MicroRNAs in Diabetic Cardiovascular Complications
DM is associated with vascular complications that represent the major cause of morbidity and mortality. The whole vascular tree is affected. Microangiopathies - angiopathies of the small arterial vessels - result in retinopathy, nephropathy and neuropathy. Macroangiopathies affect the larger arterial vessels, leading to ischaemic heart disease and arteriopathy of the lower limbs and of the supra-aortic trunks. The risk of developing complications is influenced by the duration of DM and genetic factors. Current treatment measures have resulted in a partial reduction in cardiovascular risk, and improved management strategies remain a major need for people with DM.
Diabetic microangiopathy is a leading cause of renal failure, blindness and nonhealing foot ulcers.
DM can promote ultrastructural alterations in the glomerular filtration barrier of the kidney that affect its permeability, leading to proteinuria and a decline in glomerular filtration rate. This is known as diabetic nephropathy. Poor glycaemic control and underlying hypertension worsen this condition and accelerate its progression, often resulting in end-stage renal disease (Afkarian et al. 2013). Several miRNAs have been related to the pathobiology of diabetic nephropathy. For example, the increase in transforming growth factor-p (TGF-p) that occurs during diabetic nephropathy and promotes the accumulation of extracellular matrix in the glomerulus is induced by miR-192 (Deshpande et al. 2013). MiR-192 also modulates the expression of miR-200b/c and collagen genes, contributing to glomerular hypertrophy and fibrogenesis (Kato et al. 2007). MiR-21 expression is increased in the kidneys of type 2 diabetic mice (Wang et al. 2013). Under hyperglycaemic conditions, miR-21 inhibits the tumour suppressor gene PTEN and activates Akt and TORC1 pathways, resulting in renal cell hypertrophy and fibrogenesis (Dey et al. 2011). Other miRs upregulated by high glucose levels and related to diabetic nephropathy are miR-195 and miR-377, the former involved in podocyte apoptosis by reducing expression of BCL2 and the latter contributing to fibrogenesis by inducing fibro- nectin expression (Chen et al. 2011; Wang et al. 2008). Some miRs have been found to be downregulated in the kidney under diabetic conditions, suggesting that their forced expression could be a therapeutic strategy in this context. One example is the miR-29 family, repressed in proximal tubular cells under hyperglycaemia or TGF-p treatment (Chen et al. 2014a). As miR-29 targets collagens I, III and IV, its down- regulation contributes to renal fibrosis by increasing the levels of these proteins (Qin et al. 2011). Vascular endothelial growth factor-A (VEGF-A) plays a key role in maintaining the integrity of the glomerulus. It has been shown that miR-93 targets VEGF-A, and miR-93 downregulation promotes an increase in VEGF-A under hyperglycaemic conditions. Furthermore, inhibiting the VEGF-A rise by forced overexpression of miR-93 improves kidney function in diabetic mice (Long et al.
2010) . Thus, miR-39 overexpression could be a therapeutic strategy to prevent kidney dysfunction.