ECE2017 Oral Communications Diabetes therapy and complications (5 abstracts)
Activation of the Renin-Angiotensin II-Aldosterone-System leads to increases in extracellular protein disulfide isomerase: role in insulin resistance
Ricardo Perez-Fuentes 4 , Patricia Pulido 1, , Joshua Cazares 1, , Yaritza Inostroza-Nieves 1 , Enrique Torres-Rasgado 1, , Akira Nishiyama 3 , Alicia Rivera 1 , Rudy Ortiz 2 & Jose Romero 1
1Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, Brigham and Women’s Hospital, and Harvard Medical School, Boston, Massachusetts, USA; 2Department of Molecular and Cellular Biology, University of California, Merced, California, USA; 3Department of Pharmacology, Kagawa Medical University, Kagawa 761-0793, Japan; 4Universidad Autonoma de Puebla/Instituto Mexicano Seguro Social, Puebla, Mexico.
Insulin resistance and type II diabetes (T2D) are associated with activation of the Renin-Angiotensin-Aldosterone-System (RAAS) in part via regulation of its principal effector molecule, Angiotensin II (AngII). Endothelial cell activation leads to, among other factors, increased extracellular protein disulfide isomerase (PDI), a multifunctional protein that is critical to thrombus formation and regulation of reactive oxygen species. However, the effects of RAAS on PDI are unknown. We studied the in vitro effects of AngII on EA.hy926 human endothelial cells and measured PDI activity. Our results show that AngII (10 nM), dose- and time-dependently, increased PDI activity (P<0.05, n=6); an event that was blocked by pre-incubation with 0.5 μM losartan, an AngII Type I receptor antagonist (ARB). Western blot analyses showed increased PDI following AngII that was likewise reduced by losartan. In normal in Sprague–Dawley rats, we studied the in vivo effects of exogenous AngII infusion and observed significant increases in plasma PDI levels (P<0.05, n>5) that were blunted by ARB treatment. We then studied the obese Otsuka Long Evans Tokushima Fatty (OLETF) (n=6/group) rats, a model of naturally increased AngII and RAAS-mediated insulin resistance and hypertension. Our results show that OLETF rats had increased insulin resistance and greater circulating PDI activity than lean control rats (P<0.05) and was reduced by ARB treatment to baseline levels (P<0.05). To assess the clinical relevance of our findings, we measured circulating PDI in subjects with and without T2D. PDI activity correlated with measures of insulin resistance in our cohort (HOMA2-IR, Spearman P=0.496, P<0.001, n=134) and was significantly greater in T2D patients than healthy controls (P<0.01, n=56 vs 78, respectively). Our data in human and animal models suggest that RAAS activation represents a novel mechanism for PDI secretion. Thus we posit that PDI may contribute to the deleterious effects of RAAS-mediated vascular disease.
Volume 49
Article tools
My recent searches
My recently viewed abstracts
Authors
Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
© Bioscientifica 2024 |
Privacy policy |
Cookie settings
BiosciAbstracts
Bioscientifica Abstracts is the gateway to a series of products that provide a permanent, citable record of abstracts for biomedical and life science conferences.
Find out more