RNA Interferente Pequeno/metabolismo , Receptor para Produtos Finais de Glicação Avançada/antagonistas & inibidores , Receptor para Produtos Finais de Glicação Avançada/metabolismo
16.
Mol Med Rep ; 20(2): 1754-1760, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31257485

RESUMO

Diabetic nephropathy (DN) is a major cause of chronic renal failure in diabetic patients worldwide. Betaine, a zwitterionic quaternary ammonium salt compound, is involved in numerous biological processes. The present study aimed to investigate the effects of betaine on mouse mesangial cells (MMCs) cultured under high glucose (HG) conditions and its underlying mechanisms. MMCs were treated with betaine under HG conditions. Cell proliferation and the cell cycle distribution were investigated with an MTT assay and flow cytometry, respectively. Western blotting and reverse transcription­quantitative polymerase chain reaction analyses were applied to respectively determine protein and mRNA expression levels. The results suggested that betaine decreased cell proliferation in a dose­dependent manner, while G1­phase arrest was significantly induced in MMCs. Compared with the control group, the expression levels of p21 and p27 decreased under HG conditions, but were reversed by betaine. Furthermore, the expression levels of fibronectin and type IV collagen were significantly decreased in cells treated with betaine compared with the HG group. Additionally, betaine decreased the phosphorylation of Akt, extracellular­signal­regulated kinase (Erk)1/2 and p38 mitogen­activated protein kinase (MAPK), but was enhanced under HG conditions. Overall, the results of the present study indicated that betaine serves a protective role in HG­induced MMCs by inhibiting cell proliferation and extracellular matrix deposition via regulating regulation of the Akt/Erk1/2/p38 MAPK signaling pathway.


Assuntos
Betaína/metabolismo , Glucose/metabolismo , Células Mesangiais/metabolismo , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Animais , Proliferação de Células , Células Cultivadas , Nefropatias Diabéticas/metabolismo , Ativação Enzimática , Matriz Extracelular/metabolismo , Células Mesangiais/citologia , Camundongos , Transdução de Sinais
17.
Life Sci ; 230: 197-207, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31150688

RESUMO

AIMS: Increased amounts of protein, in particular albumin within renal tubular cells (TBCs), induce the expression of inflammatory and fibrogenic mediators, which are adverse prognostic factors in tubulointerstitial fibrosis and diabetic nephropathy (DN). We sought to assess the participation of the thiol-linked tertiary structure of albumin in the mechanism of protein toxicity in a model of TBCs. MATERIALS AND METHODS: Cultured human renal proximal tubular cells, HK-2, were exposed to isolated albumin from patients with and without DN (Stages 0, 1 and 4). The magnitude of change of the albumin tertiary structure, cell viability (LDH leakage), apoptosis (Annexin V), transdifferentiation and reticulum endoplasmic stress (Western blot and flow cytometry) and lysosomal enzyme activity were assessed. KEY FINDINGS: We found that albumin from Stage 4 patients presented >50% higher thiol-dependent changes of tertiary structure compared to Stages 0 and 1. Cells incubated with Stage 4 albumin displayed 5 times less viability, accompanied by an increased number of apoptotic cells; evidence of profibrogenic markers E-cadherin and vimentin and higher expression of epithelial-to-mesenchymal transition markers α-SMA and E-cadherin and of endoplasmic reticulum stress protein GRP78 were likewise observed. Moreover, we found that cathepsin B activity in isolated lysosomes showed a significant inhibitory effect on albumin from patients in advanced stages of DN and on albumin that was intentionally modified. SIGNIFICANCE: Overall, this study showed that thiol-dependent changes in albumin's tertiary structure interfere with the lysosomal proteolysis of renal TBCs, inducing molecular changes associated with interstitial fibrosis and DN progression.


