RESUMO
How nutritional excess leads to inflammatory responses in metabolic syndrome is not well characterized. Here, we evaluated the effects of ω-3 polyunsaturated fatty acid specific G-protein coupled receptor 120 (GPR120) activation on inflammatory pathways in adipocytes, and the influence of this process on macrophage migration. Using 3T3-L1 adipocytes, we found that agonizing GPR120 using its synthetic ligand, GSK137647, attenuated both basal and lipopolysaccharide-induced production of interleukin-6 (IL-6) and C-C motif chemokine ligand 2 (CCL2). Moreover, the intervention reduced the phosphorylation of nuclear factor kappa B inhibitor alpha (IκBα) and nuclear translocation of nuclear factor kappa-B p65 subunit (p65). Furthermore, the silencing of GPR120 itself reduced IL-6 and CCL2 mRNA expression. Inhibition of protein kinase C (PKC) augmented the down-regulatory effect of GSK137647 on IL-6 and CCL2 mRNA. Using a luciferase assay to measure promoter activity of the IL-6 gene in mouse embryonic fibroblasts, we demonstrated that exogenous transfection of GPR120 alone reduced the promoter activity, which was augmented by GSK137647. Inhibition of PKC further reduced the promoter activity. Nevertheless, RAW 264.7 macrophages grown in conditioned medium collected from GSK137647-treated adipocytes attenuated the expressions of matrix metalloproteinases-9 and -3, and tissue inhibitor of metalloproteinase-1. Conditioned medium also inhibited the lipopolysaccharide-induced migration of these macrophages. Taken together, these findings provide critical evidence that although GPR120 is associated with a PKC-mediated pro-inflammatory pathway, the direct inhibitory effects of GPR120 on the nuclear factor kappa B pathway are anti-inflammatory. Moreover, GPR120 activity can attenuate the adipocyte-mediated enhanced production of extracellular matrix-modulating factors in macrophages and can reduce their migration by a paracrine mechanism.
Assuntos
Adipócitos/metabolismo , Adipocinas/metabolismo , Mediadores da Inflamação/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Células 3T3-L1 , Adipócitos/efeitos dos fármacos , Adipocinas/genética , Animais , Western Blotting , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Células Cultivadas , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Lipopolissacarídeos/farmacologia , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Metaloproteinase 3 da Matriz/genética , Metaloproteinase 3 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Inibidor de NF-kappaB alfa/metabolismo , Fosforilação/efeitos dos fármacos , Proteína Quinase C/metabolismo , Interferência de RNA , Receptores Acoplados a Proteínas G/agonistas , Receptores Acoplados a Proteínas G/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Inibidor Tecidual de Metaloproteinase-1/genética , Inibidor Tecidual de Metaloproteinase-1/metabolismo , Fator de Transcrição RelA/metabolismoRESUMO
Deterioration of adipocyte function due to increased oxidative stress predisposes patients to metabolic disorders in advanced age. However, the roles of tumor suppressors in such conditions remain largely unknown. Therefore, we aimed to address their dynamics in aged adipocytes using a long-term culture model. We compared 3T3-L1 adipocytes at 17-19 days (long-term) with those at 8-10 days (short-term) after initiation of adipogenic induction for mimicking 'aged' and 'young' adipocytes, respectively. H2O2 release and dihydroethidium (DHE) staining was increased, while superoxide dismutase (SOD) activity was reduced in long-term cultured adipocytes, which is suggestive of enhanced oxidative stress in this group. Moreover, qRT-PCR revealed increased mRNAs of Nox4 (a subunit of NADPH oxidase complex), Ccl2 (a proinflammatory chemokine) and Il6 [a marker of senescence-associated secretory phenotype (SASP)] along with decreased levels of Pparγ, Adipoq and Slc2a4 (genes related to glucose metabolism). These alterations were associated with increased expression of the tumor suppressors alternate-reading-frame protein p19Arf (Arf) and p16Ink4a. However, silencing of Arf reduced mRNAs of Adipoq and Slc2a4 and enhanced release of Il6. The effect was opposite in Arf overexpressing adipocytes, which showed reduced superoxide production as assessed with DHE staining and SOD activity. Western blots showed that Arf negatively regulates the phosphorylation of Akt. Luciferase assay in Hela cells additionally suggested that Arf negatively regulates Il6 transcriptional activity through a PI3 K/Akt mediated pathway. These findings strongly suggest that the enhanced Arf expression in oxidative stress plays compensatory protective roles against aging-related dysregulation of gene expression in adipocytes.
Assuntos
Adipócitos/metabolismo , Envelhecimento/metabolismo , Senescência Celular/fisiologia , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Espécies Reativas de Oxigênio/metabolismo , Células 3T3-L1 , Animais , Células HeLa , Humanos , Camundongos , Regulação para Cima/fisiologiaRESUMO
This study was performed to demonstrate urinary angiotensinogen as a potential prognostic marker of the albuminuria reduction effects of olmesartan in patients with metabolic syndrome. In 24 patients (eight women, 57.88 ± 2.00 years), 5-40 mg/day of olmesartan were given. Urinary concentrations of albumin and angiotensinogen (normalized by urinary concentrations of creatinine) and plasma renin activity were measured before and after the 12- and 24-week marks of olmesartan treatment. Olmesartan treatment increased plasma renin activity and decreased urinary albumin and urinary angiotensinogen significantly (p < 0.05). Based on the % change in urinary albumin, patients were divided into two groups, responders (<-50%) and non-responders (≥-50%), and a logistic analysis of urinary angiotensinogen before treatment showed the area under the curve as 0.694. When the cutoff value of urinary angiotensinogen before the treatment of 13.9 µg/g Cr was used, the maximum Youden index (0.500, specificity: 11/12 = 91.7% and sensitivity: 7/12 = 58.3%) was obtained. When all patients were re-divided into two groups, those with higher values of urinary angiotensinogen before the treatment (Group H, n = 16) and those with lower values, Group H showed significantly decreased urinary albumin (p < 0.05). Therefore, urinary angiotensinogen could be a prognostic marker of the albuminuria reduction effects of olmesartan in patients with metabolic syndrome.
