Impaired HPA axis function in diabetes involves adrenal apoptosis and phagocytosis
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ORIGINAL ARTICLE
Impaired HPA axis function in diabetes involves adrenal apoptosis and phagocytosis Esteban M. Repetto 1,2 Morena Wiszniewski2 Ana L. Bonelli2 Carolina V. Vecino2 Camila Martinez Calejman2 Pablo Arias3 Cora B. Cymeryng2,4 ●
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Received: 22 May 2018 / Accepted: 8 September 2018 © Springer Science+Business Media, LLC, part of Springer Nature 2018
Abstract Purpose The aim of the present study was to analyze the involvement of oxidative stress and inflammation in the modulation of glucocorticoid production in the adrenal cortex of diabetic rats. Methods Male Wistar rats were treated with or without streptozotocin (STZ, an insulinopenic model of diabetes) and either α-lipoic (90 mg/kg ip.), α-tocopherol (200 mg/kg po.) or with STZ and supplemented with insulin (STZ + INS: 2.5U/day) for 4 weeks. Oxidative/nitrosative stress parameters and antioxidant enzymes were determined in adrenocortical tissues. Apoptosis and macrophage activation were evaluated by immunohistochemistry (TUNEL and ED1+). Basal and ACTHstimulated corticosterone production were assessed by RIA and plasma ACTH levels were determined by an immunometric assay. Results Diabetic rats showed a diminished response to exogenous ACTH stimulation along with higher basal corticosterone and lower plasma ACTH levels. In the adrenal cortex we determined an increase in the levels of lipoperoxides, Snitrosothiols, nitric oxide synthase activity and nitro-tyrosine modified proteins while catalase activity and heme oxygenase1 expression levels were also elevated. Antioxidant treatments were effective in the prevention of these effects, and in the increase in the number of apoptotic and phagocytic (ED1+) cells detected in diabetic rats. No changes were observed in the STZ + INS group. Conclusions Generation of oxidative/nitrosative stress in the adrenal cortex of diabetic rats leads to the induction of apoptosis and the activation of adrenocortical macrophages and is associated with an elevated basal corticosteronemia and the loss of the functional capacity of the gland. Keywords Diabetes Oxidative stress Apoptosis HPA dysfuntion α-tocopherol α-lipoic acid ●
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Electronic supplementary material The online version of this article (https://doi.org/10.1007/s12020-018-1755-5) contains supplementary material, which is available to authorized users. * Esteban M. Repetto [email protected] 1
Departamento de Bioquímica Clínica, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina
2
Facultad de Medicina, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Centro de Estudios Farmacológicos y Botánicos (CEFYBO), Laboratorio de Endocrinología Molecular (LEM), Universidad de Buenos Aires, Buenos Aires, Argentina
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Departamento de Fisiología, Facultad de Medicina, Universidad Nacional de Rosario, Rosario, Argentina
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Departamento de Bioquímica Humana, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina
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Introduction Type 1 diabete
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