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Scientific article
English

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

Published inThe FASEB journal, vol. 27, no. 12, p. 5122-5130
Publication date2013
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/pharmacology
  • Calcium/metabolism
  • Calcium Signaling
  • Cells, Cultured
  • Endoplasmic Reticulum Stress
  • Estrenes/pharmacology
  • Glucose/toxicity
  • Humans
  • Inositol 1,4,5-Trisphosphate Receptors/genetics/metabolism
  • Insulin/genetics/metabolism
  • Insulin-Secreting Cells/drug effects/metabolism
  • Losartan/pharmacology
  • Phospholipase C beta/antagonists & inhibitors/metabolism
  • Phospholipase C gamma/antagonists & inhibitors/metabolism
  • Pyrrolidinones/pharmacology
  • Receptor, Angiotensin, Type 1/metabolism
  • Renin-Angiotensin System
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases/genetics/metabolism
Citation (ISO format)
MADEC, Anne-Marie et al. Losartan, an angiotensin II type 1 receptor blocker, protects human islets from glucotoxicity through the phospholipase C pathway. In: The FASEB journal, 2013, vol. 27, n° 12, p. 5122–5130. doi: 10.1096/fj.13-234104
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Article (Published version)
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Identifiers
ISSN of the journal0892-6638
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