MiR-128-3p Inhibits Apoptosis and Inflammation in LPS-induced Sepsis by Targeting TGFBR2

Overview

Journal Open Med (Wars)

Specialty General Medicine

Date 2021 Feb 24

PMID 33623823

Citations 6

Authors

Peng Yang

Jianhua Han

Shigeng Li

Shaoning Luo

Xusheng Tu

Zhiqiang Ye

Affiliations

Soon will be listed here.

Abstract

Background: Sepsis is a systemic inflammatory response that can lead to the dysfunction of many organs. The aberrant expression of miRNAs is associated with the pathogenesis of sepsis. However, the biological functions of miR-128-3p in sepsis remain largely unknown, and its mechanism should be further investigated. This study aimed to determine the regulatory network of miR-128-3p and TGFBR2 in lipopolysaccharide (LPS)-induced sepsis.

Methods: The expression levels of miR-128-3p and transforming growth factor beta receptors II (TGFBR2) were detected by quantitative polymerase chain reaction (qPCR). The protein levels of TGFBR2, Bcl-2, Bax, cleaved caspase 3, Smad2, and Smad3 were measured by western blot. Cell apoptosis was analyzed by flow cytometry. Cytokine production was detected by enzyme-linked immunosorbent assay (ELISA). The binding sites of miR-128-3p and TGFBR2 were predicted by Targetscan online software and confirmed by dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay.

Results: The level of miR-128-3p was decreased, and TGFBR2 expression was increased in serum samples of sepsis patients and LPS-induced HK2 cells. Overexpression of miR-128-3p or knockdown of TGFBR2 ameliorated LPS-induced inflammation and apoptosis. Moreover, TGFBR2 was a direct target of miR-128-3p, and its overexpression reversed the inhibitory effects of miR-128-3p overexpression on inflammation and apoptosis in LPS-induced HK2 cells. Besides, overexpression of miR-128-3p downregulated TGFBR2 to suppress the activation of the Smad signaling pathway.

Conclusion: miR-128-3p could inhibit apoptosis and inflammation by targeting TGFBR2 in LPS-induced HK2 cells, which might provide therapeutic strategy for the treatment of sepsis.

Citing Articles

The Role of MicroRNA in the Pathogenesis of Acute Kidney Injury.

Bakinowska E, Kielbowski K, Pawlik A Cells. 2024; 13(18.

PMID: 39329743 PMC: 11444149. DOI: 10.3390/cells13181559.

MiR-20a-5p Targeting the Gene Regulates Inflammatory Response of Chicken Macrophages Infected with Avian Pathogenic .

Cao X, Ge J, Ma Y, Li H, Han W, Lamont S Animals (Basel). 2024; 14(15).

PMID: 39123803 PMC: 11311048. DOI: 10.3390/ani14152277.

The Parasite-Derived Peptide, FhHDM-1, Selectively Modulates miRNA Expression in -Cells to Prevent Apoptotic Pathways Induced by Proinflammatory Cytokines.

Camaya I, Hill M, Sais D, Tran N, OBrien B, Donnelly S J Diabetes Res. 2024; 2024:8555211.

PMID: 39022651 PMC: 11254460. DOI: 10.1155/2024/8555211.

Modes of action and diagnostic value of miRNAs in sepsis.

Antonakos N, Gilbert C, Theroude C, Schrijver I, Roger T Front Immunol. 2022; 13:951798.

PMID: 35990654 PMC: 9389448. DOI: 10.3389/fimmu.2022.951798.

Long non-coding RNA OIP5-AS1 regulates smoke-related chronic obstructive pulmonary disease via targeting micro RNA -410-3p/IL-13.

Hao W, Lin F, Shi H, Guan Z, Jiang Y Bioengineered. 2021; 12(2):11664-11676.

PMID: 34872453 PMC: 8810017. DOI: 10.1080/21655979.2021.2000199.

References

Hudder A, Novak R . miRNAs: effectors of environmental influences on gene expression and disease. Toxicol Sci. 2008; 103(2):228-40. PMC: 2922762. DOI: 10.1093/toxsci/kfn033. View

Wang Z, Ruan Z, Mao Y, Dong W, Zhang Y, Yin N . miR-27a is up regulated and promotes inflammatory response in sepsis. Cell Immunol. 2014; 290(2):190-5. DOI: 10.1016/j.cellimm.2014.06.006. View

Angus D, Lidicker J, Clermont G, Carcillo J, Pinsky M . Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med. 2001; 29(7):1303-10. DOI: 10.1097/00003246-200107000-00002. View

