MicroRNA and Microvascular Complications of Diabetes

Abstract

In the last decade, miRNAs have received substantial attention as potential players of diabetes microvascular complications, affecting the kidney, the retina, and the peripheral neurons. Compelling evidence indicates that abnormally expressed miRNAs have pivotal roles in key pathogenic processes of microvascular complications, such as fibrosis, apoptosis, inflammation, and angiogenesis. Moreover, clinical research into innovative both diagnostic and prognostic tools suggests circulating miRNAs as possible novel noninvasive markers of diabetes microvascular complications. In this review, we summarize current knowledge and understanding of the role of miRNAs in the injury to the microvascular bed in diabetes and discuss the potential of miRNAs as clinical biomarkers of diabetes microvascular complications.

Figure 1

Role of miR-146a in diabetic microvascular complications. (a) In normoglycemic conditions, miR-146 is induced by NF-κB, and it inhibits NF-κB by suppressing its target genes interleukin-1 receptor-associated kinase 1/2 (IRAK1/2) and TNF receptor-associated factor 6 (TRAF6). Moreover, miR-146 represses expression of fibronectin (Fn) in retinal cells and ErbB4/Notch1 in podocytes. (b) In the presence of diabetes, there is an absolute/relative miR-146 deficiency leading to insufficient inhibition (light blue lines) of IRAK1/2/TRAF6 (enhancing inflammation), Fn expression (favoring fibrosis), and TGF-β1/ErbB4/Notch1 signaling (leading to podocyte damage). Enhanced signaling through the TGF-β1-ErbB4 pathway increases autocrine synthesis of MCP-1, further reducing miR-146a levels via MCPIP1 in a feed-forward loop. Grey boxes: miR-146 target genes; dotted lines: inhibition; continuous line: activation/induction.

Figure 2

MicroRNAs involved in renal fibrosis in diabetes. MicroRNAs (miRNAs) implicated in glomerular (cream-coloured area) and tubule-interstitial (light purple-coloured area) fibrosis in diabetes. The image shows miRNAs in red boxes that are modulated by TGF-β1 and directly control collagen/fibronectin expression, miRNAs in bronze boxes that enhance TGF-β1 signaling, and miRNAs in purple boxes that affect fibrosis independently of TGF-β1. Target genes are shown in orange boxes. Grey lines indicate induction, while red lines indicate suppression of miRNA expression. EMT: epithelial mesenchymal transition; MMT: mesangial cell to myofibroblast transition; CTNNBIP1: catenin beta interacting protein 1; TGF-β1: transforming growth factor-β1; TGFB-R1: transforming growth factor type 1 receptor; VEGF: vascular endothelial growth factor; CTGF: connective tissue growth factor.

Figure 3

MicroRNA involved in diabetes microvascular complications. miRNAs and miRNA targets (in italics) abnormally expressed in diabetic nephropathy (DN), diabetic retinopathy (DR), and diabetic neuropathy (DSP) are shown. Pink lines connect miRNAs involved in both DN and DR. Red lines connect miRNAs involved in all diabetes microvascular complications.