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RAGE binds preamyloid IAPP intermediates and mediates pancreatic β cell proteotoxicity
Andisheh Abedini, … , Daniel P. Raleigh, Ann Marie Schmidt
Andisheh Abedini, … , Daniel P. Raleigh, Ann Marie Schmidt
Published January 16, 2018
Citation Information: J Clin Invest. 2018;128(2):682-698. https://doi.org/10.1172/JCI85210.
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Research Article Cell biology

RAGE binds preamyloid IAPP intermediates and mediates pancreatic β cell proteotoxicity

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Abstract

Islet amyloidosis is characterized by the aberrant accumulation of islet amyloid polypeptide (IAPP) in pancreatic islets, resulting in β cell toxicity, which exacerbates type 2 diabetes and islet transplant failure. It is not fully clear how IAPP induces cellular stress or how IAPP-induced toxicity can be prevented or treated. We recently defined the properties of toxic IAPP species. Here, we have identified a receptor-mediated mechanism of islet amyloidosis–induced proteotoxicity. In human diabetic pancreas and in cellular and mouse models of islet amyloidosis, increased expression of the receptor for advanced glycation endproducts (RAGE) correlated with human IAPP–induced (h-IAPP–induced) β cell and islet inflammation, toxicity, and apoptosis. RAGE selectively bound toxic intermediates, but not nontoxic forms of h-IAPP, including amyloid fibrils. The isolated extracellular ligand–binding domains of soluble RAGE (sRAGE) blocked both h-IAPP toxicity and amyloid formation. Inhibition of the interaction between h-IAPP and RAGE by sRAGE, RAGE-blocking antibodies, or genetic RAGE deletion protected pancreatic islets, β cells, and smooth muscle cells from h-IAPP–induced inflammation and metabolic dysfunction. sRAGE-treated h-IAPP Tg mice were protected from amyloid deposition, loss of β cell area, β cell inflammation, stress, apoptosis, and glucose intolerance. These findings establish RAGE as a mediator of IAPP-induced toxicity and suggest that targeting the IAPP/RAGE axis is a potential strategy to mitigate this source of β cell dysfunction in metabolic disease.

Authors

Andisheh Abedini, Ping Cao, Annette Plesner, Jinghua Zhang, Meilun He, Julia Derk, Sachi A. Patil, Rosa Rosario, Jacqueline Lonier, Fei Song, Hyunwook Koh, Huilin Li, Daniel P. Raleigh, Ann Marie Schmidt

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Figure 1

Toxic, preamyloid h-IAPP intermediates upregulate RAGE expression in β cells.

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Toxic, preamyloid h-IAPP intermediates upregulate RAGE expression in β c...
h-IAPP LP species, SP amyloid fibrils, and r-IAPP aggregates were characterized by (A) thioflavin-T binding, (B) TEM (scale bars: 100 nm), and (C) Alamar Blue metabolic assays. (D) WB studies measuring RAGE protein. In C and D, β cells were treated with peptide solutions for 5 hours. RAGE levels in D were normalized to GAPDH levels and presented as the fold-change relative to r-IAPP–treated β cells. The final peptide concentration in cellular assays was 14 μM. In D, data were taken from 2 distinct WBs in order to accommodate all of the conditions; in both cases, comparisons were made with h-IAPP (LP) species. Data represent the mean ± SD (thioflavin-T and metabolic assays) and the mean ± SEM (WBs) of 3 to 4 independent experiments (3–6 technical replicates per experiment). The graphs in A–C represent more than 20 experiments repeated at different times using multiple different preparations of primary peptide stock solutions. NSD, no statistical difference. *P < 0.05, **P ≤ 0.01, and ****P ≤ 0.0001, by 1-way ANOVA.

Copyright © 2023 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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