Assuntos
Albuminúria/urina , Angiotensinogênio/urina , Síndrome Metabólica/tratamento farmacológico , Síndrome Metabólica/urina , Adulto , Albuminúria/tratamento farmacológico , Albuminúria/patologia , Biomarcadores Farmacológicos/urina , Creatinina/urina , Feminino , Humanos , Imidazóis/administração & dosagem , Masculino , Síndrome Metabólica/patologia , Pessoa de Meia-Idade , Prognóstico , Tetrazóis/administração & dosagemRESUMO
The cyclin-dependent kinase inhibitor p21 plays important roles in chronic renal disorders; however, its roles in response to acute renal stress are unclear. Here we evaluated p21 in acute kidney injury and ischemic preconditioning using wild-type and p21 knockout mice that underwent renal ischemia followed by reperfusion. The decline in renal function and histological changes were worse in the knockout than in wild-type mice. Ischemia/reperfusion increased p21 expression in the kidney of wild-type mice compared with sham surgery, suggesting p21 may confer tolerance to ischemia/reperfusion injury. We next tested whether p21 is associated with the protective effect of ischemic preconditioning, an established method to reduce ischemia/reperfusion injury. Ischemic preconditioning attenuated ischemia/reperfusion injury in wild-type but not p21-knockout mice. This preconditioning decreased the number of proliferating tubular cells before but increased them at 24 h after ischemia/reperfusion in the kidneys of wild-type mice. In p21-knockout mice, ischemic preconditioning did not change the number of proliferating cells before but decreased them after ischemia/reperfusion. Ischemic preconditioning increased renal p21 expression and the number of cells in the G1 phase of the cell cycle before ischemia/reperfusion compared with sham surgery. Thus, renal p21 is essential for the beneficial effects of renal ischemic preconditioning. Transient cell cycle arrest induced by ischemic preconditioning by a p21-dependent pathway seems to be important for subsequent tubular cell proliferation after ischemia/reperfusion.
Assuntos
Injúria Renal Aguda/metabolismo , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Precondicionamento Isquêmico , Traumatismo por Reperfusão/metabolismo , Injúria Renal Aguda/prevenção & controle , Animais , Pontos de Checagem do Ciclo Celular , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator 2 Relacionado a NF-E2/metabolismo , Traumatismo por Reperfusão/prevenção & controleRESUMO
BACKGROUND: Early graft thrombosis and bleeding complications remain important causes of early graft loss following kidney transplantation in patients with antiphospholipid syndrome. Anti-ß2-glycoprotein I IgG is a disease-specific antibody in patients with antiphospholipid syndrome. Although plasmapheresis is partially effective for antibody removal, the optimal treatment allowing successful transplantation in patients with antiphospholipid syndrome has not been established. This is the first report of a patient with antiphospholipid syndrome who successfully underwent living-donor kidney transplantation following prophylactic plasmapheresis for removal of anti-ß2-glycoprotein I IgG. CASE PRESENTATION: A 37-year-old Japanese female was scheduled to undergo a living-donor kidney transplant from her mother. At age 25 years, she experienced renal vein thrombosis, was diagnosed with antiphospholipid syndrome secondary to systemic lupus erythematosus, and was subsequently treated with prednisolone and warfarin. At age 37 years, she was diagnosed with end stage kidney disease, requiring maintenance hemodialysis because of recurrent renal vein thrombosis despite taking anticoagulation therapy. The pretreatment protocol consisted of prophylactic plasmapheresis plus full anticoagulation therapy to counteract the risks of early graft thrombosis. Anticardiolipin and anti-ß2-glycoprotein I IgGs were successfully removed by both double filtration plasmapheresis and plasma exchange. The allograft kidney began to function soon after transplantation. No obvious thrombotic complications were observed after transplantation, although anti-ß2-glycoprotein I IgG increased to the level observed before plasmapheresis. One year after transplantation, the patient's kidney function remains stable while receiving anticoagulation therapy as well as a maintenance immunosuppressive regimen. CONCLUSION: Prophylactic plasmapheresis plus full anticoagulation therapy may be an effective strategy in patients with antiphospholipid syndrome undergoing living-donor kidney transplantation.
