A Presenilin/Notch1 pathway regulated by miR-375, miR-30a, and miR-34a mediates glucotoxicity induced-pancreatic beta cell apoptosis

Abstract

The presenilin-mediated Notch1 cleavage pathway plays a critical role in controlling pancreatic beta cell fate and survival. The aim of the present study was to investigate the role of Notch1 activation in glucotoxicity-induced beta cell impairment and the contributions of miR-375, miR-30a, and miR-34a to this pathway. We found that the protein levels of presenilins (PSEN1 and PSEN2), and NOTCH1 were decreased in INS-1 cells after treatment with increased concentrations of glucose, whereas no significant alteration of mRNA level of Notch1 was observed. Targeting of miR-375, miR-30a, and miR-34a to the 3′utr of Psen1, Psen2, and Notch1, respectively, reduced the amounts of relevant proteins, thereby reducing NICD1 amounts and causing beta cell apoptosis. Overexpression of NICD1 blocked the effects of glucotoxicity as well as miRNA overabundance. Downregulating the expression of miR-375, miR-30a, and miR-34a restored PSEN1, PSEN2, and NICD1 production and prevented glucotoxicity-induced impairment of the beta cells. These patterns of miRNA regulation of the Notch1 cleavage pathway were reproduced in GK rats as well as in aged rats. Our findings demonstrated that miRNA-mediated suppression of NICD1 links the presenilin/Notch1 pathway to glucotoxicity in mature pancreatic beta cells.

Intravenous Injection of miR-34a Inhibitor Alleviates Diabetes Mellitus-Induced Vascular Endothelial Dysfunction by Targeting NOTCH1

“…miR-34a/NOTCH1 signaling is also reported to promotes osteogenic differentiation of human adipose-derived stem cells (hASCs) via a coregulatory network [27]. Our study also indicated that overexpression of miR-34a induced the downregulation of NOTCH1 in vascular endothelial cells, which has been identified as a target gene of miR-34a in tumor cells, hASCs, RAW264.7 cells and pancreatic beta cell [24,[26][27][28]. In a pilot cross-sectional study, circulatory miR-34a is significantly elevated in diabetic patients compared with healthy controls [29].…”

“…It has been reported that the miR-34a/NOTCH1 signaling pathways mediate glucotoxicity-induced pancreatic beta cell apoptosis [24].…”

Mechanisms of Beta-Cell Apoptosis in Type 2 Diabetes-Prone Situations and Potential Protection by GLP-1-Based Therapies

“…Epigenetic mechanisms may also contribute to gluco(lipo)toxicity-induced beta-cell apoptosis by modulating gene expression through chromatin modification and/or non-coding RNAs. Indeed, Li et al demonstrated that the microRNAs (miRNAs) miR-375, miR-30a and miR-34a are increased in INS-1 cells and pancreatic islets exposed to high glucose levels, as well as in islets from diabetic GK rats [ 133 ]. miRNAs are endogenous non-coding RNAs known to regulate gene expression by binding to the 3′UTR of their target mRNAs resulting in their degradation and/or translational inhibition.…”

MicroRNA‑182‑5p contributes to the protective effects of thrombospondin 1 against lipotoxicity in INS‑1 cells

“…Bioinformatics prediction. Previous studies have reported that a number of miRs are involved in regulating the occurrence and progression of T2DM (12)(13)(14)(15)(16). To further determine whether THBS-1 is regulated by other molecules in its actions on the lipotoxicity of INS-1 cells, miRanda, Targetscan and PicTar were used to predict the possible miRs that may target THBS-1.…”

“…MicroRNAs (miRs) are 19 to 22-nucleotide noncoding RNAs that can regulate cell survival, cell function, apoptosis and differentiation by suppressing the transcription of mRNA (11)(12)(13). Currently, extensive research has suggested that miRs are involved in fatty acid-induced beta cell dysfunction (14)(15)(16).…”