RESUMO
Diabetic nephropathy is the leading cause of end-stage renal disease all over the world. Diagnosis is confirmed by measuring urin albumin excretion and calculated renal function (eGFR). Once the diagnosis is confirmed there should be a search for confounding cardiovascular risk factors and even established cardiovascular disease because of the associated high cardiovascular risk. In type 1 diabetes metabolic control is the main issue. In case of renal impairment and in patients with type 2 diabetes a multifactorial approach is necessary, which consists of dietary advise, metabolic control, lowering elevated blood-pressure, cessation of smoking, ASS and lipid-lowering drug-therapy. Special drugs for the treatment of diabetes-induced renal disease are not available.
Assuntos
Diabetes Mellitus Tipo 1/diagnóstico , Diabetes Mellitus Tipo 2/diagnóstico , Nefropatias Diabéticas/diagnóstico , Adulto , Albuminúria/diagnóstico , Albuminúria/terapia , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/terapia , Criança , Terapia Combinada , Comorbidade , Estudos Transversais , Diabetes Mellitus Tipo 1/epidemiologia , Diabetes Mellitus Tipo 1/terapia , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/terapia , Nefropatias Diabéticas/epidemiologia , Nefropatias Diabéticas/terapia , Europa (Continente) , Humanos , Falência Renal Crônica/diagnóstico , Falência Renal Crônica/epidemiologia , Falência Renal Crônica/terapia , Testes de Função RenalRESUMO
Alpha-2-macroglobulin (A2M) is a proteinase inhibitor involved in deactivation of cytokines and modulation of antigen-mediated immune responses. Based on its role in inflammatory and neurodegenerative disorders, we investigated the role of A2M and its receptor low-density lipoprotein receptor-related protein (LRP) for the development of multiple sclerosis (MS). We analyzed the frequency of two polymorphisms in the A2M (Val 1000 Ile, Exon 18 del), and one polymorphism in the LRP (A216V) gene in a case control study involving 326 MS patients, and 290 controls, all defined for the expression of HLA-DR15. No association was found for any of the three polymorphism with MS. Furthermore, no differences in serum A2M levels were detected between MS patients and controls. The results do not suggest a contribution of A2M and LRP to the development of MS.
Assuntos
Esclerose Múltipla/genética , Polimorfismo Genético , Receptores Imunológicos/genética , alfa-Macroglobulinas/genética , Alelos , Substituição de Aminoácidos/genética , Estudos de Casos e Controles , Frequência do Gene , Ligação Genética , Predisposição Genética para Doença , Alemanha , Antígenos HLA-DR/genética , Subtipos Sorológicos de HLA-DR , Humanos , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade , Esclerose Múltipla/sangue , alfa-Macroglobulinas/metabolismoRESUMO
Import of proteins into the nucleus proceeds through nuclear pore complexes and is largely mediated by nuclear transport receptors of the importin beta family that use direct RanGTP-binding to regulate the interaction with their cargoes. We investigated nuclear import of the linker histone H1 and found that two receptors, importin beta (Impbeta) and importin 7 (Imp7, RanBP7), play a critical role in this process. Individually, the two import receptors bind H1 weakly, but binding is strong for the Impbeta/Imp7 heterodimer. Consistent with this, import of H1 into nuclei of permeabilized mammalian cells requires exogenous Impbeta together with Imp7. Import by the Imp7/Impbeta heterodimer is strictly Ran dependent, the Ran-requiring step most likely being the disassembly of the cargo-receptor complex following translocation into the nucleus. Disassembly is brought about by direct binding of RanGTP to Impbeta and Imp7, whereby the two Ran-binding sites act synergistically. However, whereas an Impbeta/RanGTP interaction appears essential for H1 import, Ran-binding to Imp7 is dispensable. Thus, Imp7 can function in two modes. Its Ran-binding site is essential when operating as an autonomous import receptor, i.e. independently of Impbeta. Within the Impbeta/Imp7 heterodimer, however, Imp7 plays a more passive role than Impbeta and resembles an import adapter.
Assuntos
Histonas/metabolismo , Proteínas Nucleares/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Regulação Alostérica , Animais , Sítios de Ligação , Transporte Biológico , Dimerização , Guanosina Trifosfato/metabolismo , Carioferinas , Modelos Biológicos , Proteínas Nucleares/genética , Mutação Puntual , Xenopus , Proteína ran de Ligação ao GTPRESUMO
The assembly of eukaryotic ribosomal subunits takes place in the nucleolus and requires nuclear import of ribosomal proteins. We have studied this import in a mammalian system and found that the classical nuclear import pathway using the importin alpha/beta heterodimer apparently plays only a minor role. Instead, at least four importin beta-like transport receptors, namely importin beta itself, transportin, RanBP5 and RanBP7, directly bind and import ribosomal proteins. We found that the ribosomal proteins L23a, S7 and L5 can each be imported alternatively by any of the four receptors. We have studied rpL23a in detail and identified a very basic region to which each of the four import receptors bind avidly. This domain might be considered as an archetypal import signal that evolved before import receptors diverged in evolution. The presence of distinct binding sites for rpL23a and the M9 import signal in transportin, and for rpL23a and importin alpha in importin beta might explain how a single receptor can recognize very different import signals.
