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1.
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
2.
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
3.
Diabetes Res Clin Pract ; 155: 107809, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31401150

RESUMO

AIMS: Both clinical and pathogenetic markers for accurate prediction of end-stage renal disease in diabetic nephropathy (DN) are lacking. This study aimed to establish an effective prognostic nomogram and a score for renal survival (RS) in biopsy-proven DN. METHODS: Analyses were derived from 110 DN patients who underwent renal biopsy at China-Japan Friendship Hospital between January 2006 and May 2018 with DN as the only glomerular disease diagnosis. The prognostic ability of 34 baseline clinicopathologic parameters was evaluated using univariate and multivariate Cox regression analyses. The predictive accuracy and discriminative ability of the final model were measured using the calibration curve and concordance index (C-index). Internal validation of the model was assessed using bootstrap resampling. RESULTS: Urinary proteinuria excretion, stages of chronic kidney disease, glomerular hyalinosis, and extracapillary hypercellularity were independent prognostic factors for RS, and all were selected into the nomogram. The calibration curve for the probability of survival showed good agreement between the prediction by nomogram and actual observation. The C-index for predicting survival was 0.79 (95% confidence interval (CI) 0.72-0.86). A high C-index value of 0.76 indicated good internal validation. The prognostic score had the potential to delineate two prognosis groups with median RS of 24 and 70 months, respectively. CONCLUSIONS: The proposed nomogram and score provide a useful individualized risk estimate of renal prognosis in patients with DN.


Assuntos
Nefropatias Diabéticas/diagnóstico , Nomogramas , Adulto , Idoso , Nefropatias Diabéticas/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos
4.
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
5.
Diabetes Res Clin Pract ; 155: 107807, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31394129

RESUMO

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


Assuntos
Índice de Massa Corporal , Nefropatias Diabéticas/diagnóstico , Nefropatias Diabéticas/prevenção & controle , Hemoglobina A Glicada/análise , Diabetes Mellitus Tipo 2/sangue , Nefropatias Diabéticas/patologia , Feminino , Humanos , Japão , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Pacientes Ambulatoriais , Estudos Retrospectivos
6.
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
7.
DNA Cell Biol ; 38(10): 1134-1142, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31433203

RESUMO

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


Assuntos
Captopril/farmacologia , Diabetes Mellitus Experimental/tratamento farmacológico , Nefropatias Diabéticas/tratamento farmacológico , Regulação da Expressão Gênica/efeitos dos fármacos , Hiperglicemia/tratamento farmacológico , Hipoglicemiantes/farmacologia , Espironolactona/farmacologia , Animais , Anti-Hipertensivos/farmacologia , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Nitrogênio da Ureia Sanguínea , Creatinina/sangue , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/patologia , Nefropatias Diabéticas/induzido quimicamente , Nefropatias Diabéticas/genética , Nefropatias Diabéticas/patologia , Diuréticos/farmacologia , Combinação de Medicamentos , Reposicionamento de Medicamentos , Hiperglicemia/induzido quimicamente , Hiperglicemia/genética , Hiperglicemia/patologia , Masculino , MicroRNAs/genética , MicroRNAs/metabolismo , Ratos , Ratos Wistar , Estreptozocina/administração & dosagem , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismo , Resultado do Tratamento
8.
J Diabetes Res ; 2019: 8153140, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31467929

