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1.
J Assoc Physicians India ; 67(7): 30-33, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31559765

RESUMO

Objectives: Individual with diabetes may have several from of Dyslipidemia. Dyslipidemia has been considered to be factor that plays a risk in progression of micro vascular disease, especially in diabetes.1 The present study is intended to Study of correlation between Apolipoprotein B and Dyslipidemia in type 2 diabetes patients and prevalence of dyslipidemia in type 2 diabetic patients. Material and Methods: Prospective cross- sectional study conducted on 100 cases of type 2 diabetes mellitus. Groups are divided according to A/C ratio and association of dyslipidemia was seen. Serum Apolipoprotein B was measured using immunoturbidimetric method. Results: Pearson's correlation analysis of Apo B with lipid parameters in diabetic patients showed that, LDL, TC and Tg were positively correlated with Apo- B. There was a positive and linear correlation between LDL and Tg. Apo- B was negatively correlated with HDL-C. Conclusion: The majority of patients studied had low HDL-C, elevated non HDL- C, elevated total cholesterol, elevated triglycerides, elevated LDL -C and elevated apo B. Apolipoprotein B had a positive linear correlation with total cholesterol, triglycerides, LDL-C, non-HDL-C. The strongest positive correlation was with nonHDL-C. Patients with low HDL-C had high apo B levels.


Assuntos
Apolipoproteínas B/metabolismo , Diabetes Mellitus Tipo 2/epidemiologia , Dislipidemias/epidemiologia , Proteinúria/metabolismo , HDL-Colesterol , Humanos , Estudos Prospectivos , Centros de Atenção Terciária , Triglicerídeos
2.
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
3.
Clin Biochem ; 71: 77-80, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31299318

RESUMO

Tetrabromphenol blue dye based methods are used to detect proteinuria using urinalysis dipsticks. Manufacturers have claimed that alkalinity leads to false positive proteinuria, and that high specific gravity leads to false negative protein results. However, published reports describing this phenomenon remain equivocal. This study aimed to determine whether pH and/or specific gravity affect protein detection in patient urine using three different tetrabromophenol blue dye-based dipsticks. Patient urine pools were divided into individual aliquots with varied pH or specific gravity, and measured for protein in triplicate using iChem 10SG, iChem Velocity, and Multistix 8SG dipsticks. The pH experiment involved progressive alkalinization of urine aliquots with either 1M NaOH, Na2CO3, or NaHCO3; pH was recorded by electrode. The specific gravity experiment involved mixing aliquots with NaCl and spiking with human albumin. Urine electrolytes and total CO2 were measured (Roche cobas 8000). Fresh patient urines (N = 35) were analyzed for physiological urine pH and total CO2. Urine protein results were not affected by NaOH alkalinization up to pH 10.9. False positive protein occurred at pH 9.9 and >97 mmol/L total CO2 (Na2CO3 alkalization; P < .05). Moreover, false positive protein occurred at pH 7.6 when total CO2 exceeded 137 mmol/L (NaHCO3 alkalization; P < .05). Fresh patient urines did not exceed pH 8.5 or 86 mmol/L total CO2. NaCl elevated specific gravity and caused false negative protein detection when urine ionic strength was >1100 mmol/L (P < .05). Tetrabromphenol blue dipsticks provide robust detection of proteinuria when human urine is within physiological pH, total CO2 and ionic strength.


Assuntos
Concentração de Íons de Hidrogênio , Proteinúria/metabolismo , Fitas Reagentes , Gravidade Específica , Urina/química , Artefatos
4.
Intern Med ; 58(22): 3255-3259, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31292404

RESUMO

Disturbance of the normal gut microbiota has been implicated in the pathogenesis of various diseases, including chronic kidney disease (CKD). A common CKD symptom is chronic constipation. Lubiprostone is a safe and efficacious drug for treating chronic constipation. We herein report 2 patients with IgA nephropathy treated with lubiprostone (24 µg 1×/day). The lubiprostone treatment ameliorated their chronic constipation and, unexpectedly, reduced the urinary protein excretion, urinary liver-type fatty acid binding protein and urine occult blood. These results may indicate that lubiprostone is a useful therapeutic intervention against the progression of IgA nephropathy with chronic constipation.


