RESUMO
BACKGROUND: Endothelin-1 (ET-1) is associated with progression of renal disease, acting as a vasoconstrictor and growth factor for mesangial cells. ET-1 and endothelin A receptor (ET-RA) might have a role in the development of diabetic nephropathy (DN). The aims of this study were to determine ET-1 and ET-RA expressions in patients with DN and to correlate these expressions with renal function and proteinuria. MATERIALS AND METHODS: This is a cross-sectional study comprising 13 patients with type 2 diabetes mellitus and DN, 10 patients with proteinuric IgA nephropathy, and 13 samples of normal kidney from tumor nephrectomies. Demographic and selected data were collected from medical charts. The distribution and intensity of ET-1 and ET-RA immunostaining in renal biopsies were determined by immunohistochemistry and these correlated with the estimated glomerular filtration rate (eGFR) and proteinuria. RESULTS: Patients with DN and IgA nephropathy on biopsy had markedly increased staining for ET-1 in endothelial cells of glomerular and peritubular capillaries when compared with controls (p < 0.001). ET-RA staining was also more intense and more diffuse in DN and IgA nephropathy than in controls (p = 0.019) and was restricted to tubular epithelial cells. A positive correlation was observed between ET-1 expression and proteinuria (r = 0.634, p = 0.027), but both ET-1 and ET-RA expressions did not correlate with eGFR. CONCLUSION: In this preliminary report, the higher expressions of ET-1 and ET-RA found in both DN and IgA nephropathy suggest a potential role for the endothelin system in DN as well as in other nondiabetic glomerular diseases.
Assuntos
Nefropatias Diabéticas/metabolismo , Endotelina-1/biossíntese , Rim/metabolismo , Receptor de Endotelina A/biossíntese , Adulto , Biomarcadores/metabolismo , Biópsia , Estudos Transversais , Nefropatias Diabéticas/imunologia , Nefropatias Diabéticas/patologia , Progressão da Doença , Endotelina-1/imunologia , Feminino , Seguimentos , Humanos , Imuno-Histoquímica , Rim/patologia , Masculino , Pessoa de Meia-Idade , Receptor de Endotelina A/imunologia , Estudos RetrospectivosRESUMO
Diabetic Nephropathy (DN) is a major chronic complication of diabetes mellitus (DM), and one of the main causes of new cases for dialysis, being associated with increasing mortality. The main risk factors for DN are hypertension, hyperglycemia, dyslipidemia, and genetic susceptibility. The renin-angiotensin system (RAS) plays an important role in genesis and progression of DN and there is evidence of an interrelationship between this system and the endothelins. Endothelins are powerful vasoconstrictor peptides and act as modulators of vasomotor tone, cell proliferation, and hormone production. These peptides act through two types of receptors (ET-A and ET-B) and are expressed on endothelial cells and vascular smooth-muscle cells. Activation of this receptor in renal cells leads to a complex signaling cascade resulting in stimulation of mesangial cell hypertrophy, proliferation, contraction, and extracellular matrix accumulation. These hemodynamic renal alterations are associated with the onset and progress of renal disease in DM. Elevated endothelin-1 (ET-1) levels have been reported in patients with DM. There is evidence suggesting that an increase in the production of ET-1 leads to glomerular damage. The use of ET receptor antagonists has been reported as renoprotective, correcting the early hemodynamic abnormalities in experimental DM, reinforcing the importance of this system in DN.
Assuntos
Nefropatias Diabéticas/fisiopatologia , Endotelinas/fisiologia , Animais , Biomarcadores , Nefropatias Diabéticas/etiologia , Endotelina-1/fisiologia , HumanosRESUMO
A nefropatia diabética (ND) é uma importante complicação crônica do diabetes melito (DM), sendo uma das principais causas dos novos casos de diálise e está associada ao aumento da mortalidade. Os principais fatores de risco são a hiperglicemia, a hipertensão arterial sistêmica (HAS), a dislipidemia e a susceptibilidade genética. O sistema renina-angiotensina (SRA) tem papel importante na gênese e na progressão da ND e existem evidências de interação entre este sistema e as endotelinas. As endotelinas são peptídeos com potente ação vasoconstritora que atuam modulando o tono vasomotor, a proliferação celular e a produção hormonal. Estes peptídeos agem por meio de dois receptores (ET-A e ET-B), que são expressos nas células endoteliais e no músculo liso vascular. A ativação destes receptores nas células renais leva à complexa cascata de alterações, resultando proliferação e hipertrofia das células mesangiais, vasoconstrição das arteríolas aferentes e eferentes e acúmulo de matriz extracelular. Essas alterações hemodinâmicas renais estão associadas com o aparecimento e a progressão da doença renal no DM. Níveis plasmáticos elevados de endotelina-1 (ET-1) têm sido relatados em pacientes com DM e há algumas evidências que sugerem que o aumento da produção de ET-1 poderia levar a dano glomerular. O uso de drogas antagonistas do receptor da ET-1 em situações de DM experimental tem mostrado propriedades nefroprotetoras, reforçando a importância deste sistema na ND.
Diabetic Nephropathy (DN) is a major chronic complication of diabetes mellitus (DM), and one of the main causes of new cases for dialysis, being associated with increasing mortality. The main risk factors for DN are hypertension, hyperglycemia, dyslipidemia, and genetic susceptibility. The renin-angiotensin system (RAS) plays an important role in genesis and progression of DN and there is evidence of an interrelationship between this system and the endothelins. Endothelins are powerful vasoconstrictor peptides and act as modulators of vasomotor tone, cell proliferation, and hormone production. These peptides act through two types of receptors (ET-A and ET-B) and are expressed on endothelial cells and vascular smooth-muscle cells. Activation of this receptor in renal cells leads to a complex signaling cascade resultanting in stimulation of mesangial cell hypertrophy, proliferation, contraction, and extracellular matrix accumulation. These hemodinamic renal alterations are associated with the onset and progress of renal disease in DM. Elevated endothelin-1 (ET-1) levels have been reported in patients with DM. There is evidence suggesting that an increase in the production of ET-1 leads to glomerular damage. The use of ET receptor antagonists has been reported as renoprotective, correcting the early hemodynamic abnormalities in experimental DM, reinforcing the importance of this system in DN.