RESUMO

A variety of animal models of diabetes mellitus (DM) are required to study the genetics and pathophysiology of DM. We established a novel rat strain showing nonobese type 2 diabetes with enlarged kidneys from the LEA.PET-pet congenic strain and named it Diabetes with Enlarged Kidney (DEK). The body growth of DEK affected rats was similar to that of normal rats before the development of DM but was attenuated with the deterioration of DM. There was a marked difference in the etiology of DEK by gender: DM phenotypes including polyuria, polydipsia, and hyperglycemia (nonfasting blood glucose over 300 mg/dl) were found in male rats aged over 10 weeks but not in female rats. The cumulative incidence of DM in DEK males at the age of 30 weeks was 44.8%. Oral glucose tolerance tests showed glucose intolerance and decreased insulin secretion in response to glucose loading in affected males, features which were exacerbated with age. Affected males exhibited disorganized architecture of pancreatic islets, decreased numbers of ß cells, and markedly decreased expression of insulin, despite no pathological findings of hemorrhage or infiltration of inflammatory cells in the pancreatic islet. Age-related islet fibrosis appeared similar in normal and affected males. Affected males also showed enlarged kidneys with dilation of renal tubules in both the cortex and medulla, but no obvious glomerular lesions typical of diabetic nephropathy (DN) at the age of 30 weeks. Plasma levels of urea nitrogen and creatinine were normal, but hypoalbuminemia was detected. These pathophysiological features in affected males indicated that their renal function was almost maintained despite severe DM. Taken together, these findings indicate that the affected males of the DEK strain are a novel nonobese type 2 diabetes rat model useful for studying the mechanisms underlying ß cell loss and identifying genetic factors protective against DN.


Assuntos
Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 2/patologia , Nefropatias Diabéticas/etiologia , Rim/patologia , Animais , Animais Congênicos , Glicemia/análise , Glicemia/metabolismo , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Nefropatias Diabéticas/sangue , Nefropatias Diabéticas/patologia , Feminino , Teste de Tolerância a Glucose , Hiperglicemia/complicações , Hiperglicemia/patologia , Hipertrofia/sangue , Hipertrofia/etiologia , Masculino , Polidipsia/etiologia , Polidipsia/patologia , Poliúria/etiologia , Poliúria/patologia , Ratos , Ratos Endogâmicos
9.
Life Sci ; 234: 116755, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31415769

RESUMO

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


Assuntos
Sistema Enzimático do Citocromo P-450/genética , Diabetes Mellitus Experimental/complicações , Nefropatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/etiologia , Ergocalciferóis/farmacologia , Túbulos Renais Proximais/efeitos dos fármacos , Receptores de Calcitriol/agonistas , Animais , Linhagem Celular , Sistema Enzimático do Citocromo P-450/metabolismo , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/patologia , Nefropatias Diabéticas/genética , Nefropatias Diabéticas/patologia , Ergocalciferóis/uso terapêutico , Deleção de Genes , Regulação da Expressão Gênica/efeitos dos fármacos , Glucose/metabolismo , Túbulos Renais Proximais/metabolismo , Túbulos Renais Proximais/patologia , Masculino , Camundongos , Camundongos Knockout , Receptores de Calcitriol/genética , Receptores de Calcitriol/metabolismo
10.
Int J Mol Sci ; 20(14)2019 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-31373312

RESUMO

Diabetic nephropathy is increasingly recognized as a major contributor to kidney failure in patients with obesity and type 2 diabetes. This study was designed to identify the molecular mediators of kidney injury associated with metabolic syndrome with or without hyperglycemia. We compared renal gene expression profiles in Zucker lean (ZL), Zucker obese (ZO), and Zucker diabetic (ZD) rats using cDNA microarray with quantitative verification of selected transcripts by real-time PCR. Compared to the 20-week-old ZL control (glucose: 110 ± 8 mg/dL), both prediabetic ZO (glucose: 157 ± 11 mg/dL) and diabetic ZD (glucose: 481 ± 37 mg/dL) rats displayed hyperlipidemia and kidney injury with a high degree of proteinuria. cDNA microarray identified 25 inflammation and injury-related transcriptomes whose expression levels were similarly increased in ZO and ZD kidneys. Among them, kidney injury molecule-1 (KIM-1) was found to be the most highly upregulated in both ZO and ZD kidneys. Immunofluorescence staining of kidney sections revealed a strong correlation between lipid overload and KIM-1 upregulation in proximal tubules of ZO and ZD rats. In cultured primary renal tubular epithelial cells (TECs), administration of saturated fatty acid palmitate resulted in an upregulation of KIM-1, osteopontin, and CD44, which was greatly attenuated by U0126, an inhibitor of extracellular signal-regulated kinase (ERK)1/2. Moreover, knockdown of KIM-1 by siRNA interference inhibited palmitate-induced cleaved caspase-3, osteopontin, and CD44 proteins in primary TECs. Our results indicate that KIM-1 expression is upregulated in renal lipotoxicity and may play an important role in fatty acid-induced inflammation and tubular cell damage in obesity and diabetic kidney disease.


