ABSTRACT
INTRODUCTION AND OBJECTIVE: Erectile dysfunction's physiopathology in uremia is complex and multifactorial, involving a combination of classical risk factors and specific uremia-related risk factors such as increased oxidative stress, endothelial dysfunction and inflammation. The aim of the study is to investigate the effect of chronic kidney disease (CKD) on vascular calcification and endothelial function of cavernosal bodies in apolipoprotein E deficient (apoE−/−) mice, a well known model of erectile dysfunction. MATERIALS AND METHODS: Eight-week-old male apoE−/− mice were randomly assigned to the following 3 groups: (I) subtotally nephrectomised (SNX apoE−/−, 12 mice), (II) uninephrectomised (UNX apoE−/−, 11 mice) or (III) sham operated (sham-op apoE−/−, 15 mice). At 16 weeks after surgery, aortas and penile erectile tissues were harvested for histological studies to assess atherosclerosis, vascular calcification, nitrotyrosine staining, total collagen content and macrophage staining. RESULTS: At sacrifice, SNX and UNX mice had significantly higher serum urea, total cholesterol, and triglyceride concentrations than sham-op controls. Atherosclerotic lesions in thoracic aorta were significantly larger in uremic apoE−/− mice than in controls. There were no atheromatous lesions in cavernosal bodies or penile artery observed in any group. However, SNX and UNX animals showed a significant increase in calcification score, collagen content and nitrotyrosine staining in cavernosal bodies when compared with controls. The degree of macrophage infiltration was comparable between the 3 groups. CONCLUSION: In conclusion, even mild renal dysfunction, i.e., after uninephrectomy increases calcification score and aggravates endothelial function of cavernosal bodies in apoE−/− mice and this effect might be linked to increased oxidative stress in penile endothelium
INTRODUCCIÓN Y OBJETIVOS: La fisiopatología de la disfunción eréctil en la uremia es compleja y multifactorial, e incluye una combinación de factores de riesgo clásicos y factores específicos asociados a la uremia, como el aumento del estrés oxidativo, la disfunción endotelial y la inflamación. El objetivo de este trabajo es examinar el efecto de la enfermedad renal crónica (ERC) sobre la calcificación vascular y la función endotelial de los cuerpos cavernosos en caso de deficiencia de apolipoproteína E en ratones (ratones ApoE−/−), un modelo bien conocido de disfunción eréctil. MATERIALES Y MÉTODOS: Los ratones machos de 8 semanas de edad con «ApoE−/−mice» se distribuyen aleatoriamente en 3 grupos: 1) con heminefrectomía (SNX ApoE−/−), 12 ratones; 2) con nefrectomía única (UNX ApoE−/−), 11 ratones, y 3) operación de placebo (sham-op ApoE−/−), 15 ratones. Dieciséis semanas después de la cirugía, se retiraron los tejidos eréctiles de la aorta y el pene para realizar estudios histológicos con el fin de evaluar la aterosclerosis, la calcificación vascular, las sombras de nitrotirosina, el contenido de colágeno total y las sombras de macrófagos. RESULTADOS: Durante el sacrificio, los ratones con SNX y UNX reflejaron valores de urea sérica, colesterol total y concentración de triglicéridos significativamente más elevados, en comparación con los casos controlados con placebo. Las lesiones ateroscleróticas en la aorta torácica fueron mucho mayores en los ratones urémicos «ApoE−/−» en comparación con los controles. No hubo lesiones ateromatosas en los cuerpos cavernosos ni en la arteria del pene en ninguno de los grupos. Sin embargo, los animales con nefrectomía seminal y única mostraron un aumento significativo en la calcificación, presencia de colágeno y manchas de nitrotirosina en cuerpos cavernosos en comparación con los controles. El grado de infiltración de macrófagos fue comparable entre los 3 grupos. CONCLUSIÓN: Se ha concluido que incluso una disfunción renal menor, es decir, tras una nefrectomía única, aumenta la calcificación y exacerba la función endotelial de los cuerpos cavernosos en ratones «ApoE−/−», y este efecto puede estar asociado a un aumento del estrés oxidativo en el endotelio del pene
Subject(s)
Animals , Male , Mice , Penile Diseases/veterinary , Erectile Dysfunction/physiopathology , Calcinosis/diagnosis , Apolipoproteins E/deficiency , Atherosclerosis/diagnosis , Erectile Dysfunction/veterinary , Calcinosis/therapy , Calcinosis/veterinary , Apolipoproteins E/administration & dosage , Models, Animal , Atherosclerosis/veterinaryABSTRACT
Introduction: High Density Lipoproteins (HDL) are dysfunctional in hypercholesterolemia patients. The hypothesis was tested that nicotinamide (NAM) administration will influence HDL metabolism and reverse cholesterol transport from macrophages to the liver and feces in vivo (m-RCT) in a murine model of hypercholesterolemia. Methods: Apolipoprotein E-deficient (KOE) mice were challenged with a high-fat diet for 4 weeks. The effect of different doses of NAM on cholesterol metabolism, and the ability of HDL to promote m-RCT was assessed. Results: The administration of NAM to KOE mice produced an increase (∼1.5-fold; P < 0.05) in the plasma levels of cholesterol, which was mainly accounted for by the non-HDL fraction. NAM produced a [3H]-cholesterol plasma accumulation (∼1.5-fold) in the m-RCT setting. As revealed by kinetic analysis, the latter was mainly explained by an impaired clearance of circulating non-HDL (∼0.8-fold). The relative content of [3H]-tracer was lowered in the livers (∼0.6-fold) and feces (> 0.5-fold) of NAM-treated mice. This finding was accompanied by a significant (or trend close to significance) up-regulation of the relative gene expression of Abcg5 and Abcg8 in the liver (Abcg5: 2.9-fold; P < 0.05; Abcg8: 2.4-fold; P = 0.06) and small intestine (Abcg5: 2.1-fold; P = 0.15; Abcg8: 1.9-fold; P < 0.05) of high-dose, NAM-treated mice. Conclusion: The data from this study show that the administration of NAM to KOE mice impaired m-RCT in vivo. This finding was partly due to a defective hepatic clearance of plasma non-HDL
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