Assuntos
Constipação Intestinal/tratamento farmacológico , Lubiprostona/farmacologia , Lubiprostona/uso terapêutico , Adulto , Doença Crônica , Constipação Intestinal/etiologia , Progressão da Doença , Proteínas de Ligação a Ácido Graxo/urina , Feminino , Glomerulonefrite por IGA/complicações , Glomerulonefrite por IGA/tratamento farmacológico , Humanos , Sangue Oculto , Proteinúria/metabolismo
5.
J Ethnopharmacol ; 243: 112078, 2019 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-31301369

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Rhododendron molle G. Don (Ericaceae) (RM) is a natural medicinal plant. Its root extracts have been applied in clinic and proved to be effective in chronic glomerulonephritis and rheumatoid arthritis in China. Surprising, little is understood about the key compound of RM and the exact mechanisms underlying its treatment on kidney diseases. In this study, we will explore whether rhodojaponin II (R-II), as the important compound of RM, also exerts the major effect. MATERIALS AND METHODS: Mouse model of focal segmental glomerulosclerosis was induced by single dose of adriamycin injection. Induced adriamycin nephropathy (ADRN) mice were treated individually with RM root extract (5 mg/kg, n = 5), RM root extract (60 mg/kg, n = 5), R-II (0.04 mg/kg, n = 6) or captopril (30 mg/kg, n = 5) for five weeks. Podocyte marker (nephrin and podocin) expressions were examined by immunohistochemical staining and Western Blot analysis. Fibronectin level was evaluated by immunohistochemical staining and Western Blot analysis. Interstitial infiltrated inflammatory cells (CD4+ T cells, CD8+ T cells, and CD68+ macrophages) were examined with immunohistochemical staining. The expressions of NF-ĸB p-p65 and TGF-ß1/Smad pathway associated key proteins, such as TGF-ß1, Smad3, phosphorylated-Smad3 (p-Smad3), and Smad7, were analyzed respectively by Western Blot analysis. RESULTS: RM root extract (5 mg/kg) and its important compound R-II (0.04 mg/kg) significantly ameliorated proteinuria, podocyte injury, and glomerulosclerosis, meanwhile, they hampered interstitial fibrosis in mice with ADRN. R-II significantly reduced NF-ĸB p65 phosphorylation, interstitial infiltrated CD4+ T cells, CD8+ T cells, and CD68+ macrophages, at the same time, down-regulated TGF-ß1 and p-Smad3 protein expressions in mice with ADRN. CONCLUSION: RM root extract, R-II, could effectively ameliorate proteinuria and kidney injury in ADRN, related to its anti-inflammatory effects, as well as suppression of TGF-ß1/Smad signaling pathway.


Assuntos
Anti-Inflamatórios , Glomerulosclerose Segmentar e Focal , Extratos Vegetais , Proteinúria , Rhododendron , Proteínas Smad/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Doxorrubicina , Glomerulosclerose Segmentar e Focal/induzido quimicamente , Glomerulosclerose Segmentar e Focal/tratamento farmacológico , Glomerulosclerose Segmentar e Focal/metabolismo , Glomerulosclerose Segmentar e Focal/patologia , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Masculino , Camundongos Endogâmicos BALB C , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Raízes de Plantas , Proteinúria/induzido quimicamente , Proteinúria/tratamento farmacológico , Proteinúria/metabolismo , Proteinúria/patologia , Transdução de Sinais/efeitos dos fármacos
7.
Amyloid ; 26(3): 164-170, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31240945

RESUMO

Aims: To test the hypothesis that the fibril morphology and the fibril protein primary structure are conserved across different patients suffering from the common variant of systemic Amyloid A (AA) amyloidosis. Methods: Amyloid fibrils were extracted from the renal tissue of four patients. The fibril morphology was analysed in negatively stained samples with transmission electron microscopy (TEM). The fibril protein identity and fragment length were determined by using mass spectrometry. Results: The fibrils show a consistent morphology in all four patients and exhibit an average width of ∼9.6 nm and an average pitch of ∼112 nm. All fibrils are composed of polypeptide chains that can be assigned to human serum amyloid A (SAA) 1.1 protein. All fragments lack the N-terminal arginine residue and are C-terminally truncated. Differences exist concerning the exact C-terminal cleavage site. The most prominent cleavage site occurs at residues 64-67. Conclusions: Our data demonstrate that AA amyloid fibrils are consistent at the level of the protein primary structure and fibril morphology in the four analysed patients.


