Mild exposure of RIN-5F β-cells to human islet amyloid polypeptide aggregates upregulates antioxidant enzymes via NADPH oxidase-RAGE: An hormetic stimulus

Abstract

The presence of amyloid aggregates of human islet amyloid polypeptide (hIAPP), a hallmark of type 2 diabetes, contributes to pancreatic β-cell impairment, where oxidative stress plays a key role. A contribution of NADPH oxidase to reactive oxygen species (ROS) generation after cell exposure to micromolar concentrations of hIAPP aggregates has been suggested. However, little is known about β-cells exposure to lower amounts of hIAPP aggregates, similar to those found in human pancreas. Thus, we aimed to investigate the events resulting from RIN-5F cells exposure to nanomolar concentrations of toxic hIAPP aggregates. We found an early and transient rise of NADPH oxidase activity resulting from increased Nox1 expression following the engagement of receptor for advanced glycation end-products (RAGE) by hIAPP aggregates. Unexpectedly, NADPH oxidase activation was not accompanied by a significant ROS increase and the lipoperoxidation level was significantly reduced. Indeed, cell exposure to hIAPP aggregates affected the antioxidant defences, inducing a significant increase of the expression and activity of catalase and glutathione peroxidase. We conclude that exposure of pancreatic β-cells to nanomolar concentrations of hIAPP aggregates for a short time induces an hormetic response via the RAGE-Nox1 axis; the latter stimulates the enzymatic antioxidant defences that preserve the cells against oxidative stress damage.

Oleuropein, a Bioactive Compound from Olea europaea L., as a Potential Preventive and Therapeutic Agent in Non-Communicable Diseases

“…hIAPP is a peptide hormone co-secreted with insulin by pancreatic β-cells, and fibrillar deposits of hIAPP amyloid aggregates in islets of Langerhans are a well known of T2DM. hIAPP aggregation together with oxidative stress (via NADPH-oxidase) leads to hIAPP toxicity, and plays a pivotal role in T2DM pathogenesis [127,128]. Rigacci et al [74] showed that OleA occurrence, during the aggregation process, drove the formation of structurally different aggregates by hindering their binding with the membrane cells, resulting in a decrease of membrane damage, and protection of rat insulinoma cells against aggregate cytotoxicity, the main aspect responsible for cell sufferance.…”

Vitamin D cell signalling in health and disease

“…The RAGE receptors will increase oxidative stress by activating the NADPH oxidase (NOX) that induces ROS formation (Fig. 6) [200,201].…”

Oligomannuronate prevents mitochondrial dysfunction induced by IAPP in RINm5F islet cells by inhibition of JNK activation and cell apoptosis

“…Thus, the role of JNK is complex in the mediation of distinct cellular response depending on cell contents. In addition, different concentrations of hIAPP could result in different cellular responses, for example, the activation of NADPH-oxidase induced by hIAPP at 60 nM was converse to the concentration at 500 nM [53]. And recent researches were focused on the molecular or signal changes induced by hIAPP at μM levels [1,6,7,16,40,54].…”