title: Losartan, an angiotensin II type 1 receptor blocker, protects human islets from glucotoxicity through the phospholipase C pathway.
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.
authors.affiliation: 2INSERM U1060/University Lyon 1/Inra 1235, Lyon-Sud Medicine, Faculty, 165 Chemin du Grand Revoyet-BP 12, 69921 Oullins Cedex, France. anne-marie.coquelet-madec@univ-lyon1.fr.
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Madec
authors.forename: Roméo
authors.initials: R
authors.lastname: Cassel
authors.forename: Séverine
authors.initials: S
authors.lastname: Dubois
authors.forename: Sylvie
authors.initials: S
authors.lastname: Ducreux
authors.forename: Guillaume
authors.initials: G
authors.lastname: Vial
authors.forename: Marie-Agnès
authors.initials: MA
authors.lastname: Chauvin
authors.forename: Aurélia
authors.initials: A
authors.lastname: Mesnier
authors.forename: Karim
authors.initials: K
authors.lastname: Chikh
authors.forename: Domenico
authors.initials: D
authors.lastname: Bosco
authors.forename: Jennifer
authors.initials: J
authors.lastname: Rieusset
authors.forename: Fabien
authors.initials: F
authors.lastname: Van Coppenolle
authors.forename: Charles
authors.initials: C
authors.lastname: Thivolet
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling; D002478:Cells, Cultured; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress; D004963:Estrenes / Q000494:pharmacology; D005947:Glucose / Q000633:toxicity*; D006801:Humans; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000235:genetics / Q000378:metabolism; D007328:Insulin / Q000235:genetics / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism; D019808:Losartan / Q000494:pharmacology*; D054799:Phospholipase C beta / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051966:Phospholipase C gamma / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011760:Pyrrolidinones / Q000494:pharmacology; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D012084:Renin-Angiotensin System; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000235:genetics / Q000378:metabolism
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D000091342:Endoplasmic Reticulum Chaperone BiP; D004963:Estrenes; C000717247:HSPA5 protein, human; D053496:Inositol 1,4,5-Trisphosphate Receptors; D007328:Insulin; D011760:Pyrrolidinones; D044140:Receptor, Angiotensin, Type 1; C060229:1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione; D054799:Phospholipase C beta; D051966:Phospholipase C gamma; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; C506946:ATP2A2 protein, human; D005947:Glucose; D019808:Losartan; D002118:Calcium
keywords: AT1R inhibitor; ER stress; PLC-IP3-calcium pathway; RAS; calcium homeostasis; diabetes; human pancreatic β-cells