Assuntos
Amiloide/ultraestrutura , Amiloidose de Cadeia Leve de Imunoglobulina/metabolismo , Rim/metabolismo , Proteinúria/metabolismo , Idoso , Amiloide/metabolismo , Biópsia , Creatinina/sangue , Feminino , Humanos , Amiloidose de Cadeia Leve de Imunoglobulina/patologia , Amiloidose de Cadeia Leve de Imunoglobulina/cirurgia , Rim/patologia , Masculino , Microscopia Eletrônica de Transmissão , Pessoa de Meia-Idade , Modelos Moleculares , Proteinúria/patologia , Proteinúria/cirurgia , Reto/metabolismo , Reto/cirurgia
8.
Intern Med ; 58(20): 2983-2988, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31243205

RESUMO

MYH9-related disease is a rare genetic disorder characterized by macrothrombocytopenia, with frequent proteinuric nephropathy, hearing loss, and cataract. Although proteinuric nephropathy usually progresses to renal failure, there is no established treatment for the nephropathy. We herein describe the case of a 19-year-old man carrying an E1841K MYH9 mutation, who developed persistent proteinuria. The patient was diagnosed with early-stage MYH9-related nephropathy based on the histological examination of a kidney biopsy specimen. The patient was treated with enalapril, which significantly reduced the proteinuria with no decline in his renal function. The early administration of renin-angiotensin system blockade therapy may have beneficial effects on MYH9-related nephropathy in patients with E1841K mutations. We also briefly summarize previously published cases of MYH9-related nephropathy treated with renin-angiotensin system (RAS) blockade therapy.


Assuntos
DNA/genética , Enalapril/uso terapêutico , Perda Auditiva Neurossensorial/tratamento farmacológico , Mutação , Cadeias Pesadas de Miosina/genética , Proteinúria/etiologia , Sistema Renina-Angiotensina/efeitos dos fármacos , Trombocitopenia/congênito , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Biópsia , Análise Mutacional de DNA , Perda Auditiva Neurossensorial/genética , Perda Auditiva Neurossensorial/metabolismo , Humanos , Rim/patologia , Masculino , Cadeias Pesadas de Miosina/metabolismo , Proteinúria/tratamento farmacológico , Proteinúria/metabolismo , Trombocitopenia/tratamento farmacológico , Trombocitopenia/genética , Trombocitopenia/metabolismo , Adulto Jovem
9.
J Diabetes Res ; 2019: 2981705, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31179339

RESUMO

Diabetic nephropathy (DN) is a serious kidney-related complication of type 1 and type 2 diabetes. The Chinese herbal formula Baoshenfang (BSF) shows therapeutic potential in attenuating oxidative stress and apoptosis in podocytes in DN. This study evaluated the effects of BSF on podocyte injury in vivo and in vitro and explored the possible involvement of the nicotinamide adenine dinucleotide phosphate-oxidase-4/reactive oxygen species- (NOX-4/ROS-) activated p38 pathway. In the identified compounds by mass spectrometry, some active constituents of BSF were reported to show antioxidative activity. In addition, we found that BSF significantly decreased 24-hour urinary protein, serum creatinine, and blood urea nitrogen in DN patients. BSF treatment increased the nephrin expression, alleviated oxidative cellular damage, and inhibited Bcl-2 family-associated podocyte apoptosis in high-glucose cultured podocytes and/or in diabetic rats. More importantly, BSF also decreased phospho-p38, while high glucose-mediated apoptosis was blocked by p38 mitogen-activated protein kinase inhibitor in cultured podocytes, indicating that the antiapoptotic effect of BSF is p38 pathway-dependent. High glucose-induced upexpression of NOX-4 was normalized by BSF, and NOX-4 siRNAs inhibited the phosphorylation of p38, suggesting that the activated p38 pathway is at least partially mediated by NOX-4. In conclusion, BSF can decrease proteinuria and protect podocytes from injury in DN, in part through inhibiting the NOX-4/ROS/p38 pathway.


Assuntos
Nefropatias Diabéticas/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , NADPH Oxidase 4/metabolismo , Podócitos/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Idoso , Animais , Antioxidantes/metabolismo , Apoptose/efeitos dos fármacos , Nefropatias Diabéticas/metabolismo , Feminino , Humanos , Rim/metabolismo , Masculino , Pessoa de Meia-Idade , Estresse Oxidativo , Podócitos/citologia , Proteinúria/metabolismo , Ratos , Ratos Sprague-Dawley , Método Simples-Cego
11.
Eur J Pharmacol ; 858: 172342, 2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31129156

