RESUMO
Scrotal and penile edema is a noninfectious complication of peritoneal dialysis (PD). A tear in the Spigelian fascia is occasionally recognized as a Spigelian hernia. However, there is no documented evidence that this is a contributing factor for scrotal edema in individuals undergoing PD. We encountered a case of scrotal edema in a patient undergoing PD due to bilateral metachronous tears in the Spigelian fascia, which was successfully treated through surgical repair. A 20-year-old man with end-stage kidney disease due to Alport syndrome underwent PD. Eight months after induction of PD, he heard a rupture sound in the left inguinal region after coughing and developed genital edema. A computed tomography scan showed a tear in the left Spigelian fascia. Surgical repair was successful and there was no recurrence after PD was resumed. Seven months after surgery, he heard a rupture sound in the right inguinal region after coughing and developed genital edema. A computed tomography scan showed a tear in the right Spigelian fascia. Surgical repair was successful and there has been no recurrence since. It is important to recognize that the development of scrotal edema in a patient undergoing PD may be indicative of a tear in the Spigelian fascia.
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An underestimated side effect of rituximab is late-onset neutropenia (R-LON), which often resolves spontaneously and rarely results in a severe infection. We herein report a case of febrile neutropenia due to R-LON in a 91-year-old woman with renal failure who was treated with rituximab to induce remission of MPO-ANCA-associated vasculitis. Fifty-four days after the last rituximab administration, the patient was hospitalized for febrile neutropenia due to R-LON, which improved with granulocyte colony-stimulating factor and antibiotics. Although R-LON may resolve spontaneously and remain unnoticed, it can cause severe infections in the elderly and patients with renal failure.
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We herein report a case of IgA nephropathy in a 20-year-old male who maintained a complete remission of minimal change nephrotic syndrome (MCNS) through the administration of rituximab (RTX). He was diagnosed with nephrotic syndrome at 4 years of age. After he relapsed frequently, he was diagnosed with MCNS at 8 years of age based on the findings of a kidney biopsy. At 13 years of age, RTX therapy was initiated to maintain a complete remission after steroid treatment. MCNS recurred twice, including the time in which the interval between the RTX administrations was long. Whenever he relapsed, remission induction was achieved using steroids, and remission maintenance was achieved using RTX. Five months after the 7th RTX administration, the serum IgA level started to increase. After the 9th RTX administration, he demonstrated microhematuria despite the urinary protein level indicating complete remission. At the 10th administration, the urinary protein and the red-blood cell casts were also observed. A renal biopsy was performed 84 months after the initial administration of RTX, and the patient was diagnosed with complications of IgA nephropathy. RTX is not considered to be a useful treatment for IgA nephropathy. The reasons for this are due to the fact that IgA1 does not decrease even following the administration of RTX, because B cells residing in the mucosa may not be deleted by RTX, and IgA production may also continue due to the presence of CD20- long-lived plasma cells. Even when administering RTX, if there are findings of glomerulonephritis on urine testing, the possibility of IgA nephropathy must be considered.
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A 22-year-old woman had been diagnosed with idiopathic thrombocytopenic purpura (ITP) 5 years earlier. After undergoing splenectomy, she relapsed frequently following prednisolone tapering. She was complicated with minimal change nephrotic syndrome (MCNS) while taking 20 mg of prednisolone. Despite treatment with prednisolone, cyclosporin and low-density lipoprotein-apheresis, MCNS and ITP did not improve. We added rituximab in 4 weekly infusions of 375 mg/m2. MCNS and ITP were in complete remission. After administering rituximab once, all medicines were discontinued. No relapse had occurred by 50 months following the first rituximab administration. Rituximab affects steroid-resistant MCNS and ITP for a long time without complications.
Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Síndrome Nefrótica/tratamento farmacológico , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Rituximab/uso terapêutico , Adulto , Feminino , Humanos , Resultado do Tratamento , Adulto JovemRESUMO
AIM: This study aimed to clarify the characteristics of patients who presented with severe hypermagnesemia and subsequently underwent emergency hemodialysis. METHODS: We investigated the age, gender, complications, clinical symptoms, causal drugs, electrocardiogram findings, and laboratory data of 15 patients. RESULTS: Magnesium oxide had been administered in all cases and 14 patients were over 65 years old. The male : female ratio was 6:9. Chief complaints included a disturbance of consciousness, hypotension, bradycardia, and respiratory failure. The median serum magnesium value before hemodialysis was 6.0 (3.7-18.6) mg/dL. The daily dosage of magnesium oxide was ≤ 2.0 g in 12 cases. The median serum creatinine value before hemodialysis was 5.39 (0.54-10.29) mg/dL. However, in two cases, the creatinine value was not elevated. Complications of acute kidney injury exacerbated the hypermagnesemia in nine cases. CONCLUSIONS: We recommend that the serum magnesium value should be measured in older patients who are taking magnesium oxide and are showing signs and symptoms of a disturbance of consciousness, hypotension, bradycardia, and respiratory failure of an uncertain etiology, even if the serum creatinine value is not elevated or the dosage of magnesium oxide is within recommended levels.
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Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide. Gpnmb is classified as a type 1 membrane protein and its soluble form is secreted by ADAM10-mediated cleavage. Gpnmb mRNA was found in the Kupffer cells and white adipose tissues (WATs) and its upregulation in obesity was recently found. Here, we generated aP2 promoter-driven Gpnmb transgenic (Tg) mice and the overexpression of Gpnmb ameliorated the fat accumulation and fibrosis of the liver in diet-induced obesity model. Soluble form of Gpnmb in sera was elevated in Gpnmb Tg mice and Gpnmb concentrated in hepatic macrophages and stellate cells interacted with calnexin, which resulted in the reduction of oxidative stress. In the patients with non-alcoholic steatohepatitis, serum soluble GPNMB concentrations were higher compared with the patients with simple steatosis. The GPNMB is a promising biomarker and therapeutic target for the development and progression of NAFLD in obesity.
Assuntos
Proteínas do Olho/metabolismo , Glicoproteínas de Membrana/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Células 3T3-L1 , Adipócitos/metabolismo , Adipócitos/patologia , Tecido Adiposo Branco/metabolismo , Animais , Biomarcadores/metabolismo , Calnexina/metabolismo , Proteínas do Olho/sangue , Proteínas do Olho/genética , Feminino , Regulação da Expressão Gênica , Células Estreladas do Fígado/metabolismo , Fígado/metabolismo , Fígado/patologia , Cirrose Hepática/complicações , Cirrose Hepática/patologia , Modelos Logísticos , Macrófagos/metabolismo , Masculino , Glicoproteínas de Membrana/sangue , Glicoproteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Análise Multivariada , Obesidade/complicações , Obesidade/patologia , Ligação Proteica , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos Endogâmicos OLETF , Fatores de RiscoRESUMO
PURPOSE: The unique circulating microRNAs (miRNAs) observed in patients with type 2 diabetes (T2D) are candidates as new biomarkers and therapeutic targets. In order to identify circulating miRNAs relevant to the disease process in case of type 2 diabetes, we performed the Illumina sequencing of miRNAs derived from the serum, liver and epididymal white adipose tissue (WAT) of diet-induced obese male C57BL/6J mice. BASIC PROCEDURES: We selected four miRNAs, miR-101, miR-335, miR-375, and miR-802, which are increased in the sera and tissues of obese mice, and measured the serum levels of miRNAs in T2D and subjects with normal glucose tolerance (NGT). MAIN FINDINGS: The serum concentrations of miRNAs, log(10)miR-101, log(10)miR-375, and log(10)miR-802, were significantly increased in the T2D patients compared with NGT subjects (1.41±2.01 v.s. -0.57±1.05 (P=1.36×10(-5)), 0.20±0.58 v.s. 0.038±1.00 (P=3.06×10(-6)), and 2.45±1.27 v.s. 0.97±0.98 (P=0.014), respectively). The log(10)miR-335 values did not demonstrate any significant differences between the T2D and NGT groups (-1.08±1.35 v.s. -0.38±1.21 (P=0.25)). According to the stepwise regression analysis, the HbA1c was an independent predictor of miR-101. Regarding the serum miR-802 levels, eGFR, HbA1c and HDL-C values were identified as significant determinants. PRINCIPAL CONCLUSIONS: The present findings demonstrated that the circulating miR-101, miR-375 and miR-802 levels are significantly increased in T2D patients versus NGT subjects and they may become the new biomarkers for type 2 diabetes.
