MicroRNA-155 mediates endogenous angiotensin II type 1 receptor regulation:implications for innovative type 2 diabetes mellitus management

作     者：Konstantinos I Papadopoulos Alexandra Papadopoulou Tar-Choon Aw 

作者机构：Department of R&DTHAI StemLifeBangkok 10310Thailand Occupational and Environmental Health ServicesFeelgood LundLund 223-63SkåneSweden Department of Laboratory MedicineChangi General HospitalSingapore 529889SingaporeSingapore Department of MedicineNational University of SingaporeSingapore 119228SingaporeSingapore 

出 版 物：《世界糖尿病杂志:英文版(电子版)》 (World Journal of Diabetes)

年 卷 期：2023年第14卷第9期

页      面：1334-1340页

核心收录：

学科分类：1002[医学-临床医学] 10[医学] 

主　　题：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 

摘      要：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 aldosterone 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-inflam matory cellular pathways,and promotesβ-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.