Assuntos
Síndrome Antifosfolipídica/terapia , Falência Renal Crônica/etiologia , Transplante de Rim , Lúpus Eritematoso Sistêmico/complicações , Troca Plasmática , Plasmaferese , Cuidados Pré-Operatórios/métodos , Trombofilia/terapia , Trombose/prevenção & controle , Corticosteroides/uso terapêutico , Adulto , Anticoagulantes/uso terapêutico , Síndrome Antifosfolipídica/etiologia , Autoantígenos/imunologia , Feminino , Rejeição de Enxerto/prevenção & controle , Humanos , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Imunossupressores/uso terapêutico , Falência Renal Crônica/cirurgia , Doadores Vivos , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Diálise Renal , Trombofilia/tratamento farmacológico , Trombofilia/etiologia , Varfarina/uso terapêutico , beta 2-Glicoproteína I/imunologiaRESUMO
Regulatory T cells (Tregs) play a crucial role in the negative regulation of immune responses. Recent studies suggest that Tregs are involved in the pathogenesis of atherosclerosis and myocarditis. Here, we investigated the involvement of Tregs on worsening heart failure (HF) in patients with reduced ejection fraction (HF-REF). The study population consisted of 32 HF-REF patients who were hospitalized for worsening HF, and 18 control subjects. Cardiac function was evaluated by echocardiography. A single venous blood sample was collected before discharge. Circulating T cells were evaluated by flow cytometry. Tregs were defined as CD4(+)CD25(+)Foxp3(+)T cells, and the correlations between the frequency of Tregs and CRP, IL-6 and several echoparameters were analysed. Furthermore, all HF-REF patients were followed up to 12 months from discharge to examine the predictors of recurrent hospitalization.In HF-REF patients, Tregs were significantly decreased (5.9 ± 1.4 versus 8.0 ± 2.2%, P < 0.01), while CD4(+)HLADR(+)T cells were increased (10.1 ± 5.4 versus 7.3 ± 3.1%, P < 0.05), compared with controls. Tregs were negatively correlated with left ventricular end-diastolic dimension, and levels of CRP and IL-6. Eleven of 32 HF-REF patients were rehospitalized for worsening HF within 12 months. Multivariate Cox regression analysis showed that CD4/CD8 and frequency of Tregs were independent predictors for recurrent hospitalization. Furthermore, HF-REF patients expressing under 6% Treg/CD4(+)T cells showed a significantly higher incidence of recurrent hospitalization for worsening HF within 12 months.Our data suggest that Tregs might be involved in the pathogenesis of decompensated HF, and may be a novel predictor of poor prognosis in HF-REF patients.
Assuntos
Insuficiência Cardíaca/imunologia , Ventrículos do Coração/fisiopatologia , Imunidade Celular , Volume Sistólico/fisiologia , Linfócitos T Reguladores/imunologia , Função Ventricular Esquerda , Idoso , Ecocardiografia , Seguimentos , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/fisiopatologia , Ventrículos do Coração/diagnóstico por imagem , Humanos , Masculino , PrognósticoRESUMO
BACKGROUND: The presence of chronic kidney disease is a significant independent risk factor for poor prognosis in patients with chronic heart failure. However, the mechanisms and mediators underlying this interaction are poorly understood. In this study, we tested our hypothesis that chronic cardiac volume overload leads to de novo renal dysfunction by coactivating the sympathetic nervous system and renin-angiotensin system in the kidney. We also examined the therapeutic potential of renal denervation and renin-angiotensin system inhibition to suppress renal injury in chronic heart failure. METHODS AND RESULTS: Sprague-Dawley rats underwent aortic regurgitation and were treated for 6 months with vehicle, olmesartan (an angiotensin II receptor blocker), or hydralazine. At 6 months, albuminuria and glomerular podocyte injury were significantly increased in aortic regurgitation rats. These changes were associated with increased urinary angiotensinogen excretion, kidney angiotensin II and norepinephrine (NE) levels, and enhanced angiotensinogen and angiotensin type 1a receptor gene expression and oxidative stress in renal cortical tissues. Aortic regurgitation rats with renal denervation had decreased albuminuria and glomerular podocyte injury, which were associated with reduced kidney NE, angiotensinogen, angiotensin II, and oxidative stress. Renal denervation combined with olmesartan prevented podocyte injury and albuminuria induced by aortic regurgitation. CONCLUSIONS: In this chronic cardiac volume-overload animal model, activation of the sympathetic nervous system augments kidney renin-angiotensin system and oxidative stress, which act as crucial cardiorenal mediators. Renal denervation and olmesartan prevent the onset and progression of renal injury, providing new insight into the treatment of cardiorenal syndrome.
Assuntos
Albuminúria/prevenção & controle , Insuficiência da Valva Aórtica/prevenção & controle , Rim/inervação , Podócitos/patologia , Simpatectomia , Albuminúria/complicações , Albuminúria/patologia , Animais , Insuficiência da Valva Aórtica/complicações , Insuficiência da Valva Aórtica/patologia , Linhagem Celular Transformada , Humanos , Rim/patologia , Rim/fisiologia , Masculino , Podócitos/fisiologia , Ratos , Ratos Sprague-Dawley , Simpatectomia/métodosRESUMO
INTRODUCTION: Latent mesangial immunoglobulin A (IgA) deposition in the donated kidney has been investigated in the context of kidney transplantation. However, few studies have examined the impact of mesangial expansion accompanied with IgA deposition. Therefore, we investigated the effects of latent IgA deposition and mesangial expansion on transplant prognosis following living-donor kidney transplantation. METHODS: We retrospectively analyzed 68 consecutive adult living-donor kidney transplantations performed at Kagawa University Hospital. Biopsies were performed at pre-implantation and at one year after transplantation. RESULTS: Twenty kidneys exhibited latent IgA deposition in pre-implantation biopsies, including 14 with mesangial expansion. Latent IgA deposition was not associated with renal function or donor urinalysis after donation, irrespective of mesangial expansion. Latent IgA deposition was not significantly associated with graft survival rate, allograft function, abnormal urinalysis, or the recurrence of IgA nephropathy, irrespective of mesangial expansion. At one year after transplantation, IgA deposition had disappeared in 14/20 allografts. Estimated glomerular function rate >40 mL/min/1.73 m(2) was significantly associated with the disappearance of IgA deposition. CONCLUSIONS: The present study showed that latent IgA deposition from the donor kidney, irrespective of mesangial expansion, does not affect transplant prognosis following living-donor kidney transplantation.
