Skip to main content

Advertisement

SpringerLink
Log in

MiR-194 targets Runx1/Akt pathway to reduce renal fibrosis in mice with unilateral ureteral obstruction

  • Nephrology - Original Paper
  • Published:
International Urology and Nephrology Aims and scope Submit manuscript

Abstract

Purpose

Chronic kidney disease (CKD) has become a global public health problem and accompanied by renal fibrosis. MiR-194, a tumor suppressor gene, has been previously reported to be associated with the pathogenesis of tissue fibrosis. However, the role of miR-194 in the pathogenesis of renal fibrosis remains unknown.

Methods

A renal fibrosis model was constructed by unilateral ureteral obstruction (UUO) in male C57BL/6 mice. HE and MASSON stainings were used for histological analysis. The expression level of miR-194 was detected by RT-qPCR. The protein expression was detected by western blotting. The levels of inflammatory cytokines were detected by ELISA. The relationship between miR-194 and Runx1 was further verified by dual luciferase reporter assay.

Results

The results showed that miR-194 level was downregulated in kidney tissue of UUO mice, accompanied by significantly pathological damage and renal fibrosis. MiR-194 mimics significantly reduced pathological damage and alleviated renal fibrosis that caused by UOO, and inhibited the expression levels of α-SMA and collagen I. In addition, miR-194 mimics also reduced the expression level of serum inflammatory factors. Moreover, in vitro analysis indicated that Runx1 was a downstream target gene of miR-194. Furthermore, mechanism analysis indicated that miR-194 reduced mouse renal fibrosis by inhibiting the Runx1/AKT pathway in vivo and in vitro.

Conclusion

The present findings suggested that miR-194 targets Runx1/Akt pathway to reduce renal fibrosis in UOO-induced mice. This study provides a novel strategy for the prevention and treatment of renal fibrosis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Abbreviations

CKD:

Chronic kidney disease

UUO:

Unilateral ureteral obstruction

References

  1. Campanholle G, Ligresti G, Gharib SA, Duffield JS (2013) Cellular mechanisms of tissue fibrosis. 3. Novel mechanisms of kidney fibrosis. Am J Physiol Cell Physiol 304(7):591–603. https://doi.org/10.1152/ajpcell.00414.2012

    Article  Google Scholar 

  2. Zhou T, Li X, Zou J, Cai M, Sun G, Zhang Y, Zhao Y, Zhang M, Zhang Y, Chen N (2009) Effects of DC-SIGN expression on renal tubulointerstitial fibrosis in nephritis. Front Biosci (Landmark edition) 14:3814–3824

    Article  Google Scholar 

  3. Venkatachalam MA, Weinberg JM, Kriz W, Bidani AK (2015) Failed tubule recovery, AKI-CKD transition, and kidney disease progression. J Am Soc Nephrol 26(8):1765–1776. https://doi.org/10.1681/asn.2015010006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Ye Y, Zhang F, Chen Q, Huang Z, Li M (2019) LncRNA MALAT1 modified progression of clear cell kidney carcinoma (KIRC) by regulation of miR-194-5p/ACVR2B signaling. Mol Carcinog 58(2):279–292. https://doi.org/10.1002/mc.22926

    Article  CAS  PubMed  Google Scholar 

  5. Miao J, Liu J, Niu J, Zhang Y, Shen W, Luo C, Liu Y, Li C, Li H, Yang P, Liu Y, Hou FF, Zhou L (2019) Wnt/beta-catenin/RAS signaling mediates age-related renal fibrosis and is associated with mitochondrial dysfunction.e13004. 10.1111/acel.13004

  6. Ramirez-Moya J, Santisteban P (2019) miRNA-directed regulation of the main signaling pathways in thyroid cancer. Front Endocrinol (Lausanne) 10:430. https://doi.org/10.3389/fendo.2019.00430

    Article  Google Scholar 

  7. Hu Y, Liu Q, Zhang M, Yan Y, Yu H, Ge L (2019) MicroRNA-362-3p attenuates motor deficit following spinal cord injury via targeting paired box gene 2. J Integrat Neurosci 18(1):57–64. https://doi.org/10.31083/j.jin.2019.01.12

    Article  Google Scholar 

  8. Lokeshwar SD, Talukder A, Yates TJ, Hennig MJP, Garcia-Roig M, Lahorewala SS, Mullani NN, Klaassen Z, Kava BR, Manoharan M, Soloway MS, Lokeshwar VB (2018) Molecular characterization of renal cell carcinoma: a potential three-microrna prognostic signature. Cancer Epidem Biomarkers Preven 27(4):464–472. https://doi.org/10.1158/1055-9965.epi-17-0700

    Article  CAS  Google Scholar 

  9. Xu Z, Guo B (2019) The differential expression of miRNAs and a preliminary study on the mechanism of miR-194–3p in Keloids. 10.1155/2019/8214923

  10. Lin F, Wu X, Zhang H, You X, Zhang Z, Shao R, Huang C (2015) A microrna screen to identify regulators of peritoneal fibrosis in a rat model of peritoneal dialysis. BMC Nephrol 16:48. https://doi.org/10.1186/s12882-015-0039-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Shen Y, Zhao Y, Wang L, Zhang W, Liu C, Yin A (2018) MicroRNA-194 overexpression protects against hypoxia/reperfusion-induced HK-2 cell injury through direct targeting Rheb. J Cell Biochem. https://doi.org/10.1002/jcb.28114

    Article  PubMed  PubMed Central  Google Scholar 

  12. Zhong X, Wu Y, Liu Y, Zhu F, Li X, Li D, Li Z, Zeng L, Qiao J, Chen X, Xu K (2016) Increased RUNX1 expression in patients with immune thrombocytopenia. Hum Immunol 77(8):687–691. https://doi.org/10.1016/j.humimm.2016.06.004

    Article  CAS  PubMed  Google Scholar 

  13. Sakurai M, Kunimoto H, Watanabe N, Fukuchi Y, Yuasa S, Yamazaki S, Nishimura T, Sadahira K, Fukuda K, Okano H, Nakauchi H, Morita Y, Matsumura I, Kudo K, Ito E, Ebihara Y, Tsuji K, Harada Y, Harada H, Okamoto S, Nakajima H (2014) Impaired hematopoietic differentiation of RUNX1-mutated induced pluripotent stem cells derived from FPD/AML patients. Leukemia 28(12):2344–2354. https://doi.org/10.1038/leu.2014.136

    Article  CAS  PubMed  Google Scholar 

  14. Luo MC, Zhou SY, Feng DY, Xiao J, Li WY, Xu CD, Wang HY, Zhou T (2016) Runt-related transcription factor 1 (RUNX1) binds to p50 in macrophages and enhances TLR4-triggered inflammation and septic shock. J Biolog Chem 291(42):22011–22020. https://doi.org/10.1074/jbc.M116.715953

    Article  CAS  Google Scholar 

  15. Lappas M (2018) Runt-related transcription factor 1 (RUNX1) deficiency attenuates inflammation-induced pro-inflammatory and pro-labour mediators in myometrium. Mol Cell Endocrinol 473:61–71. https://doi.org/10.1016/j.mce.2018.01.003

    Article  CAS  PubMed  Google Scholar 

  16. Scheitz CJ, Lee TS, McDermitt DJ, Tumbