Hypoxia-induced microRNA-155 promotes fibrosis in proximal tubule cells

Xie,Shenping; Chen,Huaizhou; Li,Fei; Wang,Shu; Guo,Junjun

doi:10.3892/mmr.2015.3327

Hypoxia-induced microRNA-155 promotes fibrosis in proximal tubule cells

Authors:
- Shenping Xie
- Huaizhou Chen
- Fei Li
- Shu Wang
- Junjun Guo
View Affiliations

Affiliations: Renal Transplantation and Dialysis Center, 181st Hospital of Chinese People's Liberation Army, Guilin, Guangxi 541002, P.R. China
Published online on: February 10, 2015 https://doi.org/10.3892/mmr.2015.3327
Pages: 4555-4560

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

Hypoxia has been considered to be a significant microenvironmental factor in promoting renal fibrosis, which causes progressive kidney disease and renal allograft failure. Previous studies have demonstrated versatile functions of miR‑155 in hypoxia and fibrosis of the lung and liver. However, it is unclear whether miR‑155 is able to regulate renal fibrosis and what the detailed mechanisms of this may be. In the current study, we focused on the interaction of miR‑155/hypoxia‑inducible factor 1 alpha (HIF‑1α) and the effects of miR‑155 on fibrosis in hypoxic HK‑2 cells. Analysis of the expression of miR‑155 and fibrosis‑associated cytokines revealed upregulated miR‑155, increased transforming growth factor beta 1 (TGF‑β1) and alpha‑smooth muscle actin, and decreased E‑cadherin in hypoxic HK‑2 cells. Further study demonstrated that miR‑155 played a positive role in regulating HIF‑1α and vice versa. Moreover, the data illustrated the synergistic effects of upregulated miR‑155 on fibrosis by gain‑of‑function and loss‑of‑function methods in hypoxic HK‑2 cells. Notably, the results also revealed that miR‑155 had the ability to modulate TGF‑β1 and the process of epithelial‑mesenchymal transition (EMT). In conclusion, this study not only demonstrated that hypoxia‑induced miR‑155 was a pro‑fibrotic cytokine which was positively regulated by HIF‑1α, but also revealed that miR‑155 promoted the fibrosis of proximal tubule cells by regulating both TGF‑β1 and the process of EMT under hypoxia.