Assuntos
Moléculas de Adesão Celular/metabolismo , Nefropatias Diabéticas/patologia , Hiperlipidemias/patologia , Túbulos Renais/patologia , Obesidade/patologia , Animais , Caspase 3/biossíntese , Moléculas de Adesão Celular/genética , Perfilação da Expressão Gênica , Receptores de Hialuronatos/biossíntese , Hiperglicemia/patologia , Hiperlipidemias/sangue , Túbulos Renais/lesões , Síndrome Metabólica/patologia , Osteopontina/biossíntese , Palmitatos/toxicidade , Proteinúria/urina , Interferência de RNA , RNA Interferente Pequeno/genética , Ratos , Ratos Zucker , Transcriptoma/genética
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.
Med Arch ; 73(2): 87-91, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31391693

RESUMO

Introduction: In patients with diabetes mellitus (DM), non-diabetic renal disease (NDRD) can also occurs, as well as diabetic nephropathy. NDRD is most accurately diagnosed using kidney biopsy. Aim: The aim of the study was to investigate the incidence and type of NDRD diagnosed by kidney biopsy in patients with type 2 DM and the correlation of clinical and laboratory findings with histopathological diagnosis. Material and Methods: From April 2007 to October 2018, 290 kidney biopsies were performed at the Department of Nephrology, Internal Medicine Clinic in Banja Luka, out of which 18 patients (males 9, mean age 59.8 years) were with type 2 DM. The US-guided (ultrasound device: Toshiba Famio 5) kidney biopsy was performed using an automatic biopsy instrument FAST-GUN® with needle 16G. Kidney tissue samples were analyzed by light microscopy and immunofluorescence. Results: In 18 patients with type 2 DM, the average duration of the disease was 5.9 years, 5 patients had a retinopathy, and 16 patients had hypertension. Biopsy indications were: nephrotic syndrome in 11 patients, asymptomatic urinary abnormalities in 3 patients, and rapid chronic renal failure progression. Unsatisfactory quality sample for pathohistological analysis was obtained in one patient, and out of the other 17, 6 (35.3%) had NDRD, 3 (17.6%) had NDRD superimposed with the diabetic nephropathy, and 8 (47.1%) had diabetic nephropathy. Of the patients who had NDRD, 3 had membranous glomerulonephritis, 1 had focal segmental glomerulosclerosis, and two had hypertensive nephroangiosclerosis. Out of patients with coexisting NDRD and diabetic nephropathy, 2 had hypertensive nephroangiosclerosis and one diabetic nephropathy and lupus nephritis. Conclusion: NDRD was diagnosed using kidney biopsy in 9/17 patients with type 2 DM, which confirms the significance of the kidney biopsy in patients with DM with properly indications. Accurate diagnosis provides disease specific treatment and thus significantly improves the long-term prognosis of the patient.


Assuntos
Diabetes Mellitus Tipo 2/epidemiologia , Nefropatias Diabéticas/epidemiologia , Glomerulonefrite Membranosa/epidemiologia , Glomerulosclerose Segmentar e Focal/epidemiologia , Nefrite Lúpica/epidemiologia , Nefroesclerose/epidemiologia , Insuficiência Renal Crônica/epidemiologia , Adulto , Idoso , Comorbidade , Nefropatias Diabéticas/patologia , Feminino , Glomerulonefrite Membranosa/patologia , Glomerulosclerose Segmentar e Focal/patologia , Humanos , Biópsia Guiada por Imagem , Nefrite Lúpica/patologia , Masculino , Pessoa de Meia-Idade , Nefroesclerose/patologia , Insuficiência Renal Crônica/patologia , Ultrassonografia
14.
Ren Fail ; 41(1): 682-690, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31352855