Assuntos
Animais , Humanos , Nefropatias Diabéticas/fisiopatologia , Endotelinas/fisiologia , Biomarcadores , Nefropatias Diabéticas/etiologia , Endotelina-1/fisiologiaRESUMO
The aim was to compare in patients with type 2 diabetes mellitus (DM2) the prevalence of the metabolic syndrome according to the World Health Organization (WHO) and the National Cholesterol Education Program (NCEP) definitions, and to analyze the association between them and the complications of DM2. Patients with DM2 (n= 753) were evaluated for ethnics, anthropometrics and laboratory parameters and for the presence of DM2 complications: diabetic nephropathy, coronary artery disease, stroke, diabetic retinopathy and peripheral vascular disease. Insulin resistance was estimated using the HOMA index. Metabolic syndrome was found in 671 (89%) and 657 (87%) patients using the WHO definition and the NCEP definition, respectively. In the total group, there was a moderate agreement between the two definitions (k= 0.54; 95% CI 0.49-0.59), although, it was better for black patients (k= 0.69; 95% CI 0.60-0.78) than white (k= 0.54; 95% CI 0.48-0.6) or mulattos patients (k= 0.26; 95% CI 0.09-0.43). Patients with metabolic syndrome using the NCEP criteria had higher HOMA-IR values compared to those without metabolic syndrome (p= 0.001). This differentiation was not seen using the WHO definition (p= 0.152). The proportion of diabetic complications was similar for both definitions. In conclusion, regarding the risk of diabetic complications both definitions are equivalent. However, there are some ethnic differences in the agreement between the two definitions.
Assuntos
Doenças Cardiovasculares/etiologia , Diabetes Mellitus Tipo 2/complicações , Síndrome Metabólica/complicações , Doenças Cardiovasculares/diagnóstico , Estudos Transversais , Diabetes Mellitus Tipo 2/fisiopatologia , Feminino , Humanos , Resistência à Insulina , Masculino , Síndrome Metabólica/epidemiologia , Síndrome Metabólica/fisiopatologia , Pessoa de Meia-Idade , Prevalência , Fatores de Risco , Organização Mundial da SaúdeRESUMO
O objetivo deste estudo é comparar em pacientes com diabetes melito tipo 2 (DM2) a proporção de síndrome metabólica de acordo com a definição da Organização Mundial de Saúde (OMS) e a do National Cholesterol Education Program (NCEP), e analisar qual se associa mais à presença das complicações do DM2. Foram avaliados 753 pacientes com DM2 em atendimento ambulatorial, quanto a parâmetros étnicos, antropométricos, laboratoriais e presença das complicações: nefropatia diabética, cardiopatia isquêmica, acidente vascular cerebral, retinopatia diabética e vasculopatia periférica. A resistência insulínica foi estimada através do HOMA-IR. A síndrome metabólica esteve presente em 671 (89 por cento) e 657 (87 por cento) dos pacientes utilizando a definição da OMS e do NCEP, respectivamente. No grupo total, houve uma concordância moderada entre as duas definições (k= 0,54; IC 95 por cento 0,490,59), porém foi melhor para negros (k= 0,69; IC 95 por cento 0,60,78) do que para brancos (k= 0,54; IC 95 por cento 0,480,6) e mulatos (k= 0,26; IC 95 por cento 0,090,43). Pacientes com síndrome metabólica pela definição do NCEP apresentaram valores de HOMA-IR maiores que os pacientes sem síndrome metabólica (p= 0,001). Esta diferença não foi encontrada utilizando a definição da OMS (p= 0,152). A proporção das complicações do DM2 foi semelhante nas duas definições. Em conclusão, em relação ao risco de complicações, as duas definições são equivalentes. Entretanto, existe variação na concordância entre as duas definições de acordo com a etnia.
The aim was to compare in patients with type 2 diabetes mellitus (DM2) the prevalence of the metabolic syndrome according to the World Health Organization (WHO) and the National Cholesterol Education Program (NCEP) definitions, and to analyze the association between them and the complications of DM2. Patients with DM2 (n= 753) were evaluated for ethnics, anthropometrics and laboratory parameters and for the presence of DM2 complications: diabetic nephropathy, coronary artery disease, stroke, diabetic retinopathy and peripheral vascular disease. Insulin resistance was estimated using the HOMA index. Metabolic syndrome was found in 671 (89 percent) and 657 (87 percent) patients using the WHO definition and the NCEP definition, respectively. In the total group, there was a moderate agreement between the two definitions (k= 0.54; 95 percent CI 0.490.59), although, it was better for black patients (k= 0.69; 95 percent CI 0.600.78) than white (k= 0.54; 95 percent CI 0.480.6) or mulattos patients (k= 0.26; 95 percent CI 0.090.43). Patients with metabolic syndrome using the NCEP criteria had higher HOMA-IR values compared to those without metabolic syndrome (p= 0.001). This differentiation was not seen using the WHO definition (p= 0.152). The proportion of diabetic complications was similar for both definitions. In conclusion, regarding the risk of diabetic complications both definitions are equivalent. However, there are some ethnic differences in the agreement between the two definitions.