Copyright ©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Diabetes. Sep 15, 2023; 14(9): 1334-1340
Published online Sep 15, 2023. doi: 10.4239/wjd.v14.i9.1334
MicroRNA-155 mediates endogenous angiotensin II type 1 receptor regulation: implications for innovative type 2 diabetes mellitus management
Konstantinos I Papadopoulos, Alexandra Papadopoulou, Tar-Choon Aw
Konstantinos I Papadopoulos, Department of R&D, THAI StemLife, Bangkok 10310, Thailand
Alexandra Papadopoulou, Occupational and Environmental Health Services, Feelgood Lund, Lund 223-63, Skåne, Sweden
Tar-Choon Aw, Department of Laboratory Medicine, Changi General Hospital, Singapore 529889, Singapore, Singapore
Tar-Choon Aw, Department of Medicine, National University of Singapore, Singapore 119228, Singapore, Singapore
Author contributions: Papadopoulos KI conceived and conceptualized the argumentation, designed the layout, drafted the initial manuscript, and reviewed and revised the manuscript; Papadopoulou A performed the literature search, extracted vital information, contributed to the synthesis of the minireview, and reviewed and revised the manuscript; Aw TC coordinated and supervised literature search, made substantial and direct intellectual contributions and critically reviewed the manuscript for important intellectual content; All authors approved the submitted final manuscript and agree to be accountable for all aspects of the work.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Corresponding author: Konstantinos I Papadopoulos, MD, PhD, Chief Physician, Director, Department of R&D, THAI StemLife, 566/3 THAI StemLife bldg., Soi Ramkhamhaeng 39 (Thepleela 1), Prachaouthit Rd., Wangthonglang, Bangkok 10310, Thailand.
Received: April 14, 2023
Peer-review started: April 14, 2023
First decision: June 13, 2023
Revised: June 18, 2023
Accepted: July 13, 2023
Article in press: July 13, 2023
Published online: September 15, 2023

Type 2 diabetes mellitus (T2DM) is a lifelong condition and a threat to human health. Thorough understanding of its pathogenesis is acutely needed in order to devise innovative, preventative, and potentially curative pharmacological interventions. MicroRNAs (miRNA), are small, non-coding, one-stranded RNA molecules, that can target and silence around 60% of all human genes through translational repression. MiR-155 is an ancient, evolutionarily well-conserved miRNA, with distinct expression profiles and multifunctionality, and a target repertoire of over 241 genes involved in numerous physiological and pathological processes including hematopoietic lineage differentiation, immunity, inflammation, viral infections, cancer, cardiovascular conditions, and particularly diabetes mellitus. MiR-155 Levels are progressively reduced in aging, obesity, sarcopenia, and T2DM. Thus, the loss of coordinated repression of multiple miR-155 targets acting as negative regulators, such as C/EBPβ, HDAC4, and SOCS1 impacts insulin signaling, deteriorating glucose homeostasis, and causing insulin resistance (IR). Moreover, deranged regulation of the renin angiotensin aldo-sterone system (RAAS) through loss of Angiotensin II Type 1 receptor downregulation, and negated repression of ETS-1, results in unopposed detrimental Angiotensin II effects, further promoting IR. Finally, loss of BACH1 and SOCS1 repression abolishes cytoprotective, anti-oxidant, anti-apoptotic, and anti-inflammatory cellular pathways, and promotes β-cell loss. In contrast to RAAS inhibitor treatments that further decrease already reduced miR-155 Levels, strategies to increase an ailing miR-155 production in T2DM, e.g., the use of metformin, mineralocorticoid receptor blockers (spironolactone, eplerenone, finerenone), and verapamil, alone or in various combinations, represent current treatment options. In the future, direct tissue delivery of miRNA analogs is likely.

Keywords: Angiotensin II, Angiotensin II type 1 receptor, Arginase 2, L-type calcium channel, Mineralocorticoid receptor, MiRNA-155, Renin-angiotensin aldosterone system, Type 1/2 diabetes mellitus, Verapamil

Core Tip: MicroRNAs (miRNA) are small, non-coding, one-stranded RNA molecules that can target and silence over 60% of human genes thereby effectively regulating huge genetic networks. MiRNAs are abundantly found in every human cell and their production is tightly controlled. They play critical roles in regulating almost every cellular pathway, numerous human diseases, and have been linked to the development of diabetes mellitus (DM) and the regulation of blood pressure. In this minireview, we comment on crucial miR-155 effects in type 2 DM (T2DM). Deeper mechanistical understanding of this miRNA’s permeating action may lead to innovative therapeutic approaches in T2DM.