Tesis doctorales: TESEO

Ayuda Salir

Ficha de Tesis

Imprimir

Ministerio de Universidades - Gobierno de España

Título: EFFECT OF SEX ON EXPERIMENTAL DIABETIC NEPHROPATHY AND THE RENIN-ANGIOTENSIN SYSTEM. ROLE OF ACE2
Autor: Clotet Freixas, Sergi
Universidad: Universidad Autónoma de Barcelona
Departamento: Bioquimica i biologia molecular
Fecha de Lectura: 13/09/2016
Mención Europeo / Mención Internacional: Concedido
Programa de doctorado: Programa Oficial de Doctorado en Bioquímica, Biología Molecular y Biomedicina
Dirección:
- PASCUAL SANTOS, JULIO (DIRECTOR)
- Riera Oliva, Marta (CODIRECTOR)
- SOLER ROMEO, MARÍA JOSÉ (CODIRECTOR)
- Bosch Merino, Assumpció (TUTOR/PONENTE)
Tribunal:
- MESSEGUER NAVARRO, ANNA (PRESIDENTE)
- Cruzado Garrit, Josep Maria (SECRETARIO)
- Burtey , Stephane (VOCAL)
Descriptores:
- NEFROLOGIA
- SEXO
- BIOLOGIA MOLECULAR
Localización: BIBLIOTECA DE COMUNICACIÓN Y HEMEROTECA GENERAL UAB

271635_858768.pdf

Marcador: https://www.educacion.gob.es/teseo/mostrarRef.do?ref=1288152Añadir a favoritos.
Resumen:
Male sex increases the incidence, prevalence, and progression of chronic kidney disease. However, little is known about the effect of sex hormones in diabetic nephropathy (DN). The renin-angiotensin system (RAS) is an important regulator of cardiovascular and renal function. Within this system, angiotensin-converting enzyme 2 (ACE2) plays a protective role by degrading angiotensin II (ANGII) and preventing its deleterious downstream events. RAS is altered in diabetes, and plays a critical role in the development DN. Sex differences in the renal response to RAS blockade have been demonstrated. Thus, the sexual dimorphism in DN may be related to sex-specific regulations of circulating and renal RAS. Our objective was to study the effect of sex on glomerular and tubular injury markers in a model of type 1 diabetes mellitus, the streptozotocin(STZ)-induced mice, and its relationship with sex-specific changes of RAS. We also aimed to evaluate the influence of androgen reduction by gonadectomy (GDX), Ace2 deletion, and ANGII infusion on this effect. In our model, STZ administration led to hyperglycemia, body weight loss, renal and glomerular hypertrophy, hyperfiltration, polyuria, albuminuria, mesangial expansion, podocyte loss and cortical fibrosis. The severity of these renal alterations differed between sexes. Diabetic males presented a more important worsening in all the glomerular hallmarks of DN studied, including albuminuria, hyperfiltration, glomerular hypertrophy, and mesangial matrix expansion. Male sex hormones played a direct role in this accentuated glomerular injury, as GDX prevented all these alterations. Studies in Ace2 knockout mice revealed that the role of ACE2 in DN was sex-specific. In females, loss of ACE2 aggravated DN progression by worsening albuminuria, renal hypertrophy and cortical fibrosis. In males, loss of ACE2 increased blood pressure and accentuated glomerular injury and renal fibrosis, and GDX prevented these alterations by modulating the expression of renal and circulating RAS and decreasing cortical Akt phosphorylation. In the context of experimental hypertension, loss of ACE2 accentuated ANGII-induced cardiac hypertrophy, blood pressure increase, albuminuria, and glomerular hypertrophy in diabetic females, as well as exacerbated ANGII-mediated glomerular hypertrophy, mesangial expansion and podocyte loss in diabetic males. Sexual dimorphism in experimental DN was accompanied by a sex-specific regulation of the compensatory mechanisms of RAS. In the in vitro part of this project, we performed SILAC-based proteomics in proximal tubular epithelial cells incubated with sex hormones, and discovered a novel link between dihydrotestosterone and impaired glucose and lipid metabolism in these cells. Further validation studies confirmed that male sex altered energy metabolism in the diabetic kidney, in association with increased renal hypertrophy and oxidative stress levels. In this work we demonstrate a strong effect of sex in DN progression, as well as a sex-specific renoprotective role of ACE2. With our findings, we aim to improve the current understanding of the sexual dimorphism in diabetic kidney disease, and its relation with the dysregulation of RAS.

Imprimir

Modificar Consulta Nueva Consulta

Versión 4.4