RESUMEN
We report a 2 month male child presenting with diabetic ketoacidosis (DKA) and seizures treated with intravenous fluids and intravenous insulin infusion till the ketoacidosis was reversed, thereafter responding well to sulphonylureas and at age of 13 months going into complete remission. At age of 11 mo developmental delay in the form of negative neck holding and inability to sit without support was seen. The child is 3 yr of age now ,euglycemic without any insulin or oral hypoglycemic agents but has severe developmental delay. Genetic analysis was negative for mutations of KCNJ11, 6q24, Glucokinase and IPF-1 genes. A mutation R1183W was found in the ABCC8 gene encoding SUR1, which was the cause of neonatal diabetes in this case.
Asunto(s)
Transportadoras de Casetes de Unión a ATP/genética , Cromosomas Humanos Par 6/genética , Diabetes Mellitus Tipo 1/sangre , Diabetes Mellitus Tipo 1/genética , Cetoacidosis Diabética/tratamiento farmacológico , Cetoacidosis Diabética/genética , Humanos , Hipoglucemiantes/uso terapéutico , Lactante , Insulina/uso terapéutico , Masculino , Mutación Puntual/genética , Canales de Potasio de Rectificación Interna/genética , Receptores de Droga/genética , Compuestos de Sulfonilurea/uso terapéuticoRESUMEN
We aimed to examine the effects of angiotensin II AT1 receptor blocker on the expression of major renal sodium transporters and aquaporin-2 (AQP2) in rats with chronic renal failure (CRF). During 2 wks after 5/6 nephrectomy or sham operation, both CRF rats (n=10) and sham-operated control rats (n=7) received a fixed amount of low sodium diet and had free access to water. CRF rats (n=10) were divided into two groups which were either candesartan-treated (CRF-C, n=4) or vehicletreated (CRF-V, n=6). Both CRF-C and CRF-V demonstrated azotemia, decreased GFR, polyuria, and decreased urine osmolality compared with sham-operated rats. When compared with CRF-V, CRF-C was associated with significantly higher BUN levels and lower remnant kidney weight. Semiquantitative immunoblotting demonstrated decreased AQP2 expression in both CRF-C (54% of control levels) and CRF-V (57%), whereas BSC-1 expression was increased in both CRF groups. Particularly, CRF-C was associated with higher BSC-1 expression (611%) compared with CRF-V (289%). In contrast, the expression of NHE3 (25%) and TSC (27%) was decreased in CRF-C, whereas no changes were observed in CRF-V. In conclusion, 1) candesartan treatment in an early phase of CRF is associated with decreased renal hypertrophy and increased BUN level; 2) decreased AQP2 level in CRF is likely to play a role in the decreased urine concentration, and the downregulation is not altered in response to candesartan treatment; 3) candesartan treatment decreases NHE3 and TSC expression; and 4) an increase of BSC-1 is prominent in candesartan-treated CRF rats, which could be associated with the increased delivery of sodium and water to the thick ascending limb.
Asunto(s)
Animales , Masculino , Ratas , Bloqueadores del Receptor Tipo 1 de Angiotensina II , Acuaporinas/genética , Bencimidazoles/farmacología , Nitrógeno de la Urea Sanguínea , Fallo Renal Crónico/tratamiento farmacológico , Tamaño de los Órganos/efectos de los fármacos , Ratas Sprague-Dawley , Receptores de Droga/genética , Intercambiadores de Sodio-Hidrógeno/genética , Simportadores de Cloruro de Sodio-Potasio/genética , Simportadores/genética , Tetrazoles/farmacologíaRESUMEN
Using site-directed mutagenesis technique, I have replaced serine 285 and serine 292 with the alanine, and assessed the binding of agonist and signaling such as the inhibition of adenylyl cyclase activity.I have found that serine 292 has an important role in the signal transduction of cannabinoid agonists, HU-210 and CP55940, but not in that of aminoalkylindoles derivatives WIN55,212-2. All mutants express well in protein level determined by western blot using monoclonal antibody HA 11 as compared with the wild type receptor.Interestingly, binding affinity of S285A and S292A mutants with classical cannabinoid agonist HU-243 was somewhat decreased. In signaling assay, the inhibition of adenylyl cyclase by HU-210, CP55940 and WIN55, 212-2 is the same order in both wild type receptor and S285A mutant receptor. However, S292A have been shown that the inhibition curves of adenylyl cyclase activity moved to the right by HU-210 and CP55940, but those of adenylyl cyclase activity did not by aminoalkylindole WIN55,212-2, which is indicating that this residue is closely related to the binding site with HU-210 and CP55940. In addition, serine 292 might take more important role in CB2 receptor and G-protein signaling than serine 285.
Asunto(s)
Animales , Adenilil Ciclasas/metabolismo , Unión Competitiva , Western Blotting , Células COS , Cannabinoides/metabolismo , Chlorocebus aethiops , Ciclohexanoles/metabolismo , Antagonistas de Aminoácidos Excitadores/metabolismo , Mutagénesis Sitio-Dirigida , Conformación Proteica , Estructura Terciaria de Proteína , Receptores de Cannabinoides , Receptores de Droga/genética , Serina/metabolismo , Transducción de Señal/fisiología , Dronabinol , TransfecciónRESUMEN
O receptor de sulfoniluréia (SUR1) é uma subunidade dos canais de potássio ATP-dependentes expressos nas células beta pancreáticas. O papel deste receptor nos mecanismos de secreçäo da insulina foi bem demonstrado após a descriçäo de que mutaçöes no seu gene codificador säo responsáveis pela forma neonatal de hiperinsulinismo. O possível envolvimento de variantes deste gene na predisposiçäo genética ao diabetes mellitus tipo 2 também te sido estudado. Nesta revisäo discutimos os dados da literatura que abordam o envolvimento de altraçöes genéticas do SUR1 em patologias como o diabetes tipo 2, assim como nos mecanismos de secreçäo da insulina.