RESUMO

Objective: Macrophage infiltration in kidney is a major pathological feature of diabetic nephropathy (DN), which has been demonstrated associate with macrophages autophagy homeostasis. However, the relationships between autophagy and the infiltration response related of macrophages adhesion and migration are unknown. This study aims to investigate the impact of macrophages adhesion and migration by modulating autophagy. Methods: In vivo, rats were randomly distributed into control (NC) and DN groups. The pathological changes in renal tissue were assessed, and expression of CD68, LC3, P62 were analyzed. In vitro, RAW264.7 cells were divided into NC and high glucose (HG) groups. The capacity of macrophages adhesion migration and the expression of autophagy markers were observed with and without autophagy modulators (rapamycin, 3-methyladenine, chloroquine, and bafilomycin A1 for RAPA, 3-MA, CQ, BAFA). The macrophages autophagosome and the process of degradation and fusion of autophagosome-lysosome were observed by electron microscopy. Results: In vivo, renal injury is aggravated in diabetic rat compared with NC group. The autophagy level is inhibited in renal tissues of DN group with the increasing expression of CD68 and P62, while expression level of LC3 decreased (p < .05). In vitro, HG and 3-MA reduce the numbers of autophagosome of macrophages to inhibit autophagy level with decrease expression of LC3 and Beclin-1, but increase expression of P62, which promote the adhesion and migration capacity of macrophages (p < .05). Moreover, CQ and BAFA suppress autophagy level by inhibiting the process of autophagosome-lysosome degradation and fusion of macrophages, as well as the expression of LC3 and Beclin-1. We notice an increase expression of P62 by CQ and BAFA stimulation (p < .05). CQ and BAFA further facilitate the adhesion and migration capacity of macrophages. However, RAPA increases the numbers of macrophages autophagosome that inhibited by HG, resulting in a recovery of autophagy level with increase expression of LC3 and Beclin-1, whereas a reduction expression of P62, which lead to inhibition of adhesion and migration of macrophages induced by HG (p < .05) Conclusions: High glucose efficiently reduced the level of macrophage autophagy, following macrophages adhesion and migration enhanced when autophagy is suppressed. Activation of autophagosome improve the level of autophagy, but leading to a reduction of the macrophages adhesion and migration. While, inhibiting the process of degradation and fusion of autophagosome-lysosome suppress the level of autophagy and promote the macrophages adhesion and migration. These results indicate that high glucose may play an important role in macrophages adhesion and migration through modulating autophagy activities in diabetic nephropathy.


Assuntos
Autofagia , Nefropatias Diabéticas/patologia , Macrófagos/citologia , Macrófagos/patologia , Animais , Autofagossomos/ultraestrutura , Adesão Celular , Linhagem Celular , Movimento Celular , Diabetes Mellitus Experimental/patologia , Glucose/metabolismo , Rim/patologia , Lisossomos/ultraestrutura , Masculino , Microscopia Eletrônica de Transmissão , Proteínas Associadas aos Microtúbulos/metabolismo , Ratos , Ratos Sprague-Dawley
15.
Diabetes Metab Syndr ; 13(2): 1287-1292, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31336479

