Long Noncoding RNA GAS5 Inhibits Cell Proliferation and Fibrosis in Diabetic Nephropathy by Sponging MiR-221 and Modulating SIRT1 Expression

Overview

Journal Aging (Albany NY)

Specialty Geriatrics

Date 2019 Oct 22

PMID 31631065

Citations 43

Authors

Xiaoxu Ge

Bojin Xu

Wenwei Xu

Lili Xia

Zhongqin Xu

Lisha Shen

Wenfang Peng

Shan Huang

Affiliations

Soon will be listed here.

Abstract

Diabetic nephropathy (DN) is one of the leading causes of end-stage renal diseases worldwide. This study is designed to investigate the underlying function and mechanism of a novel lncRNA GAS5 in the progression of DN. We found that lncRNA GAS5 expression level was decreased in type 2 diabetes (T2D) with DN compared with that in patients without DN. Moreover, lncRNA GAS5 expression level was negatively associated with the severity of DN-related complications. lncRNA GAS5 inhibited MCs proliferation and caused G0/1 phase arrest. lncRNA GAS5 overexpression alleviated the expression of fibrosis-related protein in mesangial cells (MCs). The dual-luciferase reporter assay and RNA binding protein immunoprecipitation (RIP) assay results revealed that lncRNA GAS5 functions as an endogenous sponge for miR-221 via both the directly targeting way and Ago2-dependent manner. Furthermore, SIRT1 was confirmed as a target gene of miR-221. lncRNA GAS5 upregulated SIRT1 expression and inhibited MCs proliferation and fibrosis by acting as an miR-221 sponge. Finally, we found that lncRNA GSA5 suppressed the development of DN in vivo. Thus, lncRNA GAS5 was involved in the progression of DN by sponging miR-221 and contributed to lncRNA-directed diagnostics and therapeutics in DN.

Citing Articles

Epigenetic Regulation by lncRNA GAS5/miRNA/mRNA Network in Human Diseases.

Nguyen L, Pyburn J, Nguyen N, Schank M, Zhao J, Wang L Int J Mol Sci. 2025; 26(3).

PMID: 39941145 PMC: 11818527. DOI: 10.3390/ijms26031377.

LncRNA GAS5 reduces blood glucose levels and alleviates renal fibrosis in diabetic nephropathy by regulating the miR-542-3p/ERBB4 axis.

Yin Q, Guo N, Liao R Diabetol Metab Syndr. 2025; 17(1):30.

PMID: 39849629 PMC: 11755873. DOI: 10.1186/s13098-025-01593-z.

LncRNA MEG3, GAS5, and HOTTIP Polymorphisms Association with Risk of Polycystic Ovary Syndrome: A Case-Control Study and Computational Analyses.

Majidpour M, Sargazi S, Ghasemi M, Akbar-Abad M, Sarhadi M, Saravani R Biochem Genet. 2024; .

PMID: 39613922 DOI: 10.1007/s10528-024-10977-1.

Association of long noncoding RNA GAS5 gene polymorphism with progression of diabetic kidney disease.

Yang P, Ting K, Tsai P, Su S, Yang S Int J Med Sci. 2024; 21(11):2201-2207.

PMID: 39239549 PMC: 11373544. DOI: 10.7150/ijms.99545.

The relevance of the non-invasive biomarkers lncRNA GAS5/miR-21 ceRNA regulatory network in the early identification of diabetes and diabetic nephropathy.

Sun H, Chen T, Li X, Zhu Y, Zhang S, He P Diabetol Metab Syndr. 2023; 15(1):197.

PMID: 37821982 PMC: 10566063. DOI: 10.1186/s13098-023-01179-7.

References

Wang X, Xu Y, Zhu Y, Wang Y, Li J, Li X . LncRNA NEAT1 promotes extracellular matrix accumulation and epithelial-to-mesenchymal transition by targeting miR-27b-3p and ZEB1 in diabetic nephropathy. J Cell Physiol. 2018; 234(8):12926-12933. DOI: 10.1002/jcp.27959. View

Iqbal M, Arora S, Prakasam G, Calin G, Syed M . MicroRNA in lung cancer: role, mechanisms, pathways and therapeutic relevance. Mol Aspects Med. 2018; 70:3-20. DOI: 10.1016/j.mam.2018.07.003. View

He F, Song Z, Chen H, Chen Z, Yang P, Li W . Long noncoding RNA PVT1-214 promotes proliferation and invasion of colorectal cancer by stabilizing Lin28 and interacting with miR-128. Oncogene. 2018; 38(2):164-179. PMC: 6329639. DOI: 10.1038/s41388-018-0432-8. View

Xu X, Tian J, Li Q . Downregulation of HOTTIP regulates insulin secretion and cell cycle in islet β cells via inhibiting MEK/ERK pathway. Eur Rev Med Pharmacol Sci. 2018; 22(15):4962-4968. DOI: 10.26355/eurrev_201808_15636. View