Assuntos
Nefropatias Diabéticas/metabolismo , Lisossomos/fisiologia , Albumina Sérica Humana/fisiologia , Adulto , Idoso , Albuminas/metabolismo , Apoptose/efeitos dos fármacos , Caderinas/metabolismo , Linhagem Celular , Sobrevivência Celular , Transdiferenciação Celular , Nefropatias Diabéticas/fisiopatologia , Estresse do Retículo Endoplasmático , Células Epiteliais/metabolismo , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Feminino , Fibrose , Humanos , Túbulos Renais/patologia , Masculino , Pessoa de Meia-Idade , Cultura Primária de Células , Estrutura Terciária de Proteína/fisiologia , Albumina Sérica Humana/metabolismo , Transdução de Sinais/efeitos dos fármacos , Vimentina/metabolismo
18.
Medicine (Baltimore) ; 98(24): e15850, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31192915

RESUMO

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


Assuntos
Nefropatias Diabéticas/tratamento farmacológico , Ubiquinona/análogos & derivados , Vitaminas/uso terapêutico , Glicemia/metabolismo , Colesterol/metabolismo , Nefropatias Diabéticas/metabolismo , Medicina Baseada em Evidências , Hemoglobina A Glicada/metabolismo , Humanos , Estudos Multicêntricos como Assunto , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento , Ubiquinona/uso terapêutico
19.
Nat Commun ; 10(1): 2461, 2019 06 05.
Artigo em Inglês | MEDLINE | ID: mdl-31165727

RESUMO

Epigenetic changes might provide the biological explanation for the long-lasting impact of metabolic alterations of diabetic kidney disease development. Here we examined cytosine methylation of human kidney tubules using Illumina Infinium 450 K arrays from 91 subjects with and without diabetes and varying degrees of kidney disease using a cross-sectional design. We identify cytosine methylation changes associated with kidney structural damage and build a model for kidney function decline. We find that the methylation levels of 65 probes are associated with the degree of kidney fibrosis at genome wide significance. In total 471 probes improve the model for kidney function decline. Methylation probes associated with kidney damage and functional decline enrich on kidney regulatory regions and associate with gene expression changes, including epidermal growth factor (EGF). Altogether, our work shows that kidney methylation differences can be detected in patients with diabetic kidney disease and improve kidney function decline models indicating that they are potentially functionally important.


Assuntos
Citosina/metabolismo , Metilação de DNA , Nefropatias Diabéticas/genética , Rim/metabolismo , Idoso , Estudos de Casos e Controles , Ilhas de CpG , Estudos Transversais , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/patologia , Progressão da Doença , Epigênese Genética , Feminino , Fibrose , Regulação da Expressão Gênica , Taxa de Filtração Glomerular , Humanos , Rim/patologia , Masculino , Pessoa de Meia-Idade
20.
Diabetes Metab Syndr ; 13(3): 1971-1973, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31235123

RESUMO

BACKGROUND: Vitamin D deficiency appears to be lower in diabetic patients. Vitamin D may affect glycemic control & diabetic nephropathy. AIM: To assess vitamin D level in type 2 diabetic patients and its relation to their glycemic control and development of nephropathy compared to healthy controls. DESIGN: and Setting: Case control study including 82 participants (41 cases and 41 controls) from Family Medicine Clinic, Cairo University Hospitals. METHOD: Participants fulfilling the inclusion criteria were allocated into two groups, diabetes and control groups. History was taken, examination was done, and blood sample was withdrawn for analysis of Vitamin D levels and HBA1C. From the diabetic group only, serum creatinine was assessed and urine sample was collected for microalbuminuria. The results were analyzed using SPSS program version 21. RESULTS: Vitamin D level was lower in the diabetic group compared to control (65.5% and 56.1%). Vitamin D level was inversely proportionate to HbA1c levels in the diabetic patients (p value 0.000 & r -0.482), as well as to the A/C ratio (p value 0.01 & r -0.396). CONCLUSION: Vitamin D level appeared to be lower in diabetic patients and is associated with poor glycemic control & microalbuminuria.


Assuntos
Biomarcadores/análise , Diabetes Mellitus Tipo 2/complicações , Nefropatias Diabéticas/etiologia , Intolerância à Glucose/etiologia , Deficiência de Vitamina D/fisiopatologia , Vitamina D/sangue , Adulto , Glicemia/análise , Estudos de Casos e Controles , Estudos Transversais , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/patologia , Feminino , Seguimentos , Intolerância à Glucose/metabolismo , Intolerância à Glucose/patologia , Hemoglobina A Glicada/análise , Índice Glicêmico , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Deficiência de Vitamina D/sangue , Vitaminas/sangue
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