RESUMEN
Albuminuria affects millions of people, and is an independent risk factor for kidney failure, cardiovascular morbidity and death. The key cell that prevents albuminuria is the terminally differentiated glomerular podocyte. Here we report the evolutionary importance of the enzyme Glycogen Synthase Kinase 3 (GSK3) for maintaining podocyte function in mice and the equivalent nephrocyte cell in Drosophila. Developmental deletion of both GSK3 isoforms (α and ß) in murine podocytes causes late neonatal death associated with massive albuminuria and renal failure. Similarly, silencing GSK3 in nephrocytes is developmentally lethal for this cell. Mature genetic or pharmacological podocyte/nephrocyte GSK3 inhibition is also detrimental; producing albuminuric kidney disease in mice and nephrocyte depletion in Drosophila. Mechanistically, GSK3 loss causes differentiated podocytes to re-enter the cell cycle and undergo mitotic catastrophe, modulated via the Hippo pathway but independent of Wnt-ß-catenin. This work clearly identifies GSK3 as a critical regulator of podocyte and hence kidney function.
Asunto(s)
Albuminuria/metabolismo , Glucógeno Sintasa Quinasa 3/metabolismo , Enfermedades Renales/metabolismo , Riñón/fisiología , Podocitos/metabolismo , Albuminuria/sangre , Albuminuria/patología , Albuminuria/orina , Animales , Ciclo Celular , Línea Celular , Modelos Animales de Enfermedad , Drosophila , Eliminación de Gen , Silenciador del Gen , Glucógeno Sintasa Quinasa 3/genética , Glucógeno Sintasa Quinasa 3 beta/efectos de los fármacos , Glucógeno Sintasa Quinasa 3 beta/genética , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Vía de Señalización Hippo , Estimación de Kaplan-Meier , Riñón/patología , Enfermedades Renales/sangre , Enfermedades Renales/patología , Enfermedades Renales/orina , Masculino , Ratones , Podocitos/enzimología , Podocitos/patología , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Proteómica , Ratas Wistar , Insuficiencia Renal , Verteporfina/farmacología , beta Catenina/metabolismoRESUMEN
BACKGROUND: The previous epidemiological study of paediatric nephrolithiasis in Britain was conducted more than 30 years ago. AIMS: To examine the presenting features, predisposing factors, and treatment strategies used in paediatric stones presenting to a British centre over the past five years. METHODS: A total of 121 children presented with a urinary tract renal stone, to one adult and one paediatric centre, over a five year period (1997-2001). All children were reviewed in a dedicated stone clinic and had a full infective and metabolic stone investigative work up. Treatment was assessed by retrospective hospital note review. RESULTS: A metabolic abnormality was found in 44% of children, 30% were classified as infective, and 26% idiopathic. Bilateral stones on presentation occurred in 26% of the metabolic group compared to 12% in the infective/idiopathic group (odds ratio 2.7, 95% CI 1.03 to 7.02). Coexisting urinary tract infection was common (49%) in the metabolic group. Surgically, minimally invasive techniques (lithotripsy, percutaneous nephrolithotomy, and endoscopy) were used in 68% of patients. CONCLUSIONS: There has been a shift in the epidemiology of paediatric renal stone disease in the UK over the past 30 years. Underlying metabolic causes are now the most common but can be masked by coexisting urinary tract infection. Treatment has progressed, especially surgically, with sophisticated minimally invasive techniques now employed. All children with renal stones should have a metabolic screen.