RESUMO

Danshen (Salvia miltiorrhiza) and prednisone are extensively applied in the treatment of kidney disease. Salvianolic acid A (SAA), the major biologically active component of Danshen, which has various biological effects. Our previous findings have demonstrated the renoprotective effect of SAA in various kidney disease rodent models. Here, we explore the therapeutic potential and possible mechanisms of SAA in combination with low-dose prednisone in adriamycin (ADR)-induced minimal change disease (MCD) rat model and mouse podocyte injury cell model. SAA was injected via tail vein at 10 mg/kg/day and prednisone at 5 mg/kg/day via gavage. Each drug was administered daily alone or in combination for 3 weeks. Combination therapy showed significant therapeutic efficacy as manifested by relieved urinary proteins, improved blood biochemical indicators including serum total protein, albumin, triglyceride, cholesterol, the indices of renal function i.e. blood urea nitrogen and serum creatinine levels, and ameliorated pathological lesions. Particularly, co-administration showed a significant anti-proteinuria effect in MCD rats. Further studies suggested that co-administration effectively ameliorated the podocyte injury as indicated by the reduction of podocyte foot processes fusion, up-regulation of synaptopodin and down-regulation of desmin. These beneficial effects are accompanied by activation of the Nrf2/HO-1 and PPARγ/Angptl4 pathways in vivo, and the effect of SAA on PPARγ/Angptl4 is also demonstrated in vitro. These findings suggested that SAA exerted podocyte-protection against MCD injury through PPARγ/Angptl4 and Nrf2/HO-1 pathways, and combined with low-dose prednisone possessed a significant anti-proteinuria and therapeutic effects in MCD rats.


Assuntos
Proteína 4 Semelhante a Angiopoietina/metabolismo , Ácidos Cafeicos/farmacologia , Heme Oxigenase (Desciclizante)/metabolismo , Lactatos/farmacologia , Fator 2 Relacionado a NF-E2/metabolismo , PPAR gama/metabolismo , Prednisona/farmacologia , Proteinúria/tratamento farmacológico , Animais , Ácidos Cafeicos/uso terapêutico , Interações de Medicamentos , Lactatos/uso terapêutico , Masculino , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Podócitos/efeitos dos fármacos , Podócitos/patologia , Prednisona/uso terapêutico , Proteinúria/metabolismo , Proteinúria/patologia , Ratos
12.
Lipids Health Dis ; 18(1): 116, 2019 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-31103046

RESUMO

BACKGROUND: Angiopoietin-like protein 3(ANGPTL3) is well acknowledged as a key regulator of lipid metabolism. Now, there have not been enough data to explain the mechanism of hyperlipidemia related proteinuria. In this study, we hoped to investigate the changes of Angiopoietin-like protein 3(ANGPTL3) levels in hyperlipidemia patients with different proteinuria levels. METHODS: Seventy-one patients with hyperlipidemia were selected, who were hospitalized in Gansu Provincial People's Hospital from September 2016 to September 2017, and 20 healthy people in the physical examination center were selected. We combed through medical history and conducted clinical biochemical indicators of blood urea nitrogen (BUN), serum creatinine (SCr), 24 h urine protein quantitation (24hUPro), cholesterol (TC), triglyceride (TG), high density lipoprotein (HDL) and low detection of density lipoproteins (LDL-C). The concentration of serum ANGPTL3 was measured by ELISA. RESULTS: 1. Serum ANGPTL3 in patients with hyperlipidemia related proteinuria was higher than that in the control group, and the difference was statistically significant (p < 0.05); 2. 24hUPro and BMI (r = 0.321, P = 0.002), TC (r = 0.465, P = 0.000), TG (r = 0.281, P = 0.007), LDL (r = 0.478, P = 0.000) in patients with hyperlipidemia related proteinuria are positively correlated, suggesting that dyslipidemia is related to the occurrence of proteinuria; 3. BMI, TC, TG and LDL in patients with hyperlipidemia related proteinuria were positively correlated with serum ANGPTL3. 4. The 24hUPro of patients with hyperlipidemia related proteinuria was positively correlated with serum ANGPTL3 levels, and BUN and SCr were not associated with serum ANGPTL3 level. 5. There was no significant difference in TC, TG, BMI, 24hUPro and serum ANGPTL3 between the statin-treated and the untreated groups in patients with hyperlipidemia related proteinuria. CONCLUSIONS: Angiopoietin-like protein 3 markedly enhanced in the hyperlipidemia related proteinuria.


Assuntos
Proteínas Semelhantes a Angiopoietina/metabolismo , Hiperlipidemias/complicações , Hiperlipidemias/metabolismo , Proteinúria/complicações , Proteinúria/metabolismo , Adolescente , Idoso , Idoso de 80 Anos ou mais , Proteínas Semelhantes a Angiopoietina/sangue , Biomarcadores/sangue , Pressão Sanguínea , Estudos de Casos e Controles , Criança , Feminino , Humanos , Hiperlipidemias/sangue , Hiperlipidemias/fisiopatologia , Rim/patologia , Lipídeos/sangue , Masculino , Pessoa de Meia-Idade , Proteinúria/sangue , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/patologia , Adulto Jovem
13.
Exp Mol Pathol ; 110: 104255, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31028725

