Inhibition of miR-25 aggravates diabetic peripheral neuropathy

Abstract

The hyperglycemia-induced enhanced oxidative stress is a key factor of diabetic peripheral neuropathy implicated in the pathogenesis of diabetic neuropathy, and microRNA may be involved, playing promotion or protection roles. In this study, we aimed to investigate the function of miR-25 during the development of oxidative/nitrative stress and in subsequent neurological problems. We detected the oxidative stress effects and expression of miR-25 on sciatic nerves from db/db diabetic model mice and analyzed the expression of related genes by qPCR and Western blotting. Interestingly, we observed increased reactive oxygen species (ROS) and Nox4 expression in db/db mice accompanied with reduced miR-25. MiR-25 inhibitor treatment increased nicotinamide adenine dinucleotide phosphate activity in Schwann cells, whereas miR-25 precursor overexpression led to opposite results. MiR-25 precursor reduced the activation of protein kinase C and decreased Nox4 expression at both mRNA and protein levels. Advanced glycation endproducts (AGEs) and the receptor for advanced glycation endproducts (RAGE) were increased in the serum and in the peripheral nerves obtained from diabetic mice, and miR-25 inhibitor treatment in Schwann cells from wt mice led to the same effect. However, miR-25 precursor transfection reduced AGEs and RAGE, and further reduced inflammatory factors that contribute to the pathological process of peripheral nerves. These findings, for the first time, indicate that miR-25 acts as a protection factor in diabetic neuropathy by downregulating AGE–RAGE and reducing nicotinamide adenine dinucleotide phosphate oxidase. miR-25 reduced protein kinase C-α phosphorylation to produce less reactive oxygen species in diabetic peripheral nerves, and therefore it played an important role in the regulation of oxidative/nitrative stress and in consequent neurological dysfunction.

The Role of microRNAs in Metabolic Syndrome-Related Oxidative Stress

“…Further, patients with diabetic nephropathy were characterized by decline in miR-423-5p, and detailed studies elucidated that HG-elicited injury of podocytes was also attributed to upregulation of direct target of miR-423-5p, NOX4 [266]. Similarly, the upregulation of NOX4 and reduction of its direct regulator, miR-25, was reported in kidneys of diabetic rat model, HG-treated mesangial cells and upon diabetic peripheral neuropathy [267,268]. Expression of another NOX, NOX5, was proved to be rescued by HG-reduced miR-485, its direct regulator, in human mesangial cells, thus enhancing their proliferation and inflammation [269].…”

Circulating microRNAs as biomarkers for diabetic neuropathy: A novel approach

“…A similar pathway has been described, involving miRNA-190a-5p downregulation and resultant impaired solute carrier family 17 member 6 gene inhibition in painful DN[18]. Conversely, medically induced downregulation of miRNA-25 exacerbated the development of DN via an increase of advanced end glycation products and their receptors in peripheral neural tissue, indicating the neuroprotective attributes of miRNA-25 molecules[19]. In an experimental model on diabetic rodents, miRNA-9 and its interaction with calcium homeostasis modulator 1 were suggested to be involved in the pathophysiological pathway of painful DN[20].…”

Emerging Roles of microRNAs as Biomarkers and Therapeutic Targets for Diabetic Neuropathy

“…In a mouse model of DN, miR-155 mimics suppressed pro-inflammatory cytokines and attenuated DN by targeting tumor necrosis factor receptorassociated factor 2 (TRAF2) and Notch2 (62). Zhang et al, reported that miR-25 decreased reactive oxygen species content in diabetic peripheral nerves by activating NADPH oxidase and upregulating Advanced glycation endproduct (AGE)-RAGE interaction (50), In a diabetic state, reduced miR-146a expression was observed in serum, leukocytes, retina, heart, and PNS (65)(66)(67). MiR-146a was also reported to be involved in DN progression (64,68).…”

“…Recent preclinical studies using exogenous double-stranded miRNAs mimic or single-stranded antisense RNAs (antimiRs) have shown promising results in rodent models of DN (50,59,63,77,79). However, the use of miRNAs as translational agents or pharmaco-targets in DN patients requires future investigations.…”