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Losartan, an angiotensin II type 1 receptor blocker, protects human islets from glucotoxicity through the phospholipase C pathway

Madec, Anne-Marie
Cassel, Roméo
Dubois, Séverine
Ducreux, Sylvie
Vial, Guillaume
Chauvin, Marie-Agnès
Mesnier, Aurélia
Chikh, Karim
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Published in FASEB Journal. 2013, vol. 27, no. 12, p. 5122-30
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 β-cell function under glucotoxic conditions. Human islets from 13 donors were cultured in 5.5 mM (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 μM), a selective PLC inhibitor, during the last 2 d. HG induced RAS activation with overexpression of AT1R (P<0.05) and angiotensinogen (P<0.001) mRNAs. HG increased endoplasmic 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-calcium 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.
Keywords Angiotensin II Type 1 Receptor Blockers/pharmacologyCalcium/metabolismCalcium SignalingCells, CulturedEndoplasmic Reticulum StressEstrenes/pharmacologyGlucose/toxicityHumansInositol 1,4,5-Trisphosphate Receptors/genetics/metabolismInsulin/genetics/metabolismInsulin-Secreting Cells/drug effects/metabolismLosartan/pharmacologyPhospholipase C beta/antagonists & inhibitors/metabolismPhospholipase C gamma/antagonists & inhibitors/metabolismPyrrolidinones/pharmacologyReceptor, Angiotensin, Type 1/metabolismRenin-Angiotensin SystemSarcoplasmic Reticulum Calcium-Transporting ATPases/genetics/metabolism
PMID: 24008754
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Research group La transplantation d'îlots de Langerhans (623)
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MADEC, Anne-Marie et al. Losartan, an angiotensin II type 1 receptor blocker, protects human islets from glucotoxicity through the phospholipase C pathway. In: FASEB Journal, 2013, vol. 27, n° 12, p. 5122-30. doi: 10.1096/fj.13-234104 https://archive-ouverte.unige.ch/unige:34324

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Deposited on : 2014-02-14

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