lncRNA uc.48+ regulates immune and inflammatory reactions mediated by the P2X7 receptor in type 2 diabetic mice

Wu,Hong; Jiang,Mei; Liu,Qiang; Wen,Fang; Nie,Yijun

doi:10.3892/etm.2020.9360

lncRNA uc.48+ regulates immune and inflammatory reactions mediated by the P2X7 receptor in type 2 diabetic mice

Authors:
- Hong Wu
- Mei Jiang
- Qiang Liu
- Fang Wen
- Yijun Nie
View Affiliations

Affiliations: Department of Clinical Laboratory, First Affiliated Hospital, Medical College of Nanchang University, Nanchang, Jiangxi 330006, P.R. China, Institute of Blood Transfusion, Jiangxi Province Blood Center, Nanchang, Jiangxi 330077, P.R. China
Published online on: October 15, 2020 https://doi.org/10.3892/etm.2020.9360
Article Number: 230
Copyright: © Wu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Diabetes and non-coding RNAs are receiving increasing attention in contemporary medical research. The present study aimed to explore the role of the long non-coding RNA uc.48+ in the pathological changes of type 2 diabetes mellitus (T2DM) by observing the effects of uc.48+ small interfering RNA (siRNA) on the abdominal cells of a mouse model of T2DM. Mice with T2DM (DM group) were established by feeding with a high-sugar and -fat diet combined with intraperitoneal injections of low-dose streptozotocin. An intraperitoneal injection of uc.48+ siRNA was administered to the diabetic mice, and the serum levels of cytokines together with other clinical parameters, namely blood pressure, heart rate, mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) were examined. Following the collection and identification of abdominal cells from the mice, the mRNA levels of uc.48+, mRNA and protein levels of the P2X7 receptor, and phosphorylation levels of ERK1/2 were evaluated by reverse transcription-PCR and western blotting, respectively. The MWT and TWL were significantly decreased in the DM group compared with the non-diabetic control group. However, the reductions in MWT and TWL were significantly attenuated following uc.48+ siRNA injection. The systolic and diastolic blood pressure, as well as the serum levels of tumor necrosis factor α and interleukin 1β of mice in the DM group were significantly increased compared with those in the control group, whereas these changes were significantly attenuated following the injection of uc.48+ siRNA. In addition, the expression levels of P2X7 receptor mRNA and protein, and the degree of phosphorylation of ERK1/2 in the abdominal cells were significantly increased in the DM group compared with the control group. These changes were also significantly attenuated following transfection with uc.48+ siRNA in vivo. In conclusion, these data suggest that uc.48+ may play an important role in the pathological changes of blood pressure, neurology and abdominal cell function in T2DM via interaction with the P2X₇ receptor.

