Estudio traslacional de la vía Notch en nefropatía hipertensiva / Translational study of the Notch pathway in hypertensive nephropathy

Introducción: La ruta de señalización de Notch está activada en una gran variedad de patologías renales humanas. Recientemente hemos demostrado que la activación de esta ruta no estaría implicada en la fibrosis renal experimental inducida por angiotensina II o hipertensión. Objetivos: Evaluar si la vía Notch está activada en la fibrosis renal asociada a nefroesclerosis hipertensiva. Para validar la hipótesis se estudiaron varias patologías glomerulares caracterizadas por fibrosis túbulo-intersticial. Métodos: Se utilizaron biopsias renales de pacientes con nefroesclerosis hipertensiva, en comparación con nefropatía diabética y nefropatía membranosa en diferentes etapas de progresión. La expresión génica y proteica se evaluó por hibridación in situ e inmunohistoquímica, respectivamente. Resultados: En nefroesclerosis hipertensiva se observó baja expresión renal de proteínas de la vía Notch, no existiendo asociación entre la fibrosis túbulo-intersticial y los niveles de estas proteínas. Por el contrario, en las patologías glomerulares estudiadas se observó una elevada expresión de los transcritos Jagged-1, HES-1 y TGF-β, y de las proteínas Jagged-1 y Notch-1, localizados principalmente en células túbulo-epiteliales. Los niveles de expresión de los componentes de la vía Notch se relacionaron con el grado de fibrosis túbulo-intersticial, lo que confirma la activación de esta vía en nefropatías progresivas. Conclusiones: Nuestros datos muestran que la vía Notch no está activada en el riñón de pacientes con nefropatía hipertensiva, ampliando los resultados de los modelos experimentales de daño renal asociado a hipertensión a la patología humana. Nuestros estudios aportan nueva información sobre la compleja regulación del sistema Notch en el riñón (AU)

Introduction: The Notch signalling pathway is activated in a wide variety of human renal diseases. We have recently demonstrated that the activation of this pathway is not involved in experimental renal fibrosis induced by angiotensin II or hypertension. Objectives: To assess whether the Notch pathway is activated in renal fibrosis related to hypertensive nephrosclerosis. To test the hypothesis, various glomerular diseases characterised by tubulointerstitial fibrosis were analysed. Method: Renal biopsies were performed on patients with hypertensive nephrosclerosis, in comparison with diabetic nephropathy and membranous nephropathy at various stages. Gene and protein expression were evaluated by in-situ hybridisation and immunohistochemistry respectively. Results: In hypertensive nephrosclerosis low renal expression of notch-related proteins was observed. There was no link between tubulointerstitial fibrosis and the levels of these proteins. By contrast, in the glomerular diseases studied we observed high expression of the transcripts Jagged-1, HES-1 and TGF-β and the proteins Jagged-1 y Notch-1, localised primarily in tubuloepithelial cells. The levels of expression of the components of the Notch pathway correlate to the degree of tubulointerstitial fibrosis, which confirms the activation of this pathway in progressive nephropathies. Conclusions: Our data demonstrate that the Notch pathway is not activated in the kidneys of patients with hypertensive nephropathy, which extends the results of experimental models of kidney damage related to hypertension to the realm of human pathology. Our studies provide new information on the complex regulation of the Notch pathway in the kidney (AU)

Translational study of the Notch pathway in hypertensive nephropathy.

INTRODUCTION: The Notch signalling pathway is activated in a wide variety of human renal diseases. We have recently demonstrated that the activation of this pathway is not involved in experimental renal fibrosis induced by angiotensin II or hypertension. OBJECTIVES: To assess whether the Notch pathway is activated in renal fibrosis related to hypertensive nephrosclerosis. To test the hypothesis, various glomerular diseases characterised by tubulointerstitial fibrosis were analysed. METHOD: Renal biopsies were performed on patients with hypertensive nephrosclerosis, in comparison with diabetic nephropathy and membranous nephropathy at various stages. Gene and protein expression were evaluated by in-situ hybridisation and immunohistochemistry respectively. RESULTS: In hypertensive nephrosclerosis low renal expression of notch-related proteins was observed. There was no link between tubulointerstitial fibrosis and the levels of these proteins. By contrast, in the glomerular diseases studied we observed high expression of the transcripts Jagged-1, HES-1 and TGF-ß and the proteins Jagged-1 y Notch-1, localised primarily in tubuloepithelial cells. The levels of expression of the components of the Notch pathway correlate to the degree of tubulointerstitial fibrosis, which confirms the activation of this pathway in progressive nephropathies. CONCLUSIONS: Our data demonstrate that the Notch pathway is not activated in the kidneys of patients with hypertensive nephropathy, which extends the results of experimental models of kidney damage related to hypertension to the realm of human pathology. Our studies provide new information on the complex regulation of the Notch pathway in the kidney.