Assuntos
Mesângio Glomerular/patologia , Glomerulonefrite por IGA/patologia , Transplante de Rim , Adulto , Feminino , Taxa de Filtração Glomerular , Glomerulonefrite por IGA/etiologia , Glomerulonefrite por IGA/terapia , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva , Estudos Retrospectivos , Fatores de Risco , Fatores de Tempo , Resultado do TratamentoRESUMO
OBJECTIVE: We previously showed that aldosterone induces insulin resistance in rat vascular smooth muscle cells (VSMCs). Because insulin-like growth factor-1 receptor (IGF1R) affects insulin signaling, we hypothesized that aldosterone induces vascular insulin resistance and remodeling via upregulation of IGF1R and its hybrid insulin/insulin-like growth factor-1 receptor. METHODS AND RESULTS: Hybrid receptor expression was measured by immunoprecipitation. Hypertrophy of VSMCs was evaluated by (3)H-labeled leucine incorporation. Aldosterone (10 nmol/L) significantly increased protein and mRNA expression of IGF1R and hybrid receptor in VSMCs but did not affect insulin receptor expression. Mineralocorticoid receptor blockade with eplerenone inhibited aldosterone-induced increases in IGF1R and hybrid receptor. Aldosterone augmented insulin (100 nmol/L)-induced extracellular signal-regulated kinase 1/2 phosphorylation. Insulin-induced leucine incorporation and α-smooth muscle actin expression were also augmented by aldosterone in VSMCs. These aldosterone-induced changes were significantly attenuated by eplerenone or picropodophyllin, an IGF1R inhibitor. Chronic infusion of aldosterone (0.75 µg/hour) increased blood pressure and aggravated glucose metabolism in rats. Expression of hybrid receptor, azan-positive area, and oxidative stress in aorta was increased in aldosterone-infused rats. Spironolactone and tempol prevented these aldosterone-induced changes. CONCLUSIONS: Aldosterone induces vascular remodeling through IGF1R- and hybrid receptor-dependent vascular insulin resistance. Mineralocorticoid receptor blockade may attenuate angiopathy in hypertensive patients with hyperinsulinemia.
Assuntos
Aldosterona/farmacologia , Resistência à Insulina , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Receptor IGF Tipo 1/metabolismo , Receptor de Insulina/metabolismo , Animais , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/metabolismo , Aorta Torácica/patologia , Pressão Sanguínea/efeitos dos fármacos , Células Cultivadas , Quimera/genética , Eplerenona , Glucose/metabolismo , Hipertrofia , Insulina/farmacologia , Masculino , Modelos Animais , Músculo Liso Vascular/patologia , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Receptor IGF Tipo 1/genética , Receptor de Insulina/genética , Espironolactona/análogos & derivados , Espironolactona/farmacologia , Regulação para Cima/efeitos dos fármacosRESUMO
Angiotensin II (Ang II) infusion into rats elevates local angiotensin II levels through an AT1 receptor-dependent pathway in the kidney. We examined whether treatment with an angiotensin-converting enzyme (ACE) inhibitor, temocapril, or an AT1-receptor blocker, olmesartan, prevented elevation of Ang II levels in the kidney of angiotensin I (Ang I)-infused rats. Rats were infused with Ang I (100 ng/min) and treated with temocapril (30 mg/kg per day, n = 10) or olmesartan (10 mg/kg per day, n = 9) for 4 weeks. Ang I infusion significantly elevated blood pressure compared with vehicle-infused rats (n = 6). Treatment with temocapril or olmesartan suppressed Ang I-induced hypertension. Temocapril suppressed both plasma and renal ACE activity. Ang I infusion increased Ang II content in the kidney. Interestingly, temocapril failed to reduce the level of Ang II in the kidney, while olmesartan markedly suppressed an increase in renal Ang II levels. These results suggest a limitation of temocapril and a benefit of olmesartan to inhibit the renal renin-angiotensin system and suggest the possible existence of an ACE inhibitor-insensitive pathway that increases Ang II levels in rat kidney.
Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Angiotensina II/urina , Angiotensina I/farmacologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Imidazóis/farmacologia , Rim/metabolismo , Tetrazóis/farmacologia , Tiazepinas/farmacologia , Angiotensina I/administração & dosagem , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Animais , Anti-Hipertensivos/farmacologia , Anti-Hipertensivos/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Hipertensão/tratamento farmacológico , Hipertensão/etiologia , Imidazóis/uso terapêutico , Masculino , Peptidil Dipeptidase A/metabolismo , Ratos , Ratos Sprague-Dawley , Sistema Renina-Angiotensina/efeitos dos fármacos , Sistema Renina-Angiotensina/fisiologia , Tetrazóis/uso terapêutico , Tiazepinas/uso terapêuticoRESUMO
BACKGROUND: Excess fluid distribution is a common disorder in peritoneal dialysis (PD) patients. Tacrolimus malabsorption may also occur in PD patients, and may lead to acute allograft rejection after transplantation. The purpose of this study was to evaluate the relationship between tacrolimus pharmacokinetics and excess fluid distribution according to pre-transplant dialysis modality. METHODS: We retrospectively analyzed 41 adult living-donor kidney transplantations, including nine PD patients and 32 hemodialysis (HD) patients. We examined tacrolimus pharmacokinetics in the peri-operative period and determined the association between the tacrolimus absorption rate and body weight reduction. The absorption efficacy of tacrolimus was evaluated as the dose-normalized tacrolimus absorption rate. Tacrolimus concentrations in PD effluent were measured by high-performance liquid chromatography. RESULTS: The tacrolimus absorption rate on the day before kidney transplantation tended to be lower in PD patients than in HD patients; however, the rate improved after kidney transplantation and was similar in both groups of patients. The peak tacrolimus concentration time was later in PD patients than in HD patients. The body weight reduction after kidney transplantation was greater in PD patients than in HD patients, and was significantly associated with the change in tacrolimus absorption rate (p=0.04, r=0.32). Only 0.002% of the oral tacrolimus dose was removed by PD itself. CONCLUSION: Excess fluid distribution in PD patients appears to contribute to tacrolimus malabsorption rather than PD itself. We should consider the risk of tacrolimus malabsorption in patients with possible excess fluid distribution, particularly in PD patients.
Assuntos
Imunossupressores/farmacocinética , Transplante de Rim , Diálise Peritoneal/efeitos adversos , Tacrolimo/farmacocinética , Desequilíbrio Hidroeletrolítico/metabolismo , Administração Oral , Adulto , Peso Corporal , Cálculos da Dosagem de Medicamento , Monitoramento de Medicamentos , Feminino , Sobrevivência de Enxerto/efeitos dos fármacos , Humanos , Imunossupressores/administração & dosagem , Imunossupressores/sangue , Absorção Intestinal , Doadores Vivos , Masculino , Pessoa de Meia-Idade , Diálise Renal/efeitos adversos , Estudos Retrospectivos , Tacrolimo/administração & dosagem , Tacrolimo/sangue , Resultado do Tratamento , Desequilíbrio Hidroeletrolítico/sangue , Desequilíbrio Hidroeletrolítico/etiologiaRESUMO
BACKGROUND: Donor shortage is a serious problem worldwide and it is now debated whether kidneys from marginal donors are suitable for renal transplantation. Recent studies have shown that the findings of preimplantation kidney biopsy are useful to evaluate vasculopathy in the donated kidney, and may predict transplant outcomes in deceased- donor kidney transplantation. However, few studies have focused on the pathological findings of preimplantation biopsy in living-donor kidney transplantation. Therefore, we investigated whether arteriosclerotic vasculopathy in living-donor kidneys at the time of transplantation predicts the recipient's kidney function (allograft function) later in life. METHODS: We retrospectively analyzed 75 consecutive adult living-donor kidney transplants performed at Kagawa University Hospital. Renal arteriosclerotic vasculopathy was defined according to the presence of fibrous intimal thickening in the interlobular artery. RESULTS: Forty-one kidneys exhibited mild arteriosclerotic vasculopathy on preimplantation kidney biopsies. The decreases in estimated glomerular filtration rate after donation were similar in donors with or without renal arteriosclerotic vasculopathy. Pre-existing arteriosclerotic vasculopathy did not affect graft survival rate, patient survival rate or the incidence of complications. Recipients of kidneys with arteriosclerotic vasculopathy had lower allograft function at 1 and 3 years after transplantation than the recipients of arteriosclerosis-free kidneys with or without donor hypertension. In multivariate analysis, fibrous intimal thickening on preimplantation biopsy was predictive of reduced allograft function at 1 year after transplantation. CONCLUSIONS: The present study demonstrated that mild arteriosclerotic vasculopathy in the donated kidney is an important pathological factor that reflects future impaired function of renal allografts from marginal donors.
