Abstract
In this study, we tested the hypothesis that overexpression of miR-9 and miR-29a may contribute to DPN development and progression. We performed a meta-analysis of miR expression profile studies in human diabetes mellitus (DM) and the data suggested that miR-9 and miR-29a were highly expressed in patients with DM, which was further verified in serum samples collected from 30 patients diagnosed as DM. Besides, ISL1 was confirmed to be a target gene of miR-9 and miR-29a. Lentivirus-mediated forced expression of insulin gene enhancer binding protein-1 (ISL1) activated the sonic hedgehog (SHH) signaling pathway, increased motor nerve conduction velocity and threshold of nociception, and modulated expression of neurotrophic factors in sciatic nerves in rats with DM developed by intraperitoneal injection of 0.45% streptozotocin, suggesting that ISL1 could delay DM progression and promote neural regeneration and repair after sciatic nerve damage. However, lentivirus-mediated forced expression of miR-9 or miR-29a exacerbated DM and antagonized the beneficial effect of ISL1 on DPN. Collectively, this study revealed potential roles of miR-9 and miR-29a as contributors to DPN development through the SHH signaling pathway by binding to ISL1. Additionally, the results provided an experimental basis for the targeted intervention treatment of miR-9 and miR-29a.
Highlights
Diabetes mellitus (DM) is one of the most serious chronic diseases across the world, affecting millions of lives [1]
Compared with the negative control (NC) group, the miR-9 mimic and miR-29a mimic groups with transfection of insulin gene enhancer binding protein-1 (ISL1)-wild type plasmid presented with significantly decreased luciferase activity (p < 0.05), while there were no obvious changes in the luciferase activity of the both groups after transfection of ISL1-mutant (p > 0.05) (Figure 1F)
A recent study has shown that various miRs play essential roles in pancreatic islet development as well as insulin secretion, notably miR-9, which participates in the regulation of insulin secretion through interaction with Onecut-2 mRNA and has low expression in insulinproducing cells [40]
Summary
Diabetes mellitus (DM) is one of the most serious chronic diseases across the world, affecting millions of lives [1]. Diabetic neuropathy is a heterogeneous disease characterized by a complicated pathophysiology, with great impact on the peripheral nervous system [3]. Clinical manifestations of DPN include increased vibration and thermal perception thresholds that progress to sensory loss, which occur in addition to degeneration of all fiber types in the peripheral nerve fibers [6]. Painful diabetic www.aging-us.com neuropathy, a known syndrome of DPN, greatly affects the quality of life of patients with DM and brings great financial burden, while currently available treatments intended fail to prevent the development of DPN [7]. To improve the life quality of patients with DM, it is essential to find an effective prevention and treatment for DPN
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