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Biomarcadores/sangue , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/diagnóstico , MicroRNAs/sangue , Adulto , Idoso , Animais , Glicemia/metabolismo , Estudos Transversais , Feminino , Teste de Tolerância a Glucose , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-IdadeRESUMO
RATIONALE: Visceral adipose tissue-derived serine proteinase inhibitor (vaspin) is an adipokine identified from visceral adipose tissues of genetically obese rats. OBJECTIVE: The role of vaspin in the diabetic vascular complications remains elusive, and we investigated the effects of vaspin on the vascular function under the diabetic milieu. METHODS AND RESULTS: Adenovirus carrying the full length of the vaspin gene (Vaspin-Ad) ameliorated intimal proliferation of balloon-injured carotid arteries in diabetic Wistar rats. The expression of Ccl2, Pdgfb, and Pdgfrb genes was significantly reduced by the treatment of Vaspin-Ad. In cuff-injured femoral arteries, the intimal proliferation was ameliorated in vaspin transgenic (Vaspin Tg) mice. The application of recombinant vaspin and Vaspin-Ad promoted the proliferation and inhibited the apoptosis of human aortic endothelial cells. Adenovirus expressing vaspin with calmodulin and streptavidin-binding peptides was applied to human aortic endothelial cells, subjected to tandem tag purification and liquid chromatography-tandem mass spectrometry, and we identified GRP78 (78-kDa glucose-regulated protein) as an interacting molecule. The complex formation of vaspin, GRP78, and voltage-dependent anion channel on the plasma membrane was confirmed by the immunoprecipitation studies using aortas of Vaspin Tg mice. The binding assay using (125)I-vaspin in human aortic endothelial cells revealed high-affinity binding (dissociation constant = 0.565×10(-9) m) by the treatment of 5 µM thapsigargin, which recruited GRP78 from the endoplasmic reticulum to plasma membrane by inducing endoplasmic reticulum stress. In human aortic endothelial cells, vaspin induced phosphorylation of Akt and inhibited the kringle 5-induced Ca(2+) influx and subsequent apoptosis. CONCLUSIONS: Vaspin is a novel ligand for the cell-surface GRP78/voltage-dependent anion channel complex in endothelial cells and promotes proliferation, inhibits apoptosis, and protects vascular injuries in diabetes mellitus.
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Adipocinas/metabolismo , Apoptose/fisiologia , Endotélio Vascular/patologia , Proteínas de Choque Térmico/metabolismo , Serpinas/metabolismo , Canais de Ânion Dependentes de Voltagem/metabolismo , Adenoviridae/genética , Adipocinas/genética , Animais , Membrana Celular/metabolismo , Proliferação de Células , Células Cultivadas , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Modelos Animais de Doenças , Chaperona BiP do Retículo Endoplasmático , Humanos , Ligantes , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Ratos , Ratos Wistar , Serpinas/genética , Estreptozocina/efeitos adversosRESUMO
BACKGROUND: Galectin-9 (Gal-9) induces apoptosis in activated T helper 1 (TH1) cells as a ligand for T cell immunoglobulin mucin-3 (Tim-3). Gal-9 also inhibits the G1 phase cell cycle arrest and hypertrophy in db/db mice, the hallmark of early diabetic nephropathy, by reversing the high glucose-induced up-regulation of cyclin dependent kinase inhibitors such as p27(Kip1) and p21(Cip1). METHODS: We investigated the serum levels of Gal-9 in the patients with type 2 diabetes and various stages of chronic kidney disease (CKD) (n=182). RESULTS: Serum Gal-9 levels in the patients with type 2 diabetes were 131.9 ± 105.4 pg/ml and Log(10)Gal-9 levels significantly and positively correlated with age (r=0.227, p=0.002), creatinine (r=0.175, p=0.018), urea nitrogen (r=0.162, p=0.028) and osmotic pressure (r=0.187, p=0.014) and negatively correlated with estimated glomerular filtration rate (eGFR) (r=-0.188, p=0.011). Log(10)Gal-9 levels increased along with the progression of GFR categories of G1 to G4, and they were statistically significant by Jonckheere-Terpstra test (p=0.012). Log(10)Gal-9 levels remained similar levels in albuminuria stages of A1 to A3. CONCLUSION: The elevation of serum Gal-9 in the patients with type 2 diabetes is closely linked to GFR and they may be related to the alteration of the immune response and inflammation of the patients with type 2 diabetes and CKD.