View Figures

View References

1	Higgins DF, Kimura K, Bernhardt, et al: Hypoxia promotes fibrogenesis in vivo via HIF-1 stimulation of epithelial-to-mesen-chymal transition. J Clin Invest. 117:3810–3820. 2007.PubMed/NCBI
2	Wynn TA: Cellular and molecular mechanisms of fibrosis. J Pathol. 214:199–210. 2008. View Article : Google Scholar
3	Wynn TA: Common and unique mechanisms regulate fibrosis in various fibroproliferative diseases. J Clin Invest. 117:524–529. 2007. View Article : Google Scholar : PubMed/NCBI
4	Romano E, Manetti M, Guiducci S, Ceccarelli C, Allanore Y and Matucci-Cerinic M: The genetics of systemic sclerosis: an update. Clin Exp Rheumatol. 29:S75–S86. 2011.PubMed/NCBI
5	Zell S, Schmitt R, Witting S, Kreipe HH, Hussein K and Becker JU: Hypoxia Induces Mesenchymal Gene Expression in Renal Tubular Epithelial Cells: An in vitro Model of Kidney Transplant Fibrosis. Nephron Extra. 3:50–58. 2013. View Article : Google Scholar : PubMed/NCBI
6	Liu Y: Cellular and molecular mechanisms of renal fibrosis. Nat Rev Nephrol. 7:684–696. 2011. View Article : Google Scholar : PubMed/NCBI
7	Li Y, Sun Y, Liu F, et al: Norcantharidin inhibits renal interstitial fibrosis by blocking the tubular epithelial-mesenchymal transition. PLoS One. 8:e663562013. View Article : Google Scholar : PubMed/NCBI
8	Kalluri R and Neilson EG: Epithelial-mesenchymal transition and its implications for fibrosis. J Clin Invest. 112:1776–1784. 2003. View Article : Google Scholar : PubMed/NCBI
9	Kriz W, Kaissling B and Le Hir M: Epithelial-mesenchymal transition (EMT) in kidney fibrosis: fact or fantasy? J Clin Invest. 121:468–474. 2011. View Article : Google Scholar : PubMed/NCBI
10	Barnes JL and Glass WF II: Renal interstitial fibrosis: a critical evaluation of the origin of myofibroblasts. Contrib Nephrol. 169:73–93. 2011. View Article : Google Scholar : PubMed/NCBI
11	Liu Y: New insights into epithelial-mesenchymal transition in kidney fibrosis. J Am Soc Nephrol. 21:212–222. 2010. View Article : Google Scholar
12	Nisticò P, Bissell MJ and Radisky DC: Epithelial-mesenchymal transition: general principles and pathological relevance with special emphasis on the role of matrix metalloproteinases. Cold Spring Harb Perspect Biol. 4:a0119082012. View Article : Google Scholar : PubMed/NCBI
13	López-Hernández FJ and López-Novoa JM: Role of TGF-β in chronic kidney disease: an integration of tubular, glomerular and vascular effects. Cell Tissue Res. 347:141–154. 2012. View Article : Google Scholar
14	Tomasek JJ, Gabbiani G, Hinz B, Chaponnier C and Brown RA: Myofibroblasts and mechano-regulation of connective tissue remodelling. Nat Rev Mol Cell Biol. 3:349–363. 2002. View Article : Google Scholar : PubMed/NCBI
15	Berk BC, Fujiwara K and Lehoux S: ECM remodeling in hypertensive heart disease. J Clin Invest. 117:568–575. 2007. View Article : Google Scholar : PubMed/NCBI
16	Lewis BP, Burge CB and Bartel DP: Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell. 120:15–20. 2005. View Article : Google Scholar : PubMed/NCBI
17	Bartel DP: MicroRNAs: target recognition and regulatory functions. Cell. 136:215–233. 2009. View Article : Google Scholar : PubMed/NCBI
18	Filipowicz W, Bhattacharyya SN and Sonenberg N: Mechanisms of post-transcriptional regulation by microRNAs: are the answers in sight? Nat Rev Genet. 9:102–114. 2008. View Article : Google Scholar : PubMed/NCBI
19	Chau BN and Brenner DA: What goes up must come down: the emerging role of microRNA in fibrosis. Hepatology. 53:4–6. 2011. View Article : Google Scholar : PubMed/NCBI
20	Pinzani M, Rosselli M and Zuckermann M: Liver cirrhosis. Best Pract Res Clin Gastroenterol. 25:281–290. 2011. View Article : Google Scholar : PubMed/NCBI
