RESUMO
Interactions between the endoplasmic reticulum (ER) and mitochondria have received insufficient attention until recently. However, distorted contacts between the ER and mitochondria were identified as an important factor in the etiopathogenesis of neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. In view of these new data, the mechanisms of ER-mitochondrial interactions are necessary to study in detail in order to develop new diagnostic and therapeutic approaches to neurodegenerative diseases and to extend basic knowledge of the physiology of the eukaryotic cell. The review focuses on the functions of mitochondria-associated ER membranes (MAMs). Structural elements of the MAM system, their contributions to the vital cell functions (calcium and lipid homeostasis, autophagy, fusion and division of mitochondria, and the regulation of their number), and the role of MAM dysfunctions in the pathogenesis of various neurodegenerative diseases are considered.
Assuntos
Esclerose Lateral Amiotrófica , Doenças Neurodegenerativas , Doença de Parkinson , Retículo Endoplasmático/genética , Retículo Endoplasmático/metabolismo , Humanos , Mitocôndrias/genética , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/metabolismo , Doença de Parkinson/metabolismoRESUMO
Reactive oxygen species (ROS), by-products of aerobic respiration, promote genetic instability and contribute to the malignant transformation of cells. Among the genes related to ROS metabolism, Bach1 is a repressor of the oxidative stress response, and a negative regulator of ROS-induced cellular senescence directed by p53 in higher eukaryotes. While ROS are intimately involved in carcinogenesis, it is not clear whether Bach1 is involved in this process. We found that senescent Bach1-deficient mouse embryonic fibroblasts (MEFs) underwent spontaneous immortalization the same as did the wild-type cells. When transduced with constitutively active Ras (H-Ras(V12)), the proliferation and colony formation of these cells in vitro were markedly reduced. When transplanted into athymic nude mice, the growth and vascularization of tumors derived from Bach1-deficient cells were also decreased. Gene expression profiling of the MEFs revealed a new H-Ras(V12) signature, which was distinct from the previously reported signatures in epithelial tumors, and was partly dependent on Bach1. The Bach1-deficient cells showed diminished phosphorylation of MEK and ERK1/2 in response to H-Ras(V12), which was consistent with the alterations in the gene expression profile, including phosphatase genes. Finally, Bach1-deficient mice were less susceptible to 4-nitroquinoline-1-oxidide (4-NQO)-induced tongue carcinoma than wild-type mice. Our data provide evidence for a critical role of Bach1 in cell transformation and tumor growth induced by activated H-Ras(V12).
Assuntos
Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Transformação Celular Neoplásica/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Fibroblastos/metabolismo , Transdução de Sinais/fisiologia , Animais , Fatores de Transcrição de Zíper de Leucina Básica/genética , Transformação Celular Neoplásica/genética , Imunofluorescência , Perfilação da Expressão Gênica , Genes ras/genética , Immunoblotting , Camundongos , Camundongos Knockout , Espécies Reativas de Oxigênio/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Transcriptoma , Proteínas ras/genética , Proteínas ras/metabolismoRESUMO
A relationship between clinical forms of glomerulonephritis and incidence of viral antigens in renal tissue was revealed: Hepatitis B virus antigens (HBsAg) are more frequently detected in the glomeruli in the patients with nephrotic glomerulonephritis, Herpes simplex antigens are detected in the glomeruli in mixed glomerulonephritis, and cytomegaloviral and Herpes simplex antigens are detected in the epithelium of the proximal canaliculi in patients with hematuric glomerulonephritis. No correlations between the persistence of Herpes simplex type 1, cytomegalovirus, and HBsAg in the renal tissue were detected. HBsAg is detected in the renal tissue mainly in the children without free HBsAg in the blood serum. This may be indicative of an important role of specific immune complexes in the pathogenesis of glomerulonephritis associated with hepatitis B viral infection. The results point to an appreciable contribution of a persistent viral infection to the progress of glomerulonephritis.
Assuntos
Antígenos Virais/análise , Glomerulonefrite/imunologia , Rim/imunologia , Biópsia , Criança , Citomegalovirus/imunologia , Antígenos de Superfície da Hepatite B/análise , Herpesvirus Humano 1/imunologia , Humanos , Rim/patologiaRESUMO
Clinicomorphological findings are reported for two children from families with hereditary predisposition to hematuria characterized by early occurrence of chronic renal insufficiency, neurosensory hypoacusis, congenital ocular abnormalities inherited by sex-linked dominant type. Light microscopy of nephrobiopsies revealed diffuse mesangial proliferation in both children. Final diagnosis of Alport's syndrome was feasible only on molecular-genetic level after polymerase chain reactions had identified mutation in collagen type 4 alpha-5-chain gene on a long arm of X-chromosome in genotypes of both patients and their mothers. Genetical, clinical, morphological, evolutional and diagnostic aspects of Alport's syndrome are reviewed.
Assuntos
DNA/genética , Rim/patologia , Nefrite Hereditária/diagnóstico , Adolescente , Adulto , Biópsia , Colágeno/genética , Diagnóstico Diferencial , Feminino , Ligação Genética , Humanos , Masculino , Mutação , Nefrite Hereditária/genética , Nefrite Hereditária/patologia , Linhagem , Reação em Cadeia da Polimerase , Federação Russa , Cromossomo X/genéticaRESUMO
The paper presents the results of clinical and laboratory examination made in 3 groups of children: populational, hospital and control (a total of 176 patients). The children were diagnosed to have variants of dysmetabolic nephropathy (DN) which had become a problem not only for urolithiasis-endemic regions, but also for the Middle Russia. The study involving characterization of cytomembranes, renal tissue biopsy allowed conclusion on nonspecific DN symptoms. Obligatory symptoms were those of OCC, microhematuria and/or mild proteinuria, changes in cytomembranes, weak tubular function, tubulo-interstitial changes. DN genesis is thought multifactorial, involving genetic predisposition, biochemical defects, ecological hazards.
Assuntos
Nefropatias/urina , Oxalatos/urina , Adolescente , Biópsia , Criança , Pré-Escolar , Doença Crônica , Cristalização , Humanos , Incidência , Lactente , Rim/patologia , Cálculos Renais/epidemiologia , Cálculos Renais/etiologia , Cálculos Renais/genética , Cálculos Renais/urina , Nefropatias/epidemiologia , Nefropatias/etiologia , Nefropatias/genética , Lipídeos/urina , Moscou/epidemiologia , Terminologia como AssuntoRESUMO
Clinical biochemistry and morphological methods were employed to examine 25 children aged 3 to 15 years with hereditary nephritis. Measurements were made of morphological alterations in renal biopsy specimens, excretion with urine of connective tissue metabolites (hydroxyproline, hydroxylysine glycosides, glycosaminoglycans), the level of the same metabolites and characteristic features of the cellular growth of skin fibroblasts in culture. The early stages of nephritis development were marked by hypoplasia of nephron elements, followed by dystrophy and destruction of its ultrastructural elements including collagen of the glomerular basal membranes. The status of the skin fibroblast cell culture corresponded with the changes seen in renal cells of mesenchymal origin. The conclusion is made that in children with hereditary nephritis, nephron cells and skin fibroblasts reflect systemic metabolic defect of the connective tissue.
Assuntos
Tecido Conjuntivo/metabolismo , Nefrite Hereditária/metabolismo , Néfrons/anormalidades , Adolescente , Biópsia , Células Cultivadas/metabolismo , Criança , Pré-Escolar , Fibroblastos/metabolismo , Humanos , Microscopia Eletrônica , Nefrite Hereditária/etiologia , Nefrite Hereditária/patologia , Néfrons/ultraestrutura , Pele/metabolismoRESUMO
Histological analysis of lung and kidney after multiple PAF i.v. injection into rabbits was performed. Under these conditions the effect of previously injected of verapamyl, calcium channel blocker, was studied. It was shown that RAF causes inflammatory reaction with cell infiltration, microcirculation disorders and thrombosis in lung and kidney, which may classify as interstitial nephritis, pneumonitis and vasculitis. Verapamyl inhibits vasospasm, abolishes fibrinogen but does not affect cell infiltration and oedema development. Thus, Ca channel-dependent mechanism of vasospasm and thrombogenesis induced by PAF in vivo is confirmed. Perhaps, another possibilities for realising PAF action in vivo may occur.
Assuntos
Rim/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Fator de Ativação de Plaquetas/farmacologia , Verapamil/farmacologia , Animais , Relação Dose-Resposta a Droga , Interações Medicamentosas , Rim/irrigação sanguínea , Rim/patologia , Pulmão/irrigação sanguínea , Pulmão/patologia , Masculino , Microcirculação/efeitos dos fármacos , Microcirculação/patologia , Coelhos , Fatores de TempoAssuntos
Angiomatose/diagnóstico , Neoplasias Renais/diagnóstico , Síndrome de Klippel-Trenaunay-Weber/diagnóstico , Síndrome Nefrótica/diagnóstico , Prednisona , Criança , Diagnóstico Diferencial , Feminino , Glomerulonefrite Membranoproliferativa/diagnóstico , Glomerulonefrite Membranoproliferativa/patologia , Humanos , Rim/patologia , Neoplasias Renais/patologia , Síndrome de Klippel-Trenaunay-Weber/patologia , Síndrome Nefrótica/patologia , Tumor de Wilms/diagnóstico , Tumor de Wilms/patologiaRESUMO
Eleven children aged 5 to 15 years with hereditary nephritis and twelve children with hypoplastic dysplastic nephropathy were studied. The children with hereditary nephritis were divided into 2 groups while correlating the level of renal excretion of hydroxylysine glycosides (HOLG) with ultrastructure of glomerular basement membrane. The first group was characterized by decreased urinary excretion of HOLG and extremely thin basement membranes, the second one - by increased HOLG excretion and thickened membranes, The children with hypoplastic dysplastic nephropathy which were divided into 2 groups according to HOLG excretion differed in presence or absence of anatomic anomalies and in the number of connective tissue dysembryogenetic stigmata. The data are suggestive of an important role and diversity of metabolic derangement of the collagenic component of basement membranes in the pathogenesis of the diseases studied.