RESUMO

The 150-kDa oxygen-regulated protein (ORP150) belongs to a family of the heat shock protein implicated in the cellular response to environmental stress. Previous data demonstrated that ORP150 regulates the secretion of vascular endothelial growth factor (VEGF) to drive progression of angiogenesis associated with proliferative diabetic retinopathy. However, the expression and biological functions of serum ORP150 levels in diabetic nephropathy (DN) remain unclear. In this study, we reported for the first time that ORP150 was up-regulated in serum of patients with DN. Moreover, we observed the dramatic increase in serum ORP150 accompanied with the elevated levels of proteinuria and serum VEGF levels in DN, indicating the possible involvement of ORP150 in regulation of albuminuria via mediating VEGF in DN. Employing the streptozotocin (STZ) to construct the DN model, we confirmed the positive correlation of ORP150 with VEGF in vivo. Monoclonal anti-ORP150 antibodies treatment significantly decreased the secretion of VEGF and albuminuria in STZ-induced DN models. Consequently, our data suggested that ORP150 levels were positively correlated with proteinuria burden via mediating VEGF in DN. It may be considered as a novel diagnostic and therapeutic target.


Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Nefropatias Diabéticas/sangue , Proteínas de Choque Térmico HSP70/sangue , Proteinúria/metabolismo , Fator A de Crescimento do Endotélio Vascular/sangue , Albuminúria/metabolismo , Animais , Anticorpos Monoclonais/farmacologia , Estudos de Casos e Controles , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/metabolismo , Nefropatias Diabéticas/tratamento farmacológico , Feminino , Proteínas de Choque Térmico HSP70/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Ratos Wistar
14.
J Am Soc Nephrol ; 30(5): 824-839, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30971456

RESUMO

BACKGROUND: About 3%-5% of adults with membranous nephropathy have autoantibodies directed against thrombospondin type 1 domain-containing 7A (THSD7A), a podocyte-expressed transmembrane protein. However, the temporal and spatial expression of THSD7A and its biologic function for podocytes are unknown, information that is needed to understand the effects of THSD7A autoantibodies in this disease. METHODS: Using a variety of microscopic techniques, we analyzed THSD7A localization in postnatal, adult, and autoantibody-injected mice as well as in human podocytes. We also analyzed THSD7A function in human podocytes using confocal microscopy; Western blotting; and adhesion and migration assays. RESULTS: We found that THSD7A expression begins on glomerular vascularization with slit diaphragm formation in development. THSD7A localizes to the basal aspect of foot processes, closely following the meanders of the slit diaphragm in human and mice. Autoantibodies binding to THSD7A localize to the slit diaphragm. In human podocytes, THSD7A expression is accentuated at filopodia and thin arborized protrusions, an expression pattern associated with decreased membrane activity of cytoskeletal regulators. We also found that, phenotypically, THSD7A expression in human podocytes is associated not only with increases in cell size, enhanced adhesion, and reduced detachment from collagen type IV-coated plates but also, with decreased ability to migrate. CONCLUSIONS: Our findings suggest that THSD7A functions as a foot process protein involved in the stabilization of the slit diaphragm of mature podocytes and that autoantibodies to THSD7A, on the basis of their localization, might structurally and functionally alter the slit diaphragm's permeability to protein.


Assuntos
Antígenos de Superfície/genética , Glomerulonefrite Membranosa/genética , Glomérulos Renais/metabolismo , Proteínas de Membrana/metabolismo , Trombospondinas/imunologia , Animais , Antígenos de Superfície/imunologia , Autoanticorpos/imunologia , Western Blotting , Células Cultivadas , Regulação da Expressão Gênica , Taxa de Filtração Glomerular , Glomerulonefrite Membranosa/fisiopatologia , Humanos , Proteínas de Membrana/genética , Proteínas de Membrana/imunologia , Camundongos , Podócitos/imunologia , Proteinúria/metabolismo , Sensibilidade e Especificidade , Trombospondinas/metabolismo
15.
PLoS One ; 14(4): e0215871, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31002704