Assuntos
Arteriosclerose/patologia , Sobrevivência de Enxerto/fisiologia , Nefropatias/patologia , Transplante de Rim , Rim/patologia , Idoso , Arteriosclerose/fisiopatologia , Biópsia , Feminino , Humanos , Rim/irrigação sanguínea , Rim/fisiologia , Nefropatias/fisiopatologia , Nefropatias/cirurgia , Doadores Vivos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Cuidados Pré-Operatórios , Artéria Renal/patologia , Artéria Renal/fisiopatologia , Estudos Retrospectivos , Transplante Homólogo , Resultado do Tratamento , Túnica Íntima/patologia , Túnica Íntima/fisiopatologiaRESUMO
BACKGROUND: Periodontitis increases the risk of atherosclerotic cardiovascular disease and ischemic stroke. In this study, we evaluated whether serum antibody levels against individual periodontal pathogens are significantly associated with ischemic stroke subtypes and their risk factors. METHODS: Patients with acute ischemic stroke (n = 132; 74 male and 58 female, 71.3 ± 10.7 years) and patients with no previous stroke (n = 77; 38 male and 39 female, 70.7 ± 9.5 years) were consecutively enrolled in this study. Stroke subtype was evaluated based on the Trial of Org 10172 in Acute Stroke Treatment classification. Serum was obtained from each patient after obtaining their consent to participate in the study. The levels of serum antibodies against Aggregatibacter actinomycetemcomitans (Aa), Porphyromonas gingivalis (Pg) and Prevotella intermedia (Pi) were evaluated by ELISA. Serum high-sensitivity C-reactive protein (hs-CRP) levels were measured by nephelometry. RESULTS: Serum hs-CRP levels were significantly associated with acute ischemic stroke even after controlling for acute ischemic stroke, hypertension, diabetes mellitus and bulb/ internal carotid artery (ICA) atherosclerosis which were statistically selected (coefficient 0.245, 95% CI 0.142-0.347, p < 0.0001). The serum-antibody level of Pi was significantly higher in atherothrombotic-stroke patients than in patients with no previous stroke (p = 0.0035). Detectable serum anti-Pg antibody was significantly associated with atrial fibrillation (overall χ(2) = 35.5, R(2) = 0.18, n = 209, p < 0.0001; anti-Pg antibody: OR 4.36, 95% CI 1.71-12.10, p = 0.0017), and detectable serum anti-Pi antibody was significantly associated with bulb/ICA atherosclerosis after controlling for the statistically selected associated factors (overall χ(2) = 46.1, R(2) = 0.18, n = 209, p < 0.0001; anti-Pg antibody: OR 16.58, 95% CI 3.96-78.93, p < 0.0001). The levels of serum anti-Pi antibody were significantly associated with atherothrombotic stroke with the statistically selected associated factors excluding bulb/ICA atherosclerosis (overall χ(2) = 77.0, R(2) = 0.44, n = 129, p < 0.0001; anti-Pi antibody: OR 23.6, 95% CI 2.65-298.2, p = 0.008). However, when we included bulb/ICA atherosclerosis in this model, the levels of serum anti-Pi antibody were no longer significantly associated with atherothrombotic stroke (overall χ(2) = 98.0, R(2) = 0.56, n = 129, p < 0.0001; anti-Pi antibody: p = 0.107). CONCLUSIONS: Our results suggest that anti-Pg antibody is associated with atrial fibrillation and that anti-Pi antibody is associated with carotid artery atherosclerosis. In addition, anti-Pi antibody may be associated with atherothrombotic stroke through its association with carotid artery atherosclerosis. Thus, periodontitis may lead to serious systemic diseases.
Assuntos
Anticorpos Antibacterianos/sangue , Infecções por Bacteroidaceae/complicações , Isquemia Encefálica/etiologia , Periodontite/complicações , Porphyromonas gingivalis/imunologia , Prevotella intermedia/imunologia , Idoso , Idoso de 80 Anos ou mais , Aterosclerose/etiologia , Infecções por Bacteroidaceae/sangue , Infecções por Bacteroidaceae/imunologia , Isquemia Encefálica/sangue , Isquemia Encefálica/imunologia , Proteína C-Reativa/metabolismo , Artérias Carótidas/metabolismo , Doenças das Artérias Carótidas/sangue , Doenças das Artérias Carótidas/etiologia , Doenças das Artérias Carótidas/imunologia , Feminino , Humanos , Hipertensão/etiologia , Masculino , Pessoa de Meia-Idade , Periodontite/imunologia , Porphyromonas gingivalis/metabolismo , Prevotella intermedia/metabolismo , Fatores de RiscoRESUMO
Left ventricular (LV) hypertrophy and diastolic dysfunction are commonly observed in hypertensive patients, and have been demonstrated to be risk factors of chronic heart failure due to LV diastolic dysfunction. Recently, reduced bone mineral density has been found in hypertensive patients compared with healthy controls. However, relationships between bone mineral density and LV hypertrophy and diastolic dysfunction have not been fully assessed. We examined relationships between bone mineral density and both LV hypertrophy and diastolic dysfunction in 38 hypertensive patients (23 males, 15 females; mean age 71 ± 8 y) who had been treated with antihypertensive drugs for at least 1 year. The bone mineral density of the calcaneus was measured with a quantitative ultrasound measurement device (A-1000 EXPRESS/InSight, GE Healthcare, Horten, Norway), and the stiffness index was determined as a parameter of bone mineral density. Echocardiography was performed to measure the left ventricular mass index as a parameter of LV hypertrophy. Left ventricular diastolic dysfunction was also assessed by early diastolic mitral annular velocity (e'), and the ratio of early transmitral flow velocity (E) to e' (E/e'). The bone mineral density did not correlate with left ventricular mass index, but did correlate with e' (r = 0.453, P < .01) and E/e' (r = -0.359, P < .05). Thus, reduced bone mineral density in hypertensive patients is not associated with LV hypertrophy but with LV diastolic dysfunction. Hypertensive patients with reduced bone mineral density may have a high risk of chronic heart failure due to LV diastolic dysfunction as well as bone fractures due to osteoporosis.