RESUMO

CONTEXT: Diabetes mellitus is a common disease which is prevalent globally, presenting with chronic complications and constitutes a major risk to the patient. Diabetic foot ulcers are the single biggest risk factor for non-traumatic lower limb amputations in persons with diabetes. We aimed to screen for the chronic vascular diabetic complications in patients with diabetic foot ulcers (DFUs) and to assess the association of diabetic foot ulcers with these complications in the study group. SUBJECTS AND METHODS: This cross-sectional study included 180 type 2 diabetic patients (aged 30-70 years) with diabetic foot ulcers who attended the Outpatient Clinic of Diabetes in Alexandria Main University Hospital. Full diabetic foot examination was done to all study subjects. DFUs were assessed using University of Texas Diabetic Wound Classification System. HbA1c, LDL-C, serum creatinine, and urinary albumin creatinine ratio (ACR) were measured for all study subjects. Estimated glomerular filtration rate (eGFR) was calculated using CKD-EPI equation. Fundus examination was done for all study subjects. RESULTS: The prevalence of diabetic kidney disease (DKD) and diabetic retinopathy (DR) was 86.1% and 90% respectively among the study group. 86.7% of patients had neuropathic DFUs, 11.1% of them had ischemic DFUs and 2.2% had neuro-ischemic DFUs. Regarding diabetic peripheral neuropathy (DPN) and peripheral arterial disease (PAD) as risk factors for developing DFU, the prevalence of both of them respectively was 82% and 20% among the study group. There was statistically significant association between both DKD, DR and peripheral neuropathy. There was also statistically significant association between both DKD, DR and peripheral arterial disease (PAD). CONCLUSION: Chronic vascular diabetic complications are common among type 2 diabetic patients with diabetic foot ulcers. There is statistically significant association between these complications and diabetic peripheral neuropathy (DPN) and peripheral arterial disease (PAD).


Assuntos
Diabetes Mellitus Tipo 2/complicações , Pé Diabético/etiologia , Nefropatias Diabéticas/etiologia , Neuropatias Diabéticas/etiologia , Retinopatia Diabética/etiologia , Adulto , Idoso , Doença Crônica , Estudos Transversais , Pé Diabético/epidemiologia , Pé Diabético/patologia , Nefropatias Diabéticas/epidemiologia , Nefropatias Diabéticas/patologia , Neuropatias Diabéticas/epidemiologia , Neuropatias Diabéticas/patologia , Retinopatia Diabética/epidemiologia , Retinopatia Diabética/patologia , Egito/epidemiologia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Prognóstico , Fatores de Risco
16.
Diabetes Metab Syndr ; 13(2): 1491-1496, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31336511

RESUMO

AIMS: Albuminuria is an established marker for endothelial dysfunction and cardiovascular risk in diabetes and prediabetes. So we aimed to explore the prevalence of albuminuria (microalbuminuria and macroalbuminuria) in patients with type2 diabetes mellitus (DM) in the Palestinian community and to determine the association between albuminuria and other health care and biochemical indicators. MATERIALS AND METHODS: A cross-sectional study was carried out at private health care center. A total of 550 diabetic patients aged 35 years and above with type 2 diabetes mellitus who attended the clinic from May 2017 through February 2018 were included. Socio-demographic, clinical, and laboratory data were obtained from the medical records of patients. Statistical analysis was carried out using the Statistical Package for the Social Sciences (SPSS, version 23). RESULTS: Out of the 550 patients recruited, the mean age and duration of diabetes were 57.8 years and 9.5 years, respectively. Approximately 62% were being managed by oral hypoglycemic agents alone, 4.3% by insulin alone, 31.7% were on a combination of oral hypoglycemic agents and insulin and slightly less than 2% were on dietary measures alone. The mean value for HbA1c was 7.71%. The overall prevalence of albuminuria among participants was found to be 34.6%; microalbuminuria (29.3%) and macroalbuminuria (5.3%). CONCLUSION: Albuminuria is highly prevalent among Palestinian population with type 2 diabetes. This calls for early and universal screening of urinary albumin. There is also an urgent need for measures that target tight glycemic and optimal blood pressure control and the use of renin-angiotensin system blockade.


Assuntos
Albuminúria/epidemiologia , Biomarcadores/análise , Diabetes Mellitus Tipo 2/complicações , Nefropatias Diabéticas/epidemiologia , Nefropatias Diabéticas/etiologia , Idoso , Albuminúria/etiologia , Albuminúria/patologia , Glicemia/análise , Estudos Transversais , Nefropatias Diabéticas/patologia , Feminino , Seguimentos , Hemoglobina A Glicada/análise , Humanos , Masculino , Pessoa de Meia-Idade , Oriente Médio/epidemiologia , Prevalência , Prognóstico , Fatores de Risco
17.
Kidney Blood Press Res ; 44(4): 449-456, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31291624