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Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/epidemiologia , Galectinas/sangue , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/epidemiologia , Biomarcadores/sangue , Comorbidade , Diabetes Mellitus Tipo 2/diagnóstico , Feminino , Humanos , Incidência , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Insuficiência Renal Crônica/diagnóstico , Reprodutibilidade dos Testes , Medição de Risco , Sensibilidade e EspecificidadeRESUMO
It is unknown whether adipokines derived from adipose tissues modulate endoplasmic reticulum (ER) stress induced in obesity. Here, we show that visceral adipose tissue-derived serine protease inhibitor (vaspin) binds to cell-surface 78-kDa glucose-regulated protein (GRP78), which is recruited from ER to plasma membrane under ER stress. Vaspin transgenic mice were protected from diet-induced obesity, glucose intolerance, and hepatic steatosis, while vaspin-deficient mice developed glucose intolerance associated with upregulation of ER stress markers. With tandem affinity tag purification using HepG2 cells, we identified GRP78 as an interacting molecule. The complex formation of vaspin, GRP78, and murine tumor cell DnaJ-like protein 1 (MTJ-1) (DnaJ homolog, subfamily C, member 1) on plasma membrane was confirmed by cell-surface labeling with biotin and immunoprecipitation in liver tissues and H-4-II-E-C3 cells. The addition of recombinant human vaspin in the cultured H-4-II-E-C3 cells also increased the phosphorylation of Akt and AMP-activated protein kinase (AMPK) in a dose-dependent manner, and anti-GRP78 antibodies completely abrogated the vaspin-induced upregulation of pAkt and pAMPK. Vaspin is a novel ligand for cell-surface GRP78/MTJ-1 complex, and its subsequent signals exert beneficial effects on ER stress-induced metabolic dysfunctions.
Assuntos
Adipocinas/metabolismo , Estresse do Retículo Endoplasmático , Proteínas de Choque Térmico HSP40/metabolismo , Proteínas de Choque Térmico/metabolismo , Gordura Intra-Abdominal/metabolismo , Proteínas de Neoplasias/metabolismo , Obesidade/metabolismo , Serpinas/metabolismo , Adipocinas/química , Adipocinas/genética , Adipocinas/isolamento & purificação , Animais , Linhagem Celular Tumoral , Membrana Celular/metabolismo , Chaperona BiP do Retículo Endoplasmático , Proteínas de Choque Térmico HSP40/antagonistas & inibidores , Proteínas de Choque Térmico HSP40/genética , Proteínas de Choque Térmico/antagonistas & inibidores , Proteínas de Choque Térmico/genética , Hepatócitos/metabolismo , Hepatócitos/patologia , Humanos , Ligantes , Masculino , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/genética , Obesidade/patologia , Transporte Proteico , Ratos , Proteínas Recombinantes/antagonistas & inibidores , Proteínas Recombinantes/isolamento & purificação , Proteínas Recombinantes/metabolismo , Serpinas/química , Serpinas/genética , Serpinas/isolamento & purificação , Transdução de Sinais , Regulação para CimaRESUMO
BACKGROUND: In nephrotic syndrome, the combination of furosemide and albumin infusion is a standard regimen to treat systemic edema. The efficacy of synthetic human atrial natriuretic peptide (hANP) for nephrotic syndrome to ameliorate the systemic edema and retain renal functions has not been fully demonstrated. TRIAL DESIGN: We conducted a prospective, randomized, controlled, open-label clinical trial. Patients were randomly assigned by a stratified biased coin design. METHODS: A total of 12 patients with nephrotic syndrome between the ages of 20 to 79 years were enrolled and randomly assigned to either the conventional (CON) group treated with furosemide and albumin, and hANP group, in which carperitide was administered in addition to the conventional therapies. The primary end points were: (1) the differences in serum creatinine levels, and (2) the reduction of total dosage of furosemide and albumin by the treatments of hANP. Secondary end points were body weight, systolic blood pressure, heart rate, serum protein, albumin, and urinary protein excretion. RESULTS: A total of 13 patients were enrolled, and one patient was excluded due to severe pneumonia. In both hANP (n = 7) and CON (n = 5) groups, body weight was reduced after 2-week treatments. Serum creatinine levels at follow-up significantly increased compared with baseline. The increase in serum creatinine levels (Δ serum creatinine) was smaller in the hANP group compared with the CON group (P = 0.31). The serum uric acid, serum urea nitrogen, and urinary protein excretion were reduced in the hANP group, and increased in the CON group, though these differences were not statistically significant. The usage of hANP significantly reduced the total dosage of furosemide (P < 0.05) during the treatment periods. No adverse effects were observed. CONCLUSIONS: The concomitant use of synthetic hANP with conventional therapies is beneficial for reducing the dosage of loop diuretics, and the elevation of serum creatinine and uric acid may be avoided.