Rendon-Ramirez E, Ortiz-Stern A, Martinez-Mejia C, Salinas-Carmona M, Rendon A, Mata-Tijerina V . TGF-β Blood Levels Distinguish Between Influenza A (H1N1)pdm09 Virus Sepsis and Sepsis due to Other Forms of Community-Acquired Pneumonia. Viral Immunol. 2015; 28(5):248-54. PMC: 4486447. DOI: 10.1089/vim.2014.0123. View

Ma F, Li Z, Cao J, Kong X, Gong G . A TGFBR2/SMAD2/DNMT1/miR-145 negative regulatory loop is responsible for LPS-induced sepsis. Biomed Pharmacother. 2019; 112:108626. DOI: 10.1016/j.biopha.2019.108626. View

Hotchkiss R, Karl I . The pathophysiology and treatment of sepsis. N Engl J Med. 2003; 348(2):138-50. DOI: 10.1056/NEJMra021333. View

Zhang C, Li J, Qiu X, Chen Y, Zhang X . SUMO protease SENP1 acts as a ceRNA for TGFBR2 and thus activates TGFBR2/Smad signaling responsible for LPS-induced sepsis. Biomed Pharmacother. 2019; 112:108620. DOI: 10.1016/j.biopha.2019.108620. View

Li B, Chen H, Wu N, Zhang W, Shang L . Deregulation of miR-128 in ovarian cancer promotes cisplatin resistance. Int J Gynecol Cancer. 2014; 24(8):1381-8. DOI: 10.1097/IGC.0000000000000252. View

Wang J, Yu M, Yu G, Bian J, Deng X, Wan X . Serum miR-146a and miR-223 as potential new biomarkers for sepsis. Biochem Biophys Res Commun. 2010; 394(1):184-8. DOI: 10.1016/j.bbrc.2010.02.145. View

10.

Cai J, Fang L, Huang Y, Li R, Xu X, Hu Z . Simultaneous overactivation of Wnt/β-catenin and TGFβ signalling by miR-128-3p confers chemoresistance-associated metastasis in NSCLC. Nat Commun. 2017; 8:15870. PMC: 5481840. DOI: 10.1038/ncomms15870. View

11.

Cecconi M, Evans L, Levy M, Rhodes A . Sepsis and septic shock. Lancet. 2018; 392(10141):75-87. DOI: 10.1016/S0140-6736(18)30696-2. View

12.

Bone R, Balk R, Cerra F, Dellinger R, Fein A, Knaus W . Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. Chest. 1992; 101(6):1644-55. DOI: 10.1378/chest.101.6.1644. View

13.

Xu F, Lin S, Yang Y, Guo R, Cao J, Liu Q . The effect of curcumin on sepsis-induced acute lung injury in a rat model through the inhibition of the TGF-β1/SMAD3 pathway. Int Immunopharmacol. 2013; 16(1):1-6. DOI: 10.1016/j.intimp.2013.03.014. View

14.

Kampmeier T, Rehberg S, Westphal M, Lange M . Vasopressin in sepsis and septic shock. Minerva Anestesiol. 2010; 76(10):844-50. View

15.

Cai Y, Yu X, Hu S, Yu J . A brief review on the mechanisms of miRNA regulation. Genomics Proteomics Bioinformatics. 2010; 7(4):147-54. PMC: 5054406. DOI: 10.1016/S1672-0229(08)60044-3. View

16.

Massague J . TGF-beta signal transduction. Annu Rev Biochem. 1998; 67:753-91. DOI: 10.1146/annurev.biochem.67.1.753. View

17.

Weinstein M, Monga S, Liu Y, Brodie S, Tang Y, Li C . Smad proteins and hepatocyte growth factor control parallel regulatory pathways that converge on beta1-integrin to promote normal liver development. Mol Cell Biol. 2001; 21(15):5122-31. PMC: 87237. DOI: 10.1128/MCB.21.15.5122-5131.2001. View

18.

Erbuyun K, Tok D, Vatansever S, Ok G, Turkoz E, Aydede H . Levosimendan up-regulates transforming growth factor-beta and smad signaling in the aorta in the early stage of sepsis. Ulus Travma Acil Cerrahi Derg. 2010; 16(4):293-9. View

19.

Lan H, Chung A . TGF-β/Smad signaling in kidney disease. Semin Nephrol. 2012; 32(3):236-43. DOI: 10.1016/j.semnephrol.2012.04.002. View

20.

Huang C, Huang X, Zhu J, Chen Z, Li X, Zhang X . miR-128-3p suppresses hepatocellular carcinoma proliferation by regulating PIK3R1 and is correlated with the prognosis of HCC patients. Oncol Rep. 2015; 33(6):2889-98. DOI: 10.3892/or.2015.3936. View