RESUMO

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


Assuntos
Nefropatias Diabéticas/tratamento farmacológico , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Animais , Nefropatias Diabéticas/patologia , Nefropatias Diabéticas/prevenção & controle , Deslocamentos de Líquidos Corporais/efeitos dos fármacos , Humanos , Substâncias Protetoras , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia
18.
Clin Chim Acta ; 496: 108-116, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31276635

RESUMO

Although diabetic kidney disease (DKD) is the most common cause of end-stage kidney disease worldwide, the pathogenic mechanisms are poorly understood. There is increasing evidence that mitochondrial dysfunction contributes to the development and progression of DKD. Because the kidney is the organ with the second highest oxygen consumption in our body, it is distinctly sensitive to mitochondrial dysfunction. Mitochondrial dysfunction contributes to the progression of chronic kidney disease irrespective of underlying cause. More importantly, high plasma glucose directly damages renal tubular cells, resulting in a wide range of metabolic and cellular dysfunction. Overproduction of reactive oxygen species (ROS), activation of apoptotic pathway, and defective mitophagy are interlinked mechanisms that play pivotal roles in the progression of DKD. Although renal tubular cells have the highest mitochondrial content, podocytes, mesangial cells, and glomerular endothelial cells may all be affected by diabetes-induced mitochondrial injury. Urinary mitochondrial DNA (mtDNA) is readily detectable and may serve as a marker of mitochondrial damage in DKD. Unfortunately, pharmacologic modulation of mitochondrial dysfunction for the treatment of DKD is still in its infancy. Nonetheless, understanding the pathobiology of mitochondrial dysfunction in DKD would facilitate the development of novel therapeutic strategies.


Assuntos
Nefropatias Diabéticas/patologia , Mitocôndrias/patologia , Nefropatias Diabéticas/tratamento farmacológico , Humanos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Insuficiência Renal Crônica/patologia
19.
Medicine (Baltimore) ; 98(27): e16333, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31277183

RESUMO

The prognostic utility of histologic features in patients with diabetic nephropathy (DN) classified according to the Renal Pathology Society (RPS) classification is controversial. Therefore, we aimed to evaluate the relationship between histologic changes and renal outcome in DN patients.We examined the renal outcome at November 30, 2017 of 74 adult patients (median age of 54.6 years, 69% male, 81% diabetes mellitus (DM) type 2, estimated GFR (eGFR) 29.6 mL/min) with biopsy proven DN between 2010 and 2015. The primary endpoint was renal replacement therapy (RRT) initiation.Half of the patients progressed to end stage renal disease (ESRD) during follow-up; they had lower eGFR, increased proteinuria, hematuria and serum cholesterol. Regarding the pathologic features, they were more frequently in class III and IV, had higher interstitial fibrosis and tubular atrophy score (IFTA), increased interstitial inflammation, more frequent arteriolar hyalinosis and higher glomerular basement membrane (GBM) thickness. The mean kidney survival time was 2.7 (95%CI 2.1, 3.3) years. In univariate time-dependent analyses, higher RPS DN class, increased IFTA, the presence of arteriolar hyalinosis and arteriosclerosis were associated with RRT initiation.In the fully adjusted model, the clinical characteristics associated with poor renal survival were longer duration of DM, lower eGFR, increased proteinuria and higher hematuria and the only pathologic lesions to remain significant were the GBM thickness and the IFTA.In conclusion, in this European cohort, the severity of glomerular lesions evaluated with the RPS DN classification had limited utility in predicting RRT initiation. However, IFTA and GBM thickness were significantly associated with renal survival.


Assuntos
Nefropatias Diabéticas/patologia , Falência Renal Crônica/etiologia , Nefropatias Diabéticas/mortalidade , Nefropatias Diabéticas/terapia , Feminino , Humanos , Falência Renal Crônica/diagnóstico , Falência Renal Crônica/terapia , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Terapia de Substituição Renal , Estudos Retrospectivos , Taxa de Sobrevida
20.
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
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