Diabetic neuropathic pain induced by streptozotocin alters the expression profile of non‑coding RNAs in the spinal cord of mice as determined by sequencing analysis

He,Jian; Wang,Han Bin; Huang,Jiang Ju; Zhang,Lei; Li,Dong Lin; He,Wan You; Xiong,Qing Ming; Qin,Zai Sheng

doi:10.3892/etm.2021.10207

Diabetic neuropathic pain induced by streptozotocin alters the expression profile of non‑coding RNAs in the spinal cord of mice as determined by sequencing analysis

Authors:
- Jian He
- Han Bin Wang
- Jiang Ju Huang
- Lei Zhang
- Dong Lin Li
- Wan You He
- Qing Ming Xiong
- Zai Sheng Qin
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Affiliations: Department of Anesthesiology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510000, P.R. China, Department of Anesthesiology, The First People's Hospital of Foshan, Foshan, Guangdong 528000, P.R. China
Published online on: May 18, 2021 https://doi.org/10.3892/etm.2021.10207
Article Number: 775
Copyright: © He et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Diabetic neuropathic pain (DNP) is one of the most serious complications of diabetes. Patients with DNP always exhibit spontaneous and stimulus‑evoked pain. However, the pathogenesis of DNP remains to be fully elucidated. Non‑coding RNAs (ncRNAs) serve important roles in several cellular processes and dysregulated expression may result in the development of several diseases, including DNP. Although ncRNAs have been suggested to be involved in the pathogenesis of DNP, their precise roles remain to be determined. In the present study, sequencing analysis was used to investigate the expression patterns of coding genes, microRNAs (miRNAs), long ncRNAs (lncRNAs) and circular RNAs (circRNAs) in the spinal cord of mice with streptozotocin (STZ)‑induced DNP. A total of 30 mRNAs, 148 miRNAs, 9 lncRNAs and 135 circRNAs exhibited signiﬁcantly dysregulated expression 42 days after STZ injection. Functional enrichment analysis indicated that protein digestion and absorption pathways were the most signiﬁcantly affected pathways of the differentially expressed (DE) mRNAs. The Rap1 signaling pathway, human T‑lymphotropic virus‑I infection and the MAPK signaling pathway were the three most signiﬁcant pathways of the DE miRNAs. A total of 2,118 distinct circRNAs were identiﬁed and the length of the majority of the circRNAs was <1,000 nucleotides (nt) (1,552 circRNAs were >1,000 nt) with a median length of 620 nt. In the present study, the expression characteristics of coding genes, miRNAs, lncRNAs and circRNAs in DNP mice were determined; it paves the road for further studies on the mechanisms associated with DNP and potentially facilitates the discovery of novel ncRNAs for therapeutic targeting in the management of DNP.