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CONTEXT: Vaspin is an adipokine with insulin-sensitizing effects identified from visceral adipose tissues of genetically obese rats. OBJECTIVE: We investigated genetic and nongenetic factors that define serum concentrations of vaspin. DESIGN, SETTING AND PARTICIPANTS: Vaspin levels were measured with RIA in Japanese subjects with normal fasting plasma glucose (NFG; n = 259) and type 2 diabetes patients (T2D; n = 275). Single nucleotide polymorphisms (SNP) at SERPINA12 (vaspin) gene locus were discovered, and five SNP were genotyped in the subjects with varied body mass index (n = 1138). RESULTS: The level of serum vaspin in 93% of the samples was found to vary from 0.2 to nearly 2 ng/ml in NFG subjects (n = 259) and from 0.2 to nearly 3 ng/ml in T2D patients (n = 275) (Vaspin(Low) group), whereas a significant subpopulation (7%) in both groups displayed much higher levels of 10-40 ng/ml (Vaspin(High) group). In the Vaspin(Low) group, serum vaspin levels in T2D were significantly higher than healthy subjects (0.99 ± 0.04 vs. 0.86 ± 0.02 ng/ml; P < 0.01). Both in T2D and genotyped Japanese population, serum vaspin levels closely correlated with homeostasis model of assessment for insulin resistance rather than anthropometric parameters. By genotyping, rs77060950 tightly linked to serum vaspin levels, i.e. CC (0.6 ± 0.4 ng/ml), CA (18.4 ± 9.6 ng/ml), and AA (30.5 ± 5.1 ng/ml) (P < 2 × 10(-16)). Putative GATA-2 and GATA-3 binding consensus site was found at rs77060950. CONCLUSIONS: Serum vaspin levels were related to insulin resistance, and higher levels of serum vaspin in 7% of the Japanese population are closely linked to minor allele sequence (A) of rs77060950.
Assuntos
Resistência à Insulina , Polimorfismo de Nucleotídeo Único , Serpinas/sangue , Serpinas/genética , Adulto , Idoso , Povo Asiático/genética , Glicemia/análise , Glicemia/genética , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/etnologia , Diabetes Mellitus Tipo 2/genética , Jejum/sangue , Jejum/fisiologia , Feminino , Predisposição Genética para Doença , Humanos , Resistência à Insulina/etnologia , Resistência à Insulina/genética , Resistência à Insulina/fisiologia , Masculino , Pessoa de Meia-Idade , Concentração Osmolar , Polimorfismo de Nucleotídeo Único/fisiologia , População , Serpinas/análise , Serpinas/fisiologiaRESUMO
Although the appearance of abnormal lipoproteins in liver diseases is well known, the precise analyses of abnormal lipoproteins remain elusive. Here, we report a 71-year-old woman with type 2 diabetes whose serum cholesterol levels were elevated to 560 mg/dL over a 4-month period. High-performance liquid chromatography demonstrated the presence of lipoprotein-X and lipoprotein-Y and sigmoid colon cancer and multiple liver metastases were found by colonoscopy and computed tomography. Remission of the primary colon cancer and liver lesions was achieved by chemotherapy with oxaliplatin and fluorouracil and her serum cholesterol went back to basal levels associated with the disappearance of abnormal lipoproteins.