View Figures

View References

1	Harris-Hayes M, Schootman M, Schootman JC and Hastings MK: The role of physical therapists in fighting the type 2 diabetes epidemic. J Orthop Sports Phys Ther. 50:5–16. 2020.PubMed/NCBI View Article : Google Scholar
2	Prattichizzo F, De Nigris V, Spiga R, Mancuso E, La Sala L, Antonicelli R, Testa R, Procopio AD, Olivieri F and Ceriello A: Inflammageing and metaflammation: The yin and yang of type 2 diabetes. Ageing Res Rev. 41:1–17. 2018.PubMed/NCBI View Article : Google Scholar
3	Bonnet F and Scheen AJ: Effects of SGLT2 inhibitors on systemic and tissue low-grade inflammation: The potential contribution to diabetes complications and cardiovascular disease. Diabetes Metab. 44:457–464. 2018.PubMed/NCBI View Article : Google Scholar
4	Ward MG, Li G and Hao M: Apoptotic β-cells induce macrophage reprogramming under diabetic conditions. J Biol Chem. 293:16160–16173. 2018.PubMed/NCBI View Article : Google Scholar
5	Saika F, Kiguchi N, Matsuzaki S, Kobayashi D and Kishioka S: Inflammatory macrophages in the sciatic nerves facilitate neuropathic pain associated with type 2 diabetes mellitus. J Pharmacol Exp Ther. 368:535–544. 2019.PubMed/NCBI View Article : Google Scholar
6	Maciel FR, Punaro GR, Rodrigues AM, Bogsan CS, Rogero MM, Oliveira MN, Mouro MG and Higa EM: Immunomodulation and nitric oxide restoration by a probiotic and its activity in gut and peritoneal macrophages in diabetic rats. Clin Nutr. 35:1066–1072. 2016.PubMed/NCBI View Article : Google Scholar
7	Breuillard C, Bonhomme S, Couderc R, Cynober L and De Bandt JP: In vitro anti-inflammatory effects of citrulline on peritoneal macrophages in Zucker diabetic fatty rats. Br J Nutr. 113:120–124. 2015.PubMed/NCBI View Article : Google Scholar
8	Wu H, Nie Y, Xiong H, Liu S, Li G, Huang A, Guo L, Wang S, Xue Y, Wu B, et al: P2X7 receptor expression in peripheral blood monocytes is correlated with plasma C-reactive protein and cytokine levels in patients with type 2 diabetes mellitus: A preliminary report. Inflammation. 38:2076–2081. 2015.PubMed/NCBI View Article : Google Scholar
9	Adinolfi E, Giuliani AL, De Marchi E, Pegoraro A, Orioli E and Di Virgilio F: The P2X7 receptor: A main player in inflammation. Biochem Pharmacol. 151:234–244. 2018.PubMed/NCBI View Article : Google Scholar
10	Bhat SA, Ahmad SM, Mumtaz PT, Malik AA, Dar MA, Urwat U, Shah RA and Ganai NA: Long non-coding RNAs: Mechanism of action and functional utility. Noncoding RNA Res. 1:43–50. 2016.PubMed/NCBI View Article : Google Scholar
11	Dinescu S, Ignat S, Lazar AD, Constantin C, Neagu M and Costache M: Epitranscriptomic signatures in lncRNAs and their possible roles in cancer. Genes (Basel). 10(52)2019.PubMed/NCBI View Article : Google Scholar
12	Wu B, Zhang C, Zou L, Ma Y, Huang K, Lv Q, Zhang X, Wang S, Xue Y, Yi Z, et al: LncRNA uc.48+ siRNA improved diabetic sympathetic neuropathy in type 2 diabetic rats mediated by P2X7 receptor in SCG. Auton Neurosci. 197:14–18. 2016.PubMed/NCBI View Article : Google Scholar
13	Wu H, Wen F, Jiang M, Liu Q and Nie Y: LncRNA uc.48+ is involved in the diabetic immune and inflammatory responses mediated by P2X7 receptor in RAW264.7 macrophages. Int J Mol Med. 42:1152–1160. 2018.PubMed/NCBI View Article : Google Scholar
14	Dos Anjos Cassado A: F4/80 as a major macrophage marker: The case of the peritoneum and spleen. Results Probl Cell Differ. 62:161–179. 2017.PubMed/NCBI View Article : Google Scholar
15	Jain R, Watson U, Vasudevan L and Saini DK: ERK activation pathways downstream of GPCRs. Int Rev Cell Mol Biol. 338:79–109. 2018.PubMed/NCBI View Article : Google Scholar