RESUMO

Tubule-interstitial injury (TII) is a critical step in the progression of renal disease. It has been proposed that changes in proximal tubule (PT) albumin endocytosis plays an important role in the development of TII. Some reports have shown protective effects of lithium on kidney injury animal models that was correlated to proteinuria. We tested the hypothesis that lithium treatment ameliorates the development of TII due to changes in albumin endocytosis. Two experimental models were used: (1) TII induced by albumin overload in an animal model; (2) LLC-PK1 cells, a PT cell line. Lithium treatment ameliorates TII induced by albumin overload measured by (1) proteinuria; (2) collagen deposition; (3) area of tubule-interstitial space, and (4) macrophage infiltration. Lithium treatment increased mTORC2 activity leading to the phosphorylation of protein kinase B (PKB) at Ser473 and its activation. This mechanism enhanced albumin endocytosis in PT cells, which decreased the proteinuria observed in TII induced by albumin overload. This effect did not involve changes in the expression of megalin, a PT albumin receptor. In addition, activation of this pathway decreased apoptosis in LLC-PK1 cells, a PT cell line, induced by higher albumin concentration, similar to that found in pathophysiologic conditions. Our results indicate that the protective role of lithium treatment on TII induced by albumin overload involves an increase in PT albumin endocytosis due to activation of the mTORC2/PKB pathway. These results open new possibilities in understanding the effects of lithium on the progression of renal disease.


Assuntos
Túbulos Renais Proximais/efeitos dos fármacos , Carbonato de Lítio/farmacologia , Alvo Mecanístico do Complexo 2 de Rapamicina/genética , Substâncias Protetoras/farmacologia , Proteinúria/tratamento farmacológico , Proteínas Proto-Oncogênicas c-akt/genética , Albuminas/metabolismo , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Endocitose/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Regulação da Expressão Gênica , Humanos , Túbulos Renais Proximais/lesões , Túbulos Renais Proximais/metabolismo , Proteína-2 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética , Proteína-2 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Alvo Mecanístico do Complexo 2 de Rapamicina/agonistas , Alvo Mecanístico do Complexo 2 de Rapamicina/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Proteinúria/metabolismo , Proteinúria/fisiopatologia , Proteínas Proto-Oncogênicas c-akt/agonistas , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos
16.
Nan Fang Yi Ke Da Xue Xue Bao ; 39(2): 227-234, 2019 02 28.
Artigo em Chinês | MEDLINE | ID: mdl-30890513

RESUMO

OBJECTIVE: To identify the main active components in Shenbing decoction Ⅲ and their targets and explore the mechanism by which Shenbing decoction Ⅲ alleviates proteinuria in chronic kidney disease (CKD) based on network pharmacology. METHODS: The active components of Shenbing decoction Ⅲ and their potential targets, along with the oral bioavailability and drug-like properties of each component were searched in the TCMSP database. The proteinuria-related targets were searched in the GeneCards database. The active component-target network was constructed using Cytoscape software, and the acquired information of the targets from ClueGO was used for enrichment analysis of the gene pathways. RESULTS: A total of 102 active components were identified from Shenbing decoction Ⅲ. These active components acted on 126 targets, among which 69 were related to proteinuria. Enrichment analysis revealed fluid shear stress- and atherosclerosisrelated pathways as the highly significant pathways in proteinuria associated with CKD. CONCLUSIONS: We preliminarily validated the prescription of Shenbing decoction Ⅲ and obtained scientific evidence that supported its use for treatment of proteinuria in CKD. The findings in this study provide a theoretical basis for further study of the mechanism of Shenbing decoction Ⅲ in the treatment of proteinuria in CKD.


Assuntos
Medicamentos de Ervas Chinesas/uso terapêutico , Proteinúria/tratamento farmacológico , Insuficiência Renal Crônica/complicações , Disponibilidade Biológica , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/farmacocinética , Humanos , Proteinúria/etiologia , Proteinúria/metabolismo , Insuficiência Renal Crônica/metabolismo
17.
Med Sci Monit ; 25: 2122-2131, 2019 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-30900683

RESUMO

BACKGROUND Lupus nephritis is one of the most serious complications of systemic lupus erythematosus (SLE) and is associated with patient mortality. This study aimed to investigate the proteomic profiles of the glomerulus in the NZB/W F1 hybrid mouse model of mild and severe lupus nephritis using two-dimensional fluorescence difference gel electrophoresis (2D-DIGE) combined with matrix-assisted laser desorption time-of-flight mass spectrometry (MALDI-TOF-MS). MATERIAL AND METHODS Female NZB/WF1 mice (n=60) at 28 weeks of age were divided into the mild proteinuria group (+1), the moderate proteinuria group (+2), and the severe proteinuria group (+3) using paper strip urine testing, and then later divided into a mild (≤1+) and severe (≥3+) proteinuria group to allow comparison of upregulation and down-regulation of proteins between the two groups. Renal glomeruli were isolated following renal perfusion with magnetic beads. Protein expression was determined by Western blot, immunohistochemistry, 2D-DIGE, and MALDI-TOF-MS. RESULTS A total of 56 differentially expressed proteins were identified from 133 protein spots, of which 18 were upregulated and 23 were down-regulated between groups 1 and 2. Expression of the proteins Ras-related GTP-binding protein B (RRAGB), serine/threonine-protein kinase 1 (SMG1), angiopoietin 2 (ANGP2), methylmalonate semialdehyde (MMSA), and ATP beta chain (ATPB) were identified by Western blot and SMG1, ANGP2, and MMSA were identified by immunohistochemistry. CONCLUSIONS In a mouse model of lupus nephritis, expression of SMG1, MMSA, and ATPB were down-regulated, and RRAGB and ANGP2 were upregulated.


