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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 2

RAGE binds only to the toxic, prefibrillar form of h-IAPP.

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RAGE binds only to the toxic, prefibrillar form of h-IAPP.
(A) Schematic...
(A) Schematic diagram showing the design of h-IAPP/sRAGE binding experiments. Blue arrows indicate the time points at which sRAGE was added to h-IAPP over the course of amyloid formation. (B) In the sRAGE Trp fluorescence assays, a 1:1 molar addition of sRAGE to h-IAPP (blue circles) led to a wave of fluorescence quenching that mirrored the wave of h-IAPP toxicity shown in D. No change in fluorescence was observed for sRAGE alone (black squares) or with a 1:1 molar addition of sRAGE to r-IAPP (white triangles). h-IAPP, in the absence of sRAGE (red circles), and r-IAPP, in the absence of sRAGE (green triangles), were used as nonfluorescent controls. (C) Thioflavin-T–binding assays, carried out concurrently with sRAGE Trp fluorescence assays and β cell metabolic assays, monitored the kinetics of amyloid formation (25°C) in the peptide solutions used in the experiments shown in B and D. h-IAPP (red circles) and r-IAPP (green triangles). (D) Time-resolved Alamar Blue metabolic assays in INS-1 β cells treated with h-IAPP (red circles) or r-IAPP (green triangles) demonstrated that LP intermediates were the most toxic form of h-IAPP. (E) SPR shows that sRAGE bound h-IAPP LP intermediates (blue line) but not t0 species (black dashed line) or SP amyloid fibrils (red dashed line). In B–D, the symbol (§) indicates the time point at which the maximum sRAGE Trp fluorescence quenching was observed. The final peptide concentration after transferring peptide aliquots into β cell assays was 14 μM. Data are representative of 3 to 10 independent experiments. Data in C and D represent the mean ± SD of a minimum of 3 to 6 technical replicates per time point. Error bars for some data points are smaller than the size of the symbols.

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