Assuntos
Adenocarcinoma/secundário , Diabetes Mellitus Tipo 2/sangue , Hipercolesterolemia/etiologia , Lipoproteína-X/sangue , Lipoproteínas/sangue , Neoplasias Hepáticas/secundário , Neoplasias do Colo Sigmoide/sangue , Adenocarcinoma/sangue , Adenocarcinoma/complicações , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cromatografia Líquida de Alta Pressão , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Dislipidemias/sangue , Dislipidemias/complicações , Feminino , Fluoruracila/administração & dosagem , Humanos , Hipertensão/complicações , Hipoglicemiantes/uso terapêutico , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/complicações , Compostos Organoplatínicos/administração & dosagem , Oxaliplatina , Indução de Remissão , Neoplasias do Colo Sigmoide/complicaçõesRESUMO
The peroxisome proliferator activated receptor-γ (PPARγ) agonist, pioglitazone (PIO), exerts anti-diabetic properties associated with increased fat mass, whereas the retinoid X receptor (RXR) antagonist HX531 demonstrates anti-obesity and anti-diabetic effects with reduced body weight and fat pad mass. The cell cycle abnormality in adipocytes has not been well-investigated in obesity or during treatment with modulators of nuclear receptors. We therefore investigated cell size and cell cycle distributions of adipocytes in vivo and examined the expression of cell cycle regulators in cultured human visceral preadipocytes. The cell size distribution and cell cycle analyses of in vivo adipocytes derived from OLETF rats demonstrated that HX531 brought about G0/G1 cell cycle arrest associated with the inhibition of cellular hypertrophy, which resulted in the reduction of fat pad mass. In contrast, PIO promoted proliferation activities associated with the increase in M + late M:G0 + G1 ratio and the appearance of both small and hypertrophied adipocytes. In cultured human visceral preadipocytes HX531 up-regulated cell cycle regulators, p53, p21(Cip1), cyclin D1, Fbxw7 and Skp2, which are known contributors towards G0 /G1 cell cycle arrest. The knockdown of p53 with a shRNA lentivirus reversed the HX531-induced up-regulation of p21(Cip1), which is one of the major p53-effector molecules. We conclude that HX531 exerts anti-obesity and anti-diabetes properties by up-regulating the p53-p21(Cip1) pathway, resulting in G0/G1 cell cycle arrest and the inhibition of cellular hypertrophy of adipocytes.
Assuntos
Adipócitos/efeitos dos fármacos , Fármacos Antiobesidade/farmacologia , Benzoatos/farmacologia , Compostos de Bifenilo/farmacologia , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Hipoglicemiantes/farmacologia , Obesidade/tratamento farmacológico , Fase de Repouso do Ciclo Celular/efeitos dos fármacos , Receptores X de Retinoides/antagonistas & inibidores , Proteína Supressora de Tumor p53/metabolismo , Adipócitos/metabolismo , Adipócitos/patologia , Animais , Proliferação de Células/efeitos dos fármacos , Tamanho Celular/efeitos dos fármacos , Células Cultivadas , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Modelos Animais de Doenças , Humanos , Hipertrofia , Glomérulos Renais/efeitos dos fármacos , Glomérulos Renais/metabolismo , Glomérulos Renais/patologia , Masculino , Obesidade/genética , Obesidade/metabolismo , Obesidade/patologia , PPAR gama/efeitos dos fármacos , PPAR gama/metabolismo , Pioglitazona , Interferência de RNA , Ratos , Ratos Endogâmicos OLETF , Receptores X de Retinoides/metabolismo , Transdução de Sinais/efeitos dos fármacos , Tiazolidinedionas/farmacologia , Fatores de Tempo , Transfecção , Proteína Supressora de Tumor p53/genética , Regulação para CimaRESUMO
Galectin-9 (Gal-9), a ligand for T cell Ig mucin-3 (Tim-3), induces apoptosis in cluster of differentiation 4 (CD4)(+) Tim-3(+) T helper 1 (T(H)1) cells via the Gal-9-Tim-3 pathway and negatively regulates T(H)1 immunity. In turn, Gal-9 activates dendritic cells (DC) to produce TNF-α, which promotes the T(H)1 response. We investigated the efficacy of Gal-9 against T(H)1-mediated autoimmune diabetes in NOD mice and compared with anti-Tim-3 monoclonal antibody (RMT3-23), which inhibited the binding between Tim-3-Ig and Gal-9 in a solid-phase binding assay. mRNA expression of Gal-9 was prominently induced by the treatment of interferon-γ in MIN6 cells, and Gal-9 was also expressed in the pancreatic ß-cells in NOD mice, suggesting Gal-9 may be released from pancreatic ß-cells to terminate T(H)1-mediated inflammation. Long-term injection of Gal-9 exhibits preventive efficacy for development of diabetes in NOD mice, but RMT3-23 demonstrated further prominent therapeutic potential compared with Gal-9. Gal-9 induced apoptosis of CD4(+)Tim-3(+) T(H)1 cells at the concentration of 0.2 µM, whereas RMT3-23 failed to enhance the apoptosis of CD4(+)Tim-3(+) T(H)1 cells. In contrast, Gal-9 induced TNF-α production in cultured DC in a dose-dependent manner; however, RMT3-23 inhibited Gal-9-induced TNF-α production in a dose-dependent manner. Although Gal-9 exhibited certain therapeutic potential against autoimmune diabetes by enhancing apoptosis of CD4(+)Tim-3(+) T(H)1 cells, RMT3-23 exhibited prominent therapeutic efficacy by suppressing the TNF-α production and activation of DC. Taken together, the inhibition of the Gal-9-Tim-3 pathway on DC, upstream of T(H)1 response, may be a new target for the treatment of type 1 diabetes.
