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- Title
Losartan, an angiotensin II type 1 receptor blocker, protects human islets from glucotoxicity through the phospholipase C pathway.
- Authors
Madec, Anne-Marie; Cassel, Roméo; Dubois, Séverine; Ducreux, Sylvie; Vial, Guillaume; Chauvin, Marie-Agnès; Mesnier, Aurélia; Chikh, Karim; Bosco, Domenico; Rieusset, Jennifer; Van Coppenolle, Fabien; Thivolet, Charles
- Abstract
As shown in a large clinical prospective trial, inhibition of the renin-angiotensin system (RAS) can delay the onset of type 2 diabetes in high-risk individuals. We evaluated the beneficial effects of RAS inhibition on é-cell function under glucotoxic conditions. Human islets from 13 donors were cultured in 5.5 µM (controls) or 16.7 mM glucose [high glucose (HG)] for 4 d with or without losartan (5 µM), a selective AT1R blocker, and/or U73122 (2 wM), a selective PLC inhibitor, during the last 2 d. HG induced RAS activation with overexpression of AT1R (P<0.05) and angio-tensinogen (P< 0.001) mRNAs. HG increased endoplas-mic reticulum (ER) stress markers (P<0.001) such as GRP78, sXBP1, and ATF4 mRNAs and Grp78 protein levels (P<0.01). HG also decreased reticular calcium concentration (P<0.0001) and modified protein expressions of ER calcium pumps with reduction of SERCA2b (P<0.01) and increase of IP3R2 (P<0.05). Losartan prevented these deleterious effects and was associated with improved insulin secretion despite HG exposure. AT1R activation triggers the PLC-IP3-cal-cium pathway. Losartan prevented the increase of PLC β1 and γ1 protein levels induced by HG (P<0.05). U73122 reproduced all the protective effects of losartan. AT1R blockade protects human islets from the deleterious effects of glucose through inhibition of the PLC-IP3-calcium pathway.
- Subjects
LOSARTAN; ANGIOTENSIN-receptor blockers; ANGIOTENSINS; PHOSPHOLIPASE C; PHOSPHOLIPASES
- Publication
FASEB Journal, 2013, Vol 27, Issue 12, p5122
- ISSN
0892-6638
- Publication type
Article
- DOI
10.1096/fj.13-234104