16	Ma L, Zhang S and Du M: Cordycepin from Cordyceps militaris prevents hyperglycemia in alloxan-induced diabetic mice. Nutr Res. 35:431–439. 2015.PubMed/NCBI View Article : Google Scholar
17	Zhang J, Qiu H, Huang J, Ding S, Huang B, Wu Q and Jiang Q: Establishment of a diabetic myocardial hypertrophy model in Mus musculus castaneus mouse. Int J Exp Pathol. 99:295–303. 2018.PubMed/NCBI View Article : Google Scholar
18	Liu S, Zou L, Xie J, Xie W, Wen S, Xie Q, Gao Y, Li G, Zhang C, Xu C, et al: LncRNA NONRATT021972 siRNA regulates neuropathic pain behaviors in type 2 diabetic rats through the P2X7 receptor in dorsal root ganglia. Mol Brain. 9(44)2016.PubMed/NCBI View Article : Google Scholar
19	Adan A, Kiraz Y and Baran Y: Cell proliferation and cytotoxicity assays. Curr Pharm Biotechnol. 17:1213–1221. 2016.PubMed/NCBI View Article : Google Scholar
20	Wang S, Xu H, Zou L, Xie J, Wu H, Wu B, Yi Z, Lv Q, Zhang X, Ying M, et al: LncRNA uc.48+ is involved in diabetic neuropathic pain mediated by the P2X3 receptor in the dorsal root ganglia. Purinergic Signal. 12:139–148. 2016.PubMed/NCBI View Article : Google Scholar
21	Begum M, Lewison G, Sommariva S, Ciani O, Tarricone R and Sullivan R: European diabetes research and its funding, 2002-2013. Diabet Med. 34:1354–1360. 2017.PubMed/NCBI View Article : Google Scholar
22	Tarquini R, Lazzeri C, Pala L, Rotella CM and Gensini GF: The diabetic cardiomyopathy. Acta Diabetol. 48:173–181. 2011.PubMed/NCBI View Article : Google Scholar
23	Andersen RE and Lim DA: Forging our understanding of lncRNAs in the brain. Cell Tissue Res. 371:55–71. 2018.PubMed/NCBI View Article : Google Scholar
24	Dong Y, Yoshitomi T, Hu JF and Cui J: Long noncoding RNAs coordinate functions between mitochondria and the nucleus. Epigenetics Chromatin. 10(41)2017.PubMed/NCBI View Article : Google Scholar
25	Lennox KA and Behlke MA: Cellular localization of long non-coding RNAs affects silencing by RNAi more than by antisense oligonucleotides. Nucleic Acids Res. 44:863–877. 2016.PubMed/NCBI View Article : Google Scholar
26	Chen X, Yan CC, Zhang X and You ZH: Long non-coding RNAs and complex diseases: From experimental results to computational models. Brief Bioinform. 18:558–576. 2017.PubMed/NCBI View Article : Google Scholar
27	Magagula L, Gagliardi M, Naidoo J and Mhlanga M: Lnc-ing inflammation to disease. Biochem Soc Trans. 45:953–962. 2017.PubMed/NCBI View Article : Google Scholar
28	He X, Ou C, Xiao Y, Han Q, Li H and Zhou S: LncRNAs: Key players and novel insights into diabetes mellitus. Oncotarget. 8:71325–71341. 2017.PubMed/NCBI View Article : Google Scholar
29	Li X, Zhao Z, Gao C, Rao L, Hao P, Jian D, Li W, Tang H and Li M: The diagnostic value of whole blood lncRNA ENST00000550337.1 for pre-diabetes and type 2 diabetes mellitus. Exp Clin Endocrinol Diabetes. 125:377–383. 2017.PubMed/NCBI View Article : Google Scholar
30	Alvarado-Vázquez PA, Grosick RL, Moracho-Vilrriales C, Ward E, Threatt T and Romero-Sandoval EA: Cytokine production capabilities of human primary monocyte-derived macrophages from patients with diabetes mellitus type 2 with and without diabetic peripheral neuropathy. J Pain Res. 12:69–81. 2018.PubMed/NCBI View Article : Google Scholar
31	Dhananjayan K, Gunawardena D, Hearn N, Sonntag T, Moran C, Gyengesi E, Srikanth V and Münch G: Activation of macrophages and microglia by interferon-γ and lipopolysaccharide increases methylglyoxal production: A new mechanism in the development of vascular complications and cognitive decline in type 2 diabetes mellitus? J Alzheimers Dis. 59:467–479. 2017.PubMed/NCBI View Article : Google Scholar