Front Endocrinol (Lausanne). 2014 Feb 28;5:23. eCollection 2014.
Skov J 1, Persson F 2, Frøkiær J 3, Christiansen JS 4.
1Department of Endocrinology and Internal Medicine, Aarhus University Hospital , Aarhus , Denmark ; Novo Nordisk A/S , Bagsvaerd , Denmark.
2Steno Diabetes Center , Gentofte , Denmark.
3Department of Clinical Physiology and Molecular Imaging, Aarhus University Hospital , Aarhus , Denmark ; Department of Clinical Medicine, Aarhus University , Aarhus , Denmark.
4Department of Endocrinology and Internal Medicine, Aarhus University Hospital , Aarhus , Denmark.
*Correspondence: Jeppe Skov, Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Norrebrogade 44, Aarhus DK-8000, Denmark e-mail: jsk at dadlnet.dk
The actions of angiotensin peptides are diverse and locally acting tissue renin-angiotensin systems (RAS) are present in almost all tissues of the body. An activated RAS strongly correlates to metabolic disease (e.g., diabetes) and its complications and blockers of RAS have been demonstrated to prevent diabetes in humans. Hyperglycemia, obesity, hypertension, and cortisol are well-known risk factors of metabolic disease and all stimulate tissue RAS whereas glucagon-like peptide-1, vitamin D, and aerobic exercise are inhibitors of tissue RAS and to some extent can prevent metabolic disease.
Furthermore, an activated tissue RAS deteriorates the same risk factors creating a system with several positive feedback pathways. The primary effector hormone of the RAS, angiotensin II, stimulates reactive oxygen species, induces tissue damage, and can be associated to most diabetic complications.
Based on these observations, we hypothesize that an activated tissue RAS is the principle cause of metabolic syndrome and type 2 diabetes, and additionally is mediating the majority of the metabolic complications. The involvement of positive feedback pathways may create a self-reinforcing state and explain why metabolic disease initiate and progress. The hypothesis plausibly unifies the major predictors of metabolic disease and places tissue RAS regulation in the center of metabolic control.
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Lack of vitamin D receptor causes stress-induced premature senescence in vascular smooth muscle cells through enhanced local angiotensin-II signals
Petya Valcheva, Anna Cardus, Sara Panizo, Eva Parisi, Milica Bozic, Jose M. Lopez Novoa, Adriana Dusso, Elvira Fernandez1, Jose M. Valdivielso1email
1EF and JMV share senior authorship.
Received: February 17, 2014; Received in revised form: April 9, 2014; Accepted: May 1, 2014; Published Online: May 13, 2014
Publication stage: In Press Accepted Manuscript
•Lacking vitamin D signaling induces premature senescence in vascular smooth muscle cells.
•The increase in senescence is mediated by an increase in cathepsin D mediated angiotensin II expression.
•The increase in angiotensin II induces an increase in NADPH oxidase-mediated free radical production.
•All these changes induce a decrease in proliferation of vascular smooth muscle cells.
The inhibition of the renal renin-angiotensin system by the active form of vitamin D contributes to the cardiovascular health benefits of a normal vitamin D status. Local production of angiotensin-II in the vascular wall is a potent mediator of oxidative stress, prompting premature senescence. Herein, our objective was to examine the impact of defective vitamin D signalling on local angiotensin-II levels and arterial health.
Primary cultures of aortic vascular smooth muscle cells (VSMC) from wild-type and vitamin D receptor-knockout (VDRKO) mice were used for the assessment of cell growth, angiotensin-II and superoxide anion production and expression levels of cathepsin D, angiotensin-II type 1 receptor and p57Kip2. The in vitro findings were confirmed histologically in aortas from wild-type and VDRKO mice.
VSMC from VDRKO mice produced more angiotensin-II in culture, and elicited higher levels of cathepsin D, an enzyme with renin-like activity, and angiotensin-II type 1 receptor, than wild-type mice. Accordingly, VDRKO VSMC showed higher intracellular superoxide anion production, which could be suppressed by cathepsin D, angiotensin-II type 1 receptor or NADPH oxidase antagonists. VDRKO cells presented higher levels of p57Kip2, impaired proliferation and premature senescence, all of them blunted upon inhibition of angiotensin-II signalling. In vivo studies confirmed higher levels of cathepsin D, angiotensin-II type 1 receptor and p57Kip2 in aortas from VDRKO mice.
The beneficial effects of active vitamin D in vascular health could be a result of the attenuation of local production of angiotensin-II and downstream free radicals, thus preventing the premature senescence of VSMC.
- Search VitaminDWiki for Renin-Angiotensin 198 items as of March 2014
- Overview Diabetes and vitamin D
- Overview Metabolic Syndrome and vitamin D
- Hypothesis: Vitamin D deficiency is due to malfunctioning renin angiotensin system – Jan 2013
Closely related hypothesis a year earlier postulated that Vitamin D deficiency was due to the Renin-Angiotensin System
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