RESUMEN
BACKGROUND AND AIMS: Oxidative stress contributes to development of diabetic nephropathy. We implicated SH3YL1 in oxidative stress-induced inflammation and examined whether SH3YL1 could be used as a new biomarker of diabetic nephropathy. METHODS AND RESULTS: In this study, we investigated the relationship between plasma level of SH3YL1 and diabetic nephropathy in patients with type 2 diabetes. In addition, we examined the physiological role of SH3YL1 in db/db mice and cultured podocytes. Plasma SH3YL1 concentration was significantly higher in patients with diabetes than in controls, even in normoalbuminuric patients, and was markedly increased in the macroalbuminuria group. Plasma SH3YL1 level was positively correlated with systolic blood pressure, HOMA-IR, postprandial blood glucose, plasma level of retinol binding protein 4 (RBP 4), and urinary albumin excretion (UAE) and was inversely correlated with BMI. Regression analysis showed that plasma level of RBP 4, UAE, and BMI were the only independent determinants of plasma SH3YL1 concentration. In db/db mice, plasma and renal SH3YL1 levels were significantly increased in mice with diabetes compared with control mice. In cultured podocytes, high glucose and angiotensin II stimuli markedly increased SH3YL1 synthesis. CONCLUSION: These findings suggest that plasma level of SH3YL1 offers a promising new biomarker for diabetic nephropathy.
Asunto(s)
Albuminuria/sangre , Diabetes Mellitus Tipo 2/sangre , Nefropatías Diabéticas/sangre , Proteínas de la Membrana/sangre , Adulto , Anciano , Albuminuria/diagnóstico , Albuminuria/etiología , Animales , Biomarcadores/sangre , Estudios de Casos y Controles , Línea Celular , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/diagnóstico , Nefropatías Diabéticas/diagnóstico , Nefropatías Diabéticas/etiología , Modelos Animales de Enfermedad , Femenino , Humanos , Masculino , Ratones Endogámicos C57BL , Persona de Mediana Edad , Podocitos/metabolismo , Proteínas Plasmáticas de Unión al Retinol/metabolismo , Regulación hacia ArribaRESUMEN
A factor stimulating a mitogenic activity of peritoneal macrophages is purified from bovine udder. It is identified as a triglyceride, 1-palmitoyl-2-linoleoyl-3-acetyl-RAC -glycerol (RAC -MADG). In this study, its enantiomers, R-(+)-and S-(-)-1-palmitoyl-2-linoleoyl-3-acetylglycerol (R-(+)-MADG, S-(-)-MADG) are synthesized. Among them, R-(+)-MADG enantiomer turns out to increase a mitogenic activity in mouse peritoneal macrophages. Also, (S)-(-)-MADG shows a low mitogenic activity. Treatment of a macrophage with R-(+)-MADG increases reactive oxygen species(ROS). Furthermore, treatment of macrophages with antioxidant, N-acetyl-L-cysteine (NAC), suppresses the R-(+)-MADG-dependent macrophage proliferation. Results show that the generation of ROS induces in R-(+)-MADG-dependent cell signaling. Treatment of a macrophage with R-(+)-MADG increases the activity of protein kinase C (PKC). Treatment of macrophages with calphostin C inhibits R-(+)-MADG-induced macrophage proliferation. Results suggest that R-(+)-MADG enhances the activity of protein kinase C (PKC) and stimulates the macrophage growth. In conclusions, R-(+)-MADG accelerates the production of ROS and increases the activity of PKC to eventually stimulate macrophage cell growth. The existence of RAC -MADG in bovine udder and milk provides passive protection for the neonate and immunostimulatory capabilities.