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1	Kesavadev J, Saboo B, Sadikot S, Das AK, Joshi S, Chawla R, Thacker H, Shankar A, Ramachandran L and Kalra S: Unproven therapies for diabetes and their implications. Adv Ther. 34:60–77. 2017.PubMed/NCBI View Article : Google Scholar
2	Sun J, Wang Y, Zhang X, Zhu S and He H: Prevalence of peripheral neuropathy in patients with diabetes: A systematic review and meta-analysis. Prim Care Diabetes. 14:435–444. 2020.PubMed/NCBI View Article : Google Scholar
3	Shillo P, Sloan G, Greig M, Hunt L, Selvarajah D, Elliott J, Gandhi R, Wilkinson ID and Tesfaye S: Painful and painless diabetic neuropathies: What is the difference? Curr Diab Rep. 19(32)2019.PubMed/NCBI View Article : Google Scholar
4	Paisley P and Serpell M: Improving pain control in diabetic neuropathy. Practitioner. 261:23–26. 2017.PubMed/NCBI
5	Dewanjee S, Das S, Das AK, Bhattacharjee N, Dihingia A, Dua TK, Kalita J and Manna P: Molecular mechanism of diabetic neuropathy and its pharmacotherapeutic targets. Eur J Pharmacol. 833:472–523. 2018.PubMed/NCBI View Article : Google Scholar
6	Sloan G, Shillo P, Selvarajah D, Wu J, Wilkinson ID, Tracey I, Anand P and Tesfaye S: A new look at painful diabetic neuropathy. Diabetes Res Clin Pract. 144:177–191. 2018.PubMed/NCBI View Article : Google Scholar
7	Yang XD, Fang PF, Xiang DX and Yang YY: Topical treatments for diabetic neuropathic pain. Exp Ther Med. 17:1963–1976. 2019.PubMed/NCBI View Article : Google Scholar
8	Mattick JS and Makunin IV: Non-coding RNA. Hum Mol Genet. 15:R17–R29. 2006.PubMed/NCBI View Article : Google Scholar
9	Schmitt AM and Chang HY: Long noncoding RNAs in cancer pathways. Cancer Cell. 29:452–463. 2016.PubMed/NCBI View Article : Google Scholar
10	Zaratiegui M, Irvine DV and Martienssen RA: Noncoding RNAs and gene silencing. Cell. 128:763–776. 2007.PubMed/NCBI View Article : Google Scholar
11	Thum T: Noncoding RNAs and myocardial fibrosis. Nat Rev Cardiol. 11:655–663. 2014.PubMed/NCBI View Article : Google Scholar
12	Li G, Jiang H, Zheng C, Zhu G, Xu Y, Sheng X, Wu B, Guo J, Zhu S, Zhan Y, et al: Long noncoding RNA MRAK009713 is a novel regulator of neuropathic pain in rats. Pain. 158:2042–2052. 2017.PubMed/NCBI View Article : Google Scholar
13	Liu C, Li C, Deng Z, Du E and Xu C: Long Non-coding RNA BC168687 is involved in TRPV1-mediated diabetic neuropathic pain in rats. Neuroscience. 374:214–222. 2018.PubMed/NCBI View Article : Google Scholar
14	Yang D, Yang Q, Wei X, Liu Y, Ma D, Li J, Wan Y and Luo Y: The role of miR-190a-5p contributes to diabetic neuropathic pain via targeting SLC17A6. J Pain Res. 10:2395–2403. 2017.PubMed/NCBI View Article : Google Scholar
15	Wu B, Guo Y, Chen Q, Xiong Q and Min S: MicroRNA-193a Downregulates HMGB1 to alleviate diabetic neuropathic pain in a mouse model. Neuroimmunomodulat. 26:250–257. 2019.PubMed/NCBI View Article : Google Scholar
16	Yu W, Zhao GQ, Cao RJ, Zhu ZH and Li K: LncRNA NONRATT021972 was associated with neuropathic pain scoring in patients with Type 2 diabetes. Behav Neurol. 2017(2941297)2017.PubMed/NCBI View Article : Google Scholar
17	Wilusz JE and Sharp PA: Molecular biology. A circuitous route to noncoding RNA. Science. 340:440–441. 2013.PubMed/NCBI View Article : Google Scholar
18	Hansen TB, Jensen TI, Clausen BH, Bramsen JB, Finsen B, Damgaard CK and Kjems J: Natural RNA circles function as efficient microRNA sponges. Nature. 495:384–388. 2013.PubMed/NCBI View Article : Google Scholar
19	Memczak S, Jens M, Elefsinioti A, Torti F, Krueger J, Rybak A, Maier L, Mackowiak SD, Gregersen LH, Munschauer M, et al: Circular RNAs are a large class of animal RNAs with regulatory potency. Nature. 495:333–338. 2013.PubMed/NCBI View Article : Google Scholar
20	Wang L, Luo T, Bao Z, Li Y and Bu W: Intrathecal circHIPK3 shRNA alleviates neuropathic pain in diabetic rats. Biochem Biophys Res Commun. 505:644–650. 2018.PubMed/NCBI View Article : Google Scholar
21	Zimmermann M: Ethical guidelines for investigations of experimental pain in conscious animals. Pain. 16:109–110. 1983.PubMed/NCBI View Article : Google Scholar
22	Stoffel EC, Ulibarri CM, Folk JE, Rice KC and Craft RM: Gonadal hormone modulation of mu, kappa, and delta opioid antinociception in male and female rats. J Pain. 6:261–274. 2005.PubMed/NCBI View Article : Google Scholar
