RESUMO
Nephrotic syndrome (NS) occurs when the glomerular filtration barrier becomes excessively permeable leading to massive proteinuria. In childhood NS, immune system dysregulation has been implicated and increasing evidence points to the central role of podocytes in the pathogenesis. Children with NS are typically treated with an empiric course of glucocorticoid (Gc) therapy; a class of steroids that are activating ligands for the glucocorticoid receptor (GR) transcription factor. Although Gc-therapy has been the cornerstone of NS management for decades, the mechanism of action, and target cell, remain poorly understood. We tested the hypothesis that Gc acts directly on the podocyte to produce clinically useful effects without involvement of the immune system. In human podocytes, we demonstrated that the basic GR-signalling mechanism is intact and that Gc induced an increase in podocyte barrier function. Defining the GR-cistrome identified Gc regulation of motility genes. These findings were functionally validated with live-cell imaging. We demonstrated that treatment with Gc reduced the activity of the pro-migratory small GTPase regulator Rac1. Furthermore, Rac1 inhibition had a direct, protective effect on podocyte barrier function. Our studies reveal a new mechanism for Gc action directly on the podocyte, with translational relevance to designing new selective synthetic Gc molecules.
Assuntos
Glucocorticoides/farmacologia , Podócitos/efeitos dos fármacos , Prednisolona/farmacologia , Substâncias Protetoras/farmacologia , Puromicina Aminonucleosídeo/antagonistas & inibidores , Receptores de Glucocorticoides/genética , Proteínas rac1 de Ligação ao GTP/genética , Antimetabólitos Antineoplásicos/toxicidade , Transporte Biológico/efeitos dos fármacos , Linhagem Celular Transformada , Membrana Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Impedância Elétrica , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Humanos , Análise em Microsséries , Podócitos/citologia , Podócitos/metabolismo , Puromicina Aminonucleosídeo/toxicidade , Receptores de Glucocorticoides/antagonistas & inibidores , Receptores de Glucocorticoides/metabolismo , Transdução de Sinais , Transcriptoma , Proteínas rac1 de Ligação ao GTP/antagonistas & inibidores , Proteínas rac1 de Ligação ao GTP/metabolismo , Proteína rhoA de Ligação ao GTP/genética , Proteína rhoA de Ligação ao GTP/metabolismoRESUMO
Mesotheliomas usually arise from the pleura and are malignant. We report an unusual case of benign peritoneal mesothelioma presenting in a 59-year-old woman. The disease resulted in bilateral hydronephrosis, colovesical fistula formation, recurrent small bowel obstruction and chronic abdominal pain. To date only a handful of cases have been reported and to the best of our knowledge, none has been so aggressive.