Assuntos
Densidade Óssea , Hipertensão/patologia , Hipertensão/fisiopatologia , Hipertrofia Ventricular Esquerda/patologia , Disfunção Ventricular Esquerda/fisiopatologia , Idoso , Idoso de 80 Anos ou mais , Diástole , Feminino , Insuficiência Cardíaca/etiologia , Hemoglobinas/metabolismo , Humanos , Hipertensão/complicações , Hipertensão/diagnóstico por imagem , Hipertrofia Ventricular Esquerda/complicações , Hipertrofia Ventricular Esquerda/diagnóstico por imagem , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Osteoporose/complicações , Osteoporose/patologia , Osteoporose/fisiopatologia , Fatores de Risco , Ultrassonografia , Disfunção Ventricular Esquerda/complicaçõesRESUMO
Intrarenal renin-angiotensin system (RAS) plays an important role for the pathogenesis of renal injuries. Experimental studies have demonstrated that angiotensinogen levels in renal tissues reflect the activity of intrarenal RAS. However, dynamics of urinary angiotensinogen have not been investigated in detail. Therefore, we examined the preservation conditions of the measured values of urinary angiotensinogen concentrations and an ultradian rhythm of urinary angiotensinogen excretion in humans. Urine samples were collected from 24 healthy volunteers. The urinary concentrations of angiotensinogen were measured by using ELISA. Two different urine preservation conditions were examined. One cycle of freeze-and-thaw did not change the measured values of urinary angiotensinogen concentrations. Moreover, to keep urine samples at room temperature for 12 hours did not change the measured values of urinary angiotensinogen concentrations. Thus, preservation conditions do not change the measured values of urinary angiotensinogen concentrations. Regarding an ultradian rhythm, blood pressure and the urinary concentrations of angiotensinogen were measured at 09:00, 13:00, and 16:00. The averaged levels of blood pressure were similar over the time. The average of urinary angiotensinogen/creatinine (Cr) ratios was 8.73 ± 1.15 ng/mg Cr at 09:00, 9.53 ± 1.58 ng/mg Cr at 13:00, and 8.58 ± 1.26 ng/mg Cr at 16:00. The urinary angiotensinogen excretion in healthy volunteers does not have an ultradian change during the daytime (P = 0.482). This may be another indication that the intrarenal RAS is independent of the systemic RAS. We have to pay attention to these findings in handling urine samples for measurements of angiotensinogen.
Assuntos
Angiotensinogênio/urina , Sistema Renina-Angiotensina/fisiologia , Manejo de Espécimes/métodos , Urinálise/métodos , Ciclos de Atividade/fisiologia , Pressão Sanguínea , Creatinina/urina , Ensaio de Imunoadsorção Enzimática , Humanos , TemperaturaRESUMO
Pioglitazone, a synthetic ligand of peroxisome proliferator-activated receptor (PPAR)γ, causes preadipocyte proliferation through a mechanism which still remains elusive. Here, to address the mechanism, we investigated the effects of PPARγ and pioglitazone on the kinetics of cyclin-dependent kinase inhibitors, especially with p16(Ink4a) (p16) centered, by employing 3T3-L1 preadipocytes. Pioglitazone promoted preadipocyte proliferation by increasing S and G(2)/M cell-cycle entry, which was accompanied by decreased p16 mRNA expression. PPARγ overexpression along with the luciferase reporter assay confirmed that PPARγ was crucial for the downregulation of p16 mRNA transcription, and that the action was augmented by pioglitazone. Thus, pioglitazone exerted cell-cycle dependent promoting effect on preadipocyte proliferation, of which mechanisms include p16-downregulation through PPARγ.
Assuntos
Adipócitos/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Inibidor p16 de Quinase Dependente de Ciclina/antagonistas & inibidores , Hipoglicemiantes/farmacologia , Tiazolidinedionas/farmacologia , Células 3T3-L1 , Adipócitos/citologia , Animais , Ciclo Celular/efeitos dos fármacos , Inibidor p16 de Quinase Dependente de Ciclina/genética , Regulação para Baixo , Camundongos , PPAR gama/agonistas , PPAR gama/metabolismo , Pioglitazona , RNA Mensageiro/antagonistas & inibidores , RNA Mensageiro/biossíntese , Transcrição Gênica/efeitos dos fármacosRESUMO
Obesity is known to be associated with a number of effects on skin physiology. KKA(y) obese mouse is a model of type 2 diabetes characterized by systemic oxidative stress because of severe obesity, hypertriglyceridaemia, hyperglycaemia and hyperinsulinaemia. We investigated lipid peroxidation and vascular endothelial growth factor (VEGF) expression in the skin of KKA(y) obese mice. We also investigated the effect of lipid peroxidation derivatives on VEGF production and proliferation in human epidermal keratinocyte cell line (HaCaT). The lipid peroxidation level in the mouse skin tissue was determined by measuring the levels of thiobarbituric acid-reactive substances. The levels of VEGF expression, p44/p42 mitogen-activated protein kinase (MAPK) activation and CD36 expression were analysed by Western blot. Their localization was examined by immunofluorescence. For the in vitro experiments, an enzyme-linked immunosorbent assay was utilized to measure VEGF secretion in the medium. In vitro experiments demonstrated that lipid peroxidation derivatives increased VEGF production in HaCaT cells, which was blocked by a p44/p42 MAPK inhibitor and anti-CD36 antibody. We observed increased levels of lipid peroxidation derivatives, p44/p42 MAPK activation and VEGF expression in the skin of KKA(y) obese mice. Notably, pitavastatin, an inhibitor of competitive 3-hydroxy-3-methylglutaryl coenzyme A reductase, suppressed all of these processes. Our results suggest that lipid peroxidation induces VEGF expression via CD36 and p44/p42 MAPK pathway in the skin of obese mice.