21	Krenning G, Zeisberg EM and Kalluri R: The origin of fibroblasts and mechanism of cardiac fibrosis. J Cell Physiol. 225:631–637. 2010. View Article : Google Scholar : PubMed/NCBI
22	Wynn TA: Integrating mechanisms of pulmonary fibrosis. J Exp Med. 208:1339–1350. 2011. View Article : Google Scholar : PubMed/NCBI
23	Wang B, Koh P, Winbanks C, et al: miR-200a prevents renal fibrogenesis through repression of TGF-β2 expression. Diabetes. 60:280–287. 2011. View Article : Google Scholar :
24	Zhong X, Chung AC, Chen HY, Meng XM and Lan HY: Smad3-mediated upregulation of miR-21 promotes renal fibrosis. J Am Soc Nephrol. 22:1668–1681. 2011. View Article : Google Scholar : PubMed/NCBI
25	Kato M, Zhang J, Wang M, et al: MicroRNA-192 in diabetic kidney glomeruli and its function in TGF-β-induced collagen expression via inhibition of E-box repressors. Proc Natl Acad Sci USA. 104:3432–3437. 2007. View Article : Google Scholar
26	Neal CS, Michael MZ, Rawlings LH, Van der Hoek MB and Gleadle JM: The VHL-dependent regulation of microRNAs in renal cancer. BMC Med. 8:642010. View Article : Google Scholar : PubMed/NCBI
27	Wang H, Peng W, Shen X, Huang Y, Ouyang X and Dai Y: Circulating levels of inflammation-associated miR-155 and endothelial-enriched miR-126 in patients with end-stage renal disease. Braz J Med Biol Res. 45:1308–1314. 2012. View Article : Google Scholar : PubMed/NCBI
28	Anglicheau D, Sharma VK, Ding R, et al: MicroRNA expression profiles predictive of human renal allograft status. Proc Natl Acad Sci USA. 106:5330–5335. 2009. View Article : Google Scholar : PubMed/NCBI
29	Pottier N, Maurin T, Chevalier B, et al: Identification of keratinocyte growth factor as a target of microRNA-155 in lung fibroblasts: implication in epithelial-mesenchymal interactions. PLoS One. 4:e67182009. View Article : Google Scholar : PubMed/NCBI
30	Wang P, Hou J, Lin L, et al: Inducible microRNA-155 feedback promotes type I IFN signaling in antiviral innate immunity by targeting suppressor of cytokine signaling 1. J Immunol. 185:6226–6233. 2010. View Article : Google Scholar : PubMed/NCBI
31	Singh P, Ricksten SE, Bragadottir G, Redfors B and Nordquist L: Renal oxygenation and haemodynamics in acute kidney injury and chronic kidney disease. Clin Exp Pharmacol Physiol. 40:138–147. 2013. View Article : Google Scholar : PubMed/NCBI
32	Kishore R, Verma SK, Mackie AR, et al: Bone marrow progenitor cell therapy-mediated paracrine regulation of cardiac miRNA-155 modulates fibrotic response in diabetic hearts. PLoS One. 8:e601612013. View Article : Google Scholar : PubMed/NCBI
33	Harris AL: Hypoxia - a key regulatory factor in tumour growth. Nat Rev Cancer. 2:38–47. 2002. View Article : Google Scholar : PubMed/NCBI
34	Semenza GL: Hypoxia-inducible factors in physiology and medicine. Cell. 148:399–408. 2012. View Article : Google Scholar : PubMed/NCBI
35	Greer SN, Metcalf JL, Wang Y and Ohh M: The updated biology of hypoxia-inducible factor. EMBO J. 31:2448–2460. 2012. View Article : Google Scholar : PubMed/NCBI
36	Higgins DF, Kimura K, Iwano M and Haase VH: Hypoxia-inducible factor signaling in the development of tissue fibrosis. Cell Cycle. 7:1128–1132. 2008. View Article : Google Scholar : PubMed/NCBI
37	Bruning U, Cerone L, Neufeld Z, et al: MicroRNA-155 promotes resolution of hypoxia-inducible factor 1alpha activity during prolonged hypoxia. Mol Cell Biol. 31:4087–4096. 2011. View Article : Google Scholar : PubMed/NCBI
38	Czyzyk-Krzeska MF and Zhang X: MiR-155 at the heart of oncogenic pathways. Oncogene. 33:677–678. 2014. View Article : Google Scholar :
39	Hills CE and Squires PE: The role of TGF-beta and epithelial-to mesenchymal transition in diabetic nephropathy. Cytokine Growth Factor Rev. 22:131–139. 2011.PubMed/NCBI
40	Kage H and Borok Z: EMT and interstitial lung disease: a mysterious relationship. Curr Opin Pulm Med. 18:517–523. 2012.PubMed/NCBI