Assuntos
Anticorpos Monoclonais/farmacologia , Diabetes Mellitus Tipo 1/tratamento farmacológico , Galectinas/metabolismo , Galectinas/farmacologia , Hipoglicemiantes/uso terapêutico , Receptores Virais/metabolismo , Animais , Células Cultivadas , Células Dendríticas , Feminino , Galectinas/genética , Regulação da Expressão Gênica , Receptor Celular 2 do Vírus da Hepatite A , Camundongos , Camundongos Endogâmicos ICR , Camundongos Endogâmicos NOD , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores Virais/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Linfócitos T/metabolismo , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Familial lecithin:cholesterol acyltransferase deficiency (FLD) is an autosomal recessive disorder characterized by corneal opacity, hemolytic anemia, low high-density lipoprotein cholesterol (HDL-C) and proteinuria. Two novel lecithin:cholesterol acyltransferase (LCAT) mutations[c.278 C>T (p.Pro69Leu); c.950 T>C (p.Met293Thr)] were identified in a 27-year-old man and in a 30-year-old woman, respectively. Both patients manifested corneal opacity, hemolytic anemia, low low-density lipoprotein cholesterol and HDL-C and proteinuria. Lipid deposits with vacuolar lucent appearance in glomerular basement membranes were observed in both cases. APOE genotype was also investigated: the first case results ϵ4/ϵ3, the second ϵ2/ϵ2; however, they shared a similar phenotype characterized by the presence of intermediate-density lipoproteins (IDL) remnant and the absence of lipoprotein-X. In conclusion, our findings suggest that APOE ϵ2/ϵ2 may not be the major determinant gene for the appearance of IDL in FLD patients.
RESUMO
BACKGROUND: Collectrin, a homologue of angiotensin converting enzyme 2, is expressed in pancreatic beta cells and renal proximal tubular and collecting duct cells under the control of hepatocyte nuclear factors-1alpha and -1beta. Because collectrin interacts with the soluble N-ethylmaleiamide-sensitive factor attachment protein receptor (SNARE) complexes, we investigated whether collectrin is involved in sodium handling in hypertension by vesicle trafficking of apical membrane proteins. METHODS AND RESULTS: Collectrin physically interacts with the SNARE complex: snapin, synaptosomal-associated protein 23 kDa, syntaxin-4, and vesicle-associated membrane protein-2 in mIMCD-3 cells. siRNA knockdown of collectrin resulted in a reduction in membrane-associated aquaporin-2, alpha-epithelial Na+ channel, and H+-ATPase. Collectrin and SNARE proteins were abundantly expressed in collecting ducts of Wistar-Kyoto rats. Wistar-Kyoto rats and spontaneously hypertensive rats 7 weeks of age were subjected to normal-salt (1% NaCl) and high-salt (8% NaCl) chow for 10 weeks. High-salt chow prominently elevated blood pressure, oral intake, and urinary excretion of NaCl and water in both groups. Although urinary excretion of aldosterone was significantly suppressed in both groups, collectrin expression was upregulated and associated with the maintenance of aquaporin-2, alpha-epithelial Na+ channel, and H+-ATPase in membrane fractions. Collectrin promoter activities and mRNA and protein expressions were upregulated and ubiquitinated collectrin was reduced by high NaCl (175 to 225 mmol/L) and not altered by 1 micromol/L aldosterone in mIMCD-3 cells. CONCLUSIONS: Upregulation of collectrin by high NaCl independent of aldosterone functionally links to the trafficking of apical membrane proteins via the SNARE complex, and collectrin may be responsible for the sodium retention in salt-sensitive hypertension.