Abstract
Aldosterone promotes non-genomic effects in endothelial and vascular smooth muscle cells via activation of mineralocorticoid receptors (MR) and G protein-coupled estrogen receptors (GPER). GPER activation is associated with beneficial/protective effects in the vasculature. Considering that vascular dysfunction plays a major role in diabetes-associated complications, we hypothesized that the beneficial effects mediated by vascular GPER activation, in response to aldosterone, are decreased in diabetes. Mesenteric resistance arteries from female, 14–16 weeks-old, control and diabetic (db/db) mice were used. Phenylephrine (PhE)-induced contractions were greater in arteries from db/db vs. control mice. Aldosterone (10 nM) increased maximal contractile responses to PhE in arteries from control mice, an effect elicited via activation of GPER. Although aldosterone did not increase PhE responses in arteries from db/db mice, blockade of GPER, and MR decreased PhE-induced contractile responses in db/db mesenteric arteries. Aldosterone also reduced the potency of acetylcholine (ACh)-induced relaxation in arteries from both control and db/db mice via MR-dependent mechanisms. GPER antagonism further decreased ACh-induced relaxation in the control group, but did not affect ACh responses in the diabetic group. Aldosterone increased extracellular signal-regulated kinase 1/2 phosphorylation in arteries from control and db/db mice by a GPER-dependent mechanism. GPER, but not MR, gene, and protein expression, determined by RT-PCR and immunoblotting/immunofluorescence assays, respectively, were increased in arteries from db/db mice vs. control arteries. These findings indicate that aldosterone activates both vascular MR and GPER and that the beneficial effects of GPER activation are decreased in arteries from diabetic animals. Our results further elucidate the mechanisms by which aldosterone influences vascular function and contributes to vascular dysfunction in diabetes. Financial Support: FAPESP, CNPq, and CAPES, Brazil.
Highlights
Diabetes represents a major public health challenge
Aldosterone and vascular G protein-coupled estrogen receptors (GPER) in diabetes altered in pathological conditions, such as diabetes mellitus, this study addressed the role of GPER activation on the vascular effects of aldosterone in control and db/db mice
The present study shows that GPER differentially contributes to the vascular effects of aldosterone in control and diabetic conditions
Summary
Diabetes represents a major public health challenge. In 2013, 382 million people exhibited diabetes and in 2035 this number will rise to 592 million (International Diabetes Federation [IDF], 2013). Aldosterone induces activation of different kinases, including protein kinase C (PKC), phosphatidylinositol 3-kinase (PI3K), tyrosine kinases, epidermal growth factor receptor (EGFR), insulin-like growth factor-1 receptor (IGF-1R), and mitogen-activated protein kinases (MAPKs; Christ et al, 1995; Krug et al, 2003; Liu et al, 2003; Callera et al, 2005; Ishizawa et al, 2005) These pathways are critically involved in pathophysiological processes associated with vascular inflammation and injury (Callera et al, 2011; Whaley-Connell and Sowers, 2011; Bender et al, 2013). MR antagonists, such as eplerenone and spironolactone, have been shown to reverse hypertensionand diabetes-associated vascular dysfunction (Swaminathan et al, 2008; Schafer et al, 2010; Briones et al, 2012)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