Gao J, Wang W, Wang F, Guo C . LncRNA-NR_033515 promotes proliferation, fibrogenesis and epithelial-to-mesenchymal transition by targeting miR-743b-5p in diabetic nephropathy. Biomed Pharmacother. 2018; 106:543-552. DOI: 10.1016/j.biopha.2018.06.104. View

Hu Q, Li C, Wang S, Li Y, Wen B, Zhang Y . LncRNAs-directed PTEN enzymatic switch governs epithelial-mesenchymal transition. Cell Res. 2019; 29(4):286-304. PMC: 6461864. DOI: 10.1038/s41422-018-0134-3. View

Zhao B, Li H, Liu J, Han P, Zhang C, Bai H . MicroRNA-23b Targets Ras GTPase-Activating Protein SH3 Domain-Binding Protein 2 to Alleviate Fibrosis and Albuminuria in Diabetic Nephropathy. J Am Soc Nephrol. 2016; 27(9):2597-608. PMC: 5004638. DOI: 10.1681/ASN.2015030300. View

Pickering R, Rosado C, Sharma A, Buksh S, Tate M, de Haan J . Recent novel approaches to limit oxidative stress and inflammation in diabetic complications. Clin Transl Immunology. 2018; 7(4):e1016. PMC: 5905388. DOI: 10.1002/cti2.1016. View

Li A, Peng R, Sun Y, Liu H, Peng H, Zhang Z . LincRNA 1700020I14Rik alleviates cell proliferation and fibrosis in diabetic nephropathy via miR-34a-5p/Sirt1/HIF-1α signaling. Cell Death Dis. 2018; 9(5):461. PMC: 5919933. DOI: 10.1038/s41419-018-0527-8. View

10.

Sun Z, Ma Y, Chen F, Wang S, Chen B, Shi J . miR-133b and miR-199b knockdown attenuate TGF-β1-induced epithelial to mesenchymal transition and renal fibrosis by targeting SIRT1 in diabetic nephropathy. Eur J Pharmacol. 2018; 837:96-104. DOI: 10.1016/j.ejphar.2018.08.022. View

11.

Shan T, Lv S, Tian Z, Liu X, Liu F, Sun X . Knockdown of lncRNA H19 inhibits abnormal differentiation of small intestinal epithelial cells in diabetic mice. J Cell Physiol. 2018; 234(1):837-848. DOI: 10.1002/jcp.26902. View

12.

Zeng B, Li Y, Jiang F, Wei C, Chen G, Zhang W . LncRNA GAS5 suppresses proliferation, migration, invasion, and epithelial-mesenchymal transition in oral squamous cell carcinoma by regulating the miR-21/PTEN axis. Exp Cell Res. 2018; 374(2):365-373. DOI: 10.1016/j.yexcr.2018.12.014. View

13.

Yu F, Hu M, Wang X, Li X, Zhang B, Lu X . Effects of microRNA-370 on mesangial cell proliferation and extracellular matrix accumulation by binding to canopy 1 in a rat model of diabetic nephropathy. J Cell Physiol. 2018; 234(5):6898-6907. DOI: 10.1002/jcp.27448. View

14.

Calvopina D, Coleman M, Lewindon P, Ramm G . Function and Regulation of MicroRNAs and Their Potential as Biomarkers in Paediatric Liver Disease. Int J Mol Sci. 2016; 17(11). PMC: 5133796. DOI: 10.3390/ijms17111795. View

15.

Dong H, Hu J, Zou K, Ye M, Chen Y, Wu C . Activation of LncRNA TINCR by H3K27 acetylation promotes Trastuzumab resistance and epithelial-mesenchymal transition by targeting MicroRNA-125b in breast Cancer. Mol Cancer. 2019; 18(1):3. PMC: 6323810. DOI: 10.1186/s12943-018-0931-9. View

16.

Lightell Jr D, Moss S, Woods T . Upregulation of miR-221 and -222 in response to increased extracellular signal-regulated kinases 1/2 activity exacerbates neointimal hyperplasia in diabetes mellitus. Atherosclerosis. 2017; 269:71-78. PMC: 5812823. DOI: 10.1016/j.atherosclerosis.2017.12.016. View

17.

Araki E, Nishikawa T . Oxidative stress: A cause and therapeutic target of diabetic complications. J Diabetes Investig. 2014; 1(3):90-6. PMC: 4008021. DOI: 10.1111/j.2040-1124.2010.00013.x. View

18.

Giacco F, Brownlee M . Oxidative stress and diabetic complications. Circ Res. 2010; 107(9):1058-70. PMC: 2996922. DOI: 10.1161/CIRCRESAHA.110.223545. View

19.

Huang T, Yin L, Wu J, Gu J, Wu J, Chen D . MicroRNA-19b-3p regulates nasopharyngeal carcinoma radiosensitivity by targeting TNFAIP3/NF-κB axis. J Exp Clin Cancer Res. 2016; 35(1):188. PMC: 5139034. DOI: 10.1186/s13046-016-0465-1. View

20.

Bible E . Diabetic nephropathy: Sirt1 attenuates diabetic albuminuria. Nat Rev Nephrol. 2013; 9(12):696. DOI: 10.1038/nrneph.2013.228. View