Assuntos
Glomérulos Renais/metabolismo , Nefrite Lúpica/metabolismo , Proteômica/métodos , Angiopoietina-2/análise , Angiopoietina-2/metabolismo , Animais , Western Blotting , Modelos Animais de Doenças , Feminino , Perfilação da Expressão Gênica/métodos , Imuno-Histoquímica , Rim/metabolismo , Nefropatias , Lúpus Eritematoso Sistêmico/metabolismo , Nefrite Lúpica/fisiopatologia , Metilmalonato-Semialdeído Desidrogenase (Acilante)/análise , Metilmalonato-Semialdeído Desidrogenase (Acilante)/metabolismo , Camundongos , Camundongos Endogâmicos NZB , Proteínas Serina-Treonina Quinases/análise , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas/metabolismo , Proteinúria/metabolismo , Transcriptoma/genética
18.
Toxicon ; 162: 1-8, 2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30849452

RESUMO

Microcystin-LR (MCLR) is a cyanotoxin produced by blue-green algae that causes liver and kidney toxicities. MCLR toxicity is dependent on cellular uptake through the organic anion transporting polypeptide (OATP) transporters. Nonalcoholic fatty liver disease (NAFLD) progresses through multiple stages, alters expression of hepatic OATPs, and is associated with chronic kidney disease. The purpose of this study was to determine whether NAFLD increases systemic exposure to MCLR and influences acute liver and kidney toxicities. Rats were fed a control diet or two dietary models of NAFLD; methionine and choline deficient (MCD) or high fat/high cholesterol (HFHC). Two studies were performed in these groups: 1) a single dose intravenous toxicokinetic study (20 µg/kg), and 2) a single dose intraperitoneal toxicity study (60 µg/kg). Compared to control rats, plasma MCLR area under the concentration-time curve (AUC) in MCD rats doubled, whereas biliary clearance (Clbil) was unchanged; in contrast, plasma AUC in HFHC rats was unchanged, whereas Clbil approximately doubled. Less MCLR bound to PP2A was observed in the liver of MCD rats. This shift in exposure decreased the severity of liver pathology only in the MCD rats after a single toxic dose of MCLR (60 µg/kg). In contrast, the single toxic dose of MCLR increased hepatic inflammation, plasma cholesterol, proteinuria, and urinary KIM1 in HFHC rats more than MCLR exposed control rats. In conclusion, rodent models of NAFLD alter MCLR toxicokinetics and acute toxicity and may have implications for liver and kidney pathologies in NAFLD patients.


Assuntos
Fígado/efeitos dos fármacos , Microcistinas/toxicidade , Hepatopatia Gordurosa não Alcoólica/metabolismo , Animais , Moléculas de Adesão Celular/urina , Colesterol/metabolismo , Colina/metabolismo , Dieta Hiperlipídica , Eliminação Hepatobiliar , Inflamação/metabolismo , Rim/efeitos dos fármacos , Rim/metabolismo , Fígado/metabolismo , Fígado/fisiopatologia , Masculino , Metionina/deficiência , Microcistinas/metabolismo , Hepatopatia Gordurosa não Alcoólica/induzido quimicamente , Hepatopatia Gordurosa não Alcoólica/fisiopatologia , Transportadores de Ânions Orgânicos/metabolismo , Proteína Fosfatase 2/metabolismo , Proteinúria/induzido quimicamente , Proteinúria/metabolismo , Ratos Sprague-Dawley , Toxicocinética
19.
Biomed Pharmacother ; 111: 1088-1102, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30841422

