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. 2020 Feb 18:13:413-422.
doi: 10.2147/DMSO.S242789. eCollection 2020.

Long Non‑Coding RNAs Regulate Inflammation in Diabetic Peripheral Neuropathy by Acting as ceRNAs Targeting miR-146a-5p

Yonghao Feng #  1 , Ying Ge #  2 , Men Wu  1 , Yangmei Xie  3 , Ming Wang  3 , Yinghui Chen  3 , Xiaohong Shi  1
Affiliations

Long Non‑Coding RNAs Regulate Inflammation in Diabetic Peripheral Neuropathy by Acting as ceRNAs Targeting miR-146a-5p

Yonghao Feng et al. Diabetes Metab Syndr Obes. .

Abstract

Background: Long non-coding RNAs (lncRNAs), as competing endogenous RNAs (ceRNAs), can regulate various pathophysiological processes by binding competitively to microRNAs at the post-transcription level. Our previous work demonstrated that miR-146a-5p was lowly expressed in diabetic peripheral neuropathy (DPN) rats. However, the ceRNA network in DPN mediated by lncRNAs and miR-146a-5p remains to be explored.

Methods: Two groups of rats (n=4 per group), a type 2 diabetes (T2DM) group and a DPN group, were used in this study. Sciatic nerve conduction velocity (NCV) of each rat was determined at the 6th and the 12th week. LncRNA microarray analysis was performed in the sciatic nerve of DPN and T2DM rats. Based on the TargetScan algorithm and the miRanda database, we determined the differentially expressed (DE) lncRNAs bound to miR-146a-5p. Furthermore, we verified the DE lncRNAs potentially bound to miR-146a-5p by qRT-PCR. The genes targeted by miR-146a-5p were identified by bioinformatics prediction and experimental techniques.

Results: We found 413 DE lncRNAs between DPN and T2DM rats (|log2FC| ≥ 2 and adjust P ≤ 0.05). Eight DE lncRNAs were predicted to bind to miR-146a-5p by both algorithms, of which four were verified by qRT-PCR. TRAF6, IRAK1, and SMAD4 were identified as miR-146a-5p targeted genes and were predominantly enriched in the inflammatory signaling pathway.

Conclusion: LncRNAs may contribute to the pathogenesis of DPN by regulating inflammation through functioning as ceRNAs of miR-146a-5p.

Keywords: MicroRNA; diabetic peripheral neuropathy; inflammation; long non-coding RNA.

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Conflict of interest statement

The authors report no conflicts of interest for this work.

Figures

Figure 1
Figure 1
Detailed flow chart of establishing T2DM and DPN rat model.
Figure 2
Figure 2
NCV values for T2DM and DPN groups (m/s). (A) MNCV values for T2DM and DPN groups at assessed time points. (B) SNCV values for T2DM and DPN groups at assessed time points. ** P < 0.01.
Figure 3
Figure 3
The heatmap of DE lncRNA for T2DM and DPN rats (log2FC| ≥ 2 and adjust P < 0.05). Cluster analysis of the test sample from the sciatic nerve of T2DM rats and DPN rats. These lncRNAs were selected on the basis of their differential expression (|log2FC| ≥ 2 and adjust P < 0.05). The values shown were the means of the normalized expressions from two independent group. Upregulated and downregulated lncRNAs in sciatic nerve were shown in red and green respectively.
Figure 4
Figure 4
DE lncRNAs predicted to bind miR-146a-5p. (A) DE lncRNAs predicted to bind miR-146a-5p by the algorithm of the TargetScan database. miR-146a-5p and lncRNAs were shown in red and green respectively. (B) DE lncRNAs predicted to bind miR-146a-5p by the algorithm of the miRanda database. miR-146a-5p and lncRNAs were shown in red and green respectively. (C) DE lncRNAs predicted to bind miR-146a-5p overlapping for the two algorithms, which was shown in gray. (D) Potential binding sites between miR-146a-5p and DE lncRNAs.
Figure 5
Figure 5
mRNAs targeted by miR-146a-5p. (A) mRNAs targeted by miR-146a-5p as predicted by the miRDB database. miR-146a-5p and mRNAs were shown in red and green respectively. (B) mRNAs targeted by miR-146a-5p as predicted by the TargetScan database. miR-146a-5p and mRNAs were shown in red and green respectively. (C) mRNAs targeted by miR-146a-5p as predicted by the miRTarBase database. miR-146a-5p and mRNAs were shown in red and green respectively. (D) Overlapping mRNAs targeted by miR-146a-5p in all three databases, which was shown in gray.
Figure 6
Figure 6
Network of ceRNAs mediated by DE lncRNAs. miR-146a-5p was shown in yellow. DE lncRNAs were shown in red. mRNAs were shown in green.
Figure 7
Figure 7
Validation of DE lncRNAs. Using qRT-PCR analysis, DE lncRNAs were measured in sciatic nerves of T2DM and DPN group rats. (A) The expression of XR_589933, XR_351905, XR_357013, and XR_589615. (B) The expression of XR_353891, XR_600244, XR_595664, and XR_598132. ** P < 0.01, * P < 0.05.
Figure 8
Figure 8
The potential mechanism of DE lncRNA decoying miR-146a-5p.
See this image and copyright information in PMC

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