23	Chaplan SR, Bach FW, Pogrel JW, Chung JM and Yaksh TL: Quantitative assessment of tactile allodynia in the rat paw. J Neurosci Methods. 53:55–63. 1994.PubMed/NCBI View Article : Google Scholar
24	Furman BL: Streptozotocin-Induced diabetic models in mice and rats. Curr Protoc Pharmacol. 70:5.47.1–5.47.20. 2015.PubMed/NCBI View Article : Google Scholar
25	Jeck WR and Sharpless NE: Detecting and characterizing circular RNAs. Nat Biotechnol. 32:453–461. 2014.PubMed/NCBI View Article : Google Scholar
26	You X, Vlatkovic I, Babic A, Will T, Epstein I, Tushev G, Akbalik G, Wang M, Glock C, Quedenau C, et al: Neural circular RNAs are derived from synaptic genes and regulated by development and plasticity. Nat Neurosci. 18:603–610. 2015.PubMed/NCBI View Article : Google Scholar
27	Ding X, Zhang S, Li X, Feng C, Huang Q, Wang S, Wang S, Xia W, Yang F, Yin R, et al: Profiling expression of coding genes, long noncoding RNA, and circular RNA in lung adenocarcinoma by ribosomal RNA-depleted RNA sequencing. FEBS Open Bio. 8:544–555. 2018.PubMed/NCBI View Article : Google Scholar
28	Prescott SA, Ma Q and De Koninck Y: Normal and abnormal coding of somatosensory stimuli causing pain. Nat Neurosci. 17:183–191. 2014.PubMed/NCBI View Article : Google Scholar
29	López-González MJ, Landry M and Favereaux A: MicroRNA and chronic pain: From mechanisms to therapeutic potential. Pharmacol Ther. 180:1–15. 2017.PubMed/NCBI View Article : Google Scholar
30	Ma F, Wang C, Yoder WE, Westlund KN, Carlson CR, Miller CS and Danaher RJ: Efficacy of herpes simplex virus vector encoding the human preproenkephalin gene for treatment of facial pain in mice. J Oral Facial Pain Headache. 30:42–50. 2016.PubMed/NCBI View Article : Google Scholar
31	Altshuler D, Daly MJ and Lander ES: Genetic mapping in human disease. Science. 322:881–888. 2008.PubMed/NCBI View Article : Google Scholar
32	Li L, Zhang K, Lee J, Cordes S, Davis DP and Tang Z: Discovering cancer genes by integrating network and functional properties. BMC Med Genomics. 2(61)2009.PubMed/NCBI View Article : Google Scholar
33	Du J, Li M, Yuan Z, Guo M, Song J, Xie X and Chen Y: A decision analysis model for KEGG pathway analysis. BMC Bioinformatics. 17(407)2016.PubMed/NCBI View Article : Google Scholar
34	Ni HD, Yao M, Huang B, Xu LS, Zheng Y, Chu YX, Wang HQ, Liu MJ, Xu SJ and Li HB: Glial activation in the periaqueductal gray promotes descending facilitation of neuropathic pain through the p38 MAPK signaling pathway. J Neurosci Res. 94:50–61. 2016.PubMed/NCBI View Article : Google Scholar
35	Singhmar P, Huo X, Eijkelkamp N, Berciano SR, Baameur F, Mei FC, Zhu Y, Cheng X, Hawke D, Mayor F Jr, et al: Critical role for Epac1 in inflammatory pain controlled by GRK2-mediated phosphorylation of Epac1. Proc Natl Acad Sci USA. 113:3036–3041. 2016.PubMed/NCBI View Article : Google Scholar
36	Chen NF, Huang SY, Chen WF, Chen CH, Lu CH, Chen CL, Yang SN, Wang HM and Wen ZH: TGF-β1 attenuates spinal neuroinflammation and the excitatory amino acid system in rats with neuropathic pain. J Pain. 14:1671–1685. 2013.PubMed/NCBI View Article : Google Scholar
37	Wu J, Wang C and Ding H: LncRNA MALAT1 promotes neuropathic pain progression through the miR-154-5p/AQP9 axis in CCI rat models. Mol Med Rep. 21:291–303. 2020.PubMed/NCBI View Article : Google Scholar
38	Ren X, Yang R, Li L, Xu X and Liang S: Long non coding RNAs involved in MAPK pathway mechanism mediates diabetic neuropathic pain. Cell Biol Int. 44:2372–2379. 2020.PubMed/NCBI View Article : Google Scholar
39	van Rossum D, Verheijen BM and Pasterkamp RJ: Circular RNAs: Novel regulators of neuronal development. Front Mol Neurosci. 9(74)2016.PubMed/NCBI View Article : Google Scholar
40	Zheng Q, Bao C, Guo W, Li S, Chen J, Chen B, Luo Y, Lyu D, Li Y, Shi G, et al: Circular RNA profiling reveals an abundant circHIPK3 that regulates cell growth by sponging multiple miRNAs. Nat Commun. 7(11215)2016.PubMed/NCBI View Article : Google Scholar
41	Guo JU, Agarwal V, Guo H and Bartel DP: Expanded identification and characterization of mammalian circular RNAs. Genome Biol. 15(409)2014.PubMed/NCBI View Article : Google Scholar