Assuntos
Peroxidação de Lipídeos/fisiologia , Pele/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Animais , Anticorpos/imunologia , Anticorpos/farmacologia , Antígenos CD36/imunologia , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Diabetes Mellitus Tipo 2/metabolismo , Modelos Animais de Doenças , Epiderme/efeitos dos fármacos , Epiderme/metabolismo , Epiderme/patologia , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Queratinócitos/efeitos dos fármacos , Queratinócitos/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Lipoproteínas LDL/farmacologia , Lisofosfatidilcolinas/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Proteína Quinase 1 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Fosforilação/efeitos dos fármacos , Quinolinas/farmacologia , Pele/efeitos dos fármacos , Pele/patologia , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismoRESUMO
We examined which echocardiographic parameter correlated best with plasma brain natriuteric peptide (BNP) levels in treated hypertensive patients. Enrolled in the study were 122 treated hypertensive patients (70 ± 9 y). The left ventricular mass index and left atrial dimension (LAD) were measured using echocardiography as indexes of left ventricular hypertrophy and left atrial enlargement, respectively. Among all the echocardiographic parameters, LAD correlated best with BNP (r = 0.343, p < 0.001). Stepwise regression analysis showed that LAD (ß coefficient = 0.513, p < 0.001) was independently associated with BNP. Left atrial enlargement, rather than left ventricular hypertrophy, may be clinically useful for predicting elevated BNP levels in treated hypertensive patients.
Assuntos
Anti-Hipertensivos/uso terapêutico , Átrios do Coração/diagnóstico por imagem , Átrios do Coração/patologia , Hipertensão/sangue , Hipertensão/tratamento farmacológico , Hipertrofia Ventricular Esquerda/diagnóstico por imagem , Peptídeo Natriurético Encefálico/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Biomarcadores/sangue , Estudos Transversais , Feminino , Humanos , Hipertrofia , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Análise de Regressão , Estudos Retrospectivos , UltrassonografiaRESUMO
Hypertension and osteoporosis are two common diseases in the elderly population. Recently, reduced bone mineral density has been found in hypertensive patients compared with healthy controls. Reduced bone mineral density is associated with increased arterial stiffness in chronic dialysis patients and healthy postmenopausal women. However, relationships between bone mineral density and arterial stiffness in hypertensive patients have not been fully assessed. We examined the relationships between bone mineral density and both arterial stiffness and nutritional status in 52 hypertensive patients (27 male and 25 female subjects; mean age 71±8 years) who had been treated with antihypertensive drugs for at least one year. The bone mineral density of the calcaneus was measured with a quantitative ultrasound measurement device, and the stiffness index was determined as a parameter of the bone mineral density. We measured the cardio-ankle vascular index (CAVI) to assess arterial stiffness and used the serum albumin to assess nutritional status. Increased arterial stiffness as assessed with CAVI is associated with reduced bone mineral density (r=-0.289, p=0.038). However, the correlation between CAVI and bone mineral density is not as strong as the correlation between serum albumin and bone mineral density (r=0.501, p<0.001). In conclusion, nutritional status is an important indicator of bone mineral density in hypertensive patients. Moreover, increased arterial stiffness is associated with reduced bone mineral density in hypertensive patients. Therefore, hypertensive patients with increased arterial stiffness may have a high risk of bone fracture due to osteoporosis.
Assuntos
Artérias/fisiopatologia , Densidade Óssea/fisiologia , Hipertensão/fisiopatologia , Idoso , Idoso de 80 Anos ou mais , Índice Tornozelo-Braço/estatística & dados numéricos , Pressão Sanguínea/fisiologia , Peso Corporal/fisiologia , Feminino , Humanos , Hipertensão/epidemiologia , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Estado Nutricional/fisiologia , Albumina Sérica/análise , Resistência Vascular/fisiologiaRESUMO
Seasonal variations in blood pressures should be kept in mind when controlling blood pressure in hypertensive patients. Seasonal variations in glomerular filtration rate (GFR) also may have a clinical significance. However, it is time-consuming to measure GFR directly. We therefore examined the seasonal variation in estimated glomerular filtration rate (eGFR) based on serum creatinine levels in hypertensive patients without CKD (eGFR ≥ 60 mL/min/1.73 m(2)) and those with chronic kidney disease (CKD) (eGFR < 60 mL/min/1.73 m(2)). This study included 47 hypertensive patients without CKD (69 ± 11 yrs) and 55 hypertensive patients with CKD (76 ± 8 yrs). The eGFR was determined from the equation: eGFR = 194 × age(-0.287) × (serum creatinine)(-1.094) (× 0.739 if female). Overall, both groups of hypertensive patients demonstrated similar seasonal variations in eGFR. Importantly, hypertensive patients without CKD and those with CKD showed the lower eGFR in summer (June-August) (71.8 ± 13.2 and 37.2 ± 13.0 mL/min/1.73 m(2), respectively) compared with the eGFR in spring (March-May) (77.9 ± 13.0 and 43.0 ± 14.0 mL/min/1.73 m(2), respectively) (p < 0.05). The decrease in eGFR from spring to summer was similar for both types of hypertensive patients (without CKD, -6.1 ± 7.0; with CKD, -5.8 ± 5.2 mL/min/1.73 m(2)). However, the percent change in eGFR from spring to summer was greater in hypertensive patients with CKD (-13.8 ± 9.4 %) than in those without CKD (-7.7 ± 8.3 %) (p = 0.001). In conclusion, careful observation regarding renal function is needed for hypertensive patients with CKD during summer.