RESUMO

This study tested whether sitagliptin and shock wave (SW)-assisted circulatory-derived autologous endothelial progenitor cell (EPC) therapy would effectively preserve residual renal function in chronic kidney disease (CKD) induced by 5/6 left-nephrectomy/remove right kidney plus daily feeding high-protein diet (HPD) in rat. Adult-male SD rats (n = 40) were categorized into group 1 (sham-operated control with HPD), group 2 (HPD-CKD), group 3 [HPD-CKD + EPC (1.2 × 106 cell)/intra-vessel administration by day 14 after CKD-induction], group 4 [HPD-CKD + SW (0.12 mJ/mm2/180 shorts) at days 14/21/28 after CKD-induction by ultrasound-guided application] and group 5 [HPD-CKD + SW + EPC + sitagliptin (Sita; 600 mg/kg/day since day 14 after CKD induction)]. All animals were euthanized by day 60. By day 60, renal blood flow (RBF) was highest in group 1 and progressively increased from groups 2 to 5, whereas the levels of creatinine/BUN/proteinuria exhibited an opposite pattern of RBF among the five groups (all p < 0.001). The circulating levels of GLP-1/SDF-1α and protein levels of angiogenesis (VEGF/SDF-1α/CXCR4) and GLP-1R in kidney were progressively increased from groups 1 to 5, whereas circulating DPP4 activity exhibited an opposite pattern of SDF-1α among the groups (all p < 0.0001). The protein expressions of oxidative-stress (NOX-1/NOX-2/oxidized protein), apoptosis (Bax/caspase-3/PARP), fibrosis (Smad3/TGF-ß) and inflammation (TNF-α/NF-κB/MMP-2) and kidney injury score displayed an opposite pattern, whereas the protein expressions of TMP2, endothelial-cell markers (CD31/eNOS) and podocyte integrity biomarkers (podocin/ZO-1/synaptopodin) exhibited an identical pattern of RBF among the groups (all p < 0.001). In conclusion Sita associated SW-assisted EPC effectively protected residual renal function in CKD.


Assuntos
Dipeptidil Peptidase 4/metabolismo , Inibidores da Dipeptidil Peptidase IV/farmacologia , Células Progenitoras Endoteliais/fisiologia , Rim/efeitos dos fármacos , Insuficiência Renal Crônica/tratamento farmacológico , Fosfato de Sitagliptina/farmacologia , Animais , Biomarcadores/metabolismo , Terapia Baseada em Transplante de Células e Tecidos/métodos , Creatinina/metabolismo , Células Progenitoras Endoteliais/metabolismo , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Hipoglicemiantes/farmacologia , Rim/metabolismo , Rim/fisiopatologia , Masculino , Estresse Oxidativo/efeitos dos fármacos , Proteinúria/tratamento farmacológico , Proteinúria/metabolismo , Ratos , Ratos Sprague-Dawley , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/fisiopatologia
20.
Can J Cardiol ; 35(1): 77-91, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30595186

RESUMO

BACKGROUND: There is ongoing controversy around the surrogacy of proteinuria or albuminuria, particularly for cardiovascular (CV) outcomes, which remain the leading cause of morbidity and mortality among patients with chronic kidney disease. We performed a systematic review and meta-analysis of the literature to assess the surrogacy of changing proteinuria or albuminuria for CV events, end-stage renal disease (ESRD), and all-cause mortality. METHODS: CENTRAL, EMBASE, and MEDLINE were searched (from inception to October 2017). All randomized controlled trials in adults that reported change in proteinuria or albuminuria and ≥ 10 CV, ESRD, or all-cause mortality events were included. We calculated treatment effect ratios (TERs), defined as the ratio of the treatment effect on a clinical outcome and the effect on the change in the surrogate outcome. TERs close to 1 indicate greater agreement between the clinical outcome and changing proteinuria or albuminuria. RESULTS: Thirty-six trials were included in the meta-analysis. We observed inconsistent treatment effects for proteinuria and CV events (20 trials; TER 1.11 [95% confidence interval (CI), 1.01-1.22]) with moderate heterogeneity (I2 = 51%, P = 0.005). Treatment effects on proteinuria or albuminuria were also inconsistent with the effects on all-cause mortality (21 trials; TER 1.17 [95% CI, 1.07-1.28]; I2 = 35%, P for heterogeneity = 0.06), although they were similar with the effects on ESRD (23 trials; TER 0.99 [95% CI, 0.88-1.13]; I2 = 9%, P for heterogeneity = 0.337). CONCLUSIONS: Change in proteinuria or albuminuria might be a suitable surrogate outcome for ESRD. However, overall treatment effects on these potential surrogates are inconsistent and overestimate the treatment effects on CV events and all-cause mortality.


Assuntos
Albuminúria/complicações , Doenças Cardiovasculares/etiologia , Falência Renal Crônica/complicações , Proteinúria/complicações , Medição de Risco/métodos , Albuminúria/metabolismo , Biomarcadores/sangue , Biomarcadores/urina , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/urina , Causas de Morte/tendências , Creatinina/sangue , Progressão da Doença , Saúde Global , Humanos , Incidência , Falência Renal Crônica/metabolismo , Proteinúria/metabolismo , Taxa de Sobrevida/tendências
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