RESUMO
BACKGROUND: Cystic kidneys and vascular aneurysms are clinical manifestations seen in patients with polycystic kidney disease, a cilia-associated pathology (ciliopathy). Survivin overexpression is associated with cancer, but the clinical pathology associated with survivin downregulation or knockout has never been studied before. The present studies aim to examine whether and how cilia function (Pkd1 or Pkd2) and structure (Tg737) play a role in cystic kidney and aneurysm through survivin downregulation. METHODS AND RESULTS: Cysts and aneurysms from polycystic kidney disease patients, Pkd mouse, and zebrafish models are characterized by chromosome instability and low survivin expression. This triggers cytokinesis defects and formation of nuclear polyploidy or aneuploidy. In vivo conditional mouse and zebrafish models confirm that survivin gene deletion in the kidneys results in a cystic phenotype. As in hypertensive Pkd1, Pkd2, and Tg737 models, aneurysm formation can also be induced in vascular-specific normotensive survivin mice. Survivin knockout also contributes to abnormal oriented cell division in both kidney and vasculature. Furthermore, survivin expression and ciliary localization are regulated by flow-induced cilia activation through protein kinase C, Akt and nuclear factor-κB. Circumventing ciliary function by re-expressing survivin can rescue polycystic kidney disease phenotypes. CONCLUSIONS: For the first time, our studies offer a unifying mechanism that explains both renal and vascular phenotypes in polycystic kidney disease. Although primary cilia dysfunction accounts for aneurysm formation and hypertension, hypertension itself does not cause aneurysm. Furthermore, aneurysm formation and cyst formation share a common cellular and molecular pathway involving cilia function or structure, survivin expression, cytokinesis, cell ploidy, symmetrical cell division, and tissue architecture orientation.
Assuntos
Aneurisma/genética , Proteínas Inibidoras de Apoptose/genética , Doenças Renais Císticas/genética , Túbulos Renais Coletores/citologia , Rim Policístico Autossômico Dominante/genética , Proteínas Repressoras/genética , Proteínas de Peixe-Zebra/genética , Aneuploidia , Aneurisma/metabolismo , Aneurisma/patologia , Animais , Divisão Celular/genética , Cílios/patologia , Regulação para Baixo/genética , Humanos , Hipertensão/genética , Hipertensão/metabolismo , Hipertensão/patologia , Proteínas Inibidoras de Apoptose/metabolismo , Camundongos , Camundongos Knockout , NF-kappa B/metabolismo , Fenótipo , Rim Policístico Autossômico Dominante/metabolismo , Rim Policístico Autossômico Dominante/patologia , Cultura Primária de Células , Proteína Quinase C/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Repressoras/metabolismo , Survivina , Urotélio/citologia , Peixe-Zebra , Proteínas de Peixe-Zebra/metabolismoRESUMO
Lymphoplasmacytic lymphoma is a chronic lymphoproliferative disorder characterized by a proliferation of plasma cells, small lymphocytes, plasmacytoid lymphocytes and the production of monoclonal IgM. Primary central nervous system lymphomas (PCNSL) are rare non-Hodgkin lymphomas (NHL) that can be found in the brain, leptomeninges, eyes or spinal cord, and are mostly intracerebral. PCNSLs constitute 3-4% of primary brain tumors, and in most cases are diffuse large B-cell lymphomas (DLBCL).(1) Low grade lymphomas as primary central nervous system (CNS) lymphoma are very rare. We present here a case report of a woman who presented with headache and was found to have primary intracranial lymphoplasmacytic lymphoma (LPL).
Assuntos
Neoplasias do Sistema Nervoso Central/diagnóstico , Linfoma Difuso de Grandes Células B/diagnóstico , Neoplasias do Sistema Nervoso Central/diagnóstico por imagem , Neoplasias do Sistema Nervoso Central/radioterapia , Feminino , Raios gama , Humanos , Linfoma Difuso de Grandes Células B/diagnóstico por imagem , Linfoma Difuso de Grandes Células B/radioterapia , Imageamento por Ressonância Magnética , Pessoa de Meia-Idade , Imagem Multimodal , Plasmócitos/metabolismo , Plasmócitos/patologia , Tomografia por Emissão de Pósitrons , Tomografia Computadorizada por Raios XRESUMO
Autosomal-dominant polycystic kidney disease (ADPKD) is the most common hereditary and systemic disorder associated with various cardiovascular complications. It has been implicated with dysfunction in primary cilia. We and others have shown that the immediate function of endothelial cilia is to sense extracellular signal. The long-term function of cilia is hypothesized to regulate cell cycle. Here, we show that ciliary function (polycystins) and structure (polaris) are required for proper cellular division. Cilia mutant cells undergo abnormal cell division with apparent defects in mitotic spindle formation, cellular spindle assembly checkpoint and centrosome amplification. Down-regulation of the chromosomal passenger survivin contributes to these abnormalities, which further result in cell polyploidy. Re-expression of survivin restores a competent spindle assembly checkpoint and reduces polyploidy. Aged animals show a more severe phenotype in cellular division, consistent with progression of cardiovascular complications seen in older ADPKD patients. For the first time, we show that structure and function of mechanosensory cilia are crucial in maintaining proper cellular proliferation. Furthermore, developmental aging plays a crucial role in the progression of these abnormal cellular phenotypes. We propose that abnormal function or structure of primary cilia not only causes failure to transmit extracellular signals, but also is associated with cytokinesis defects in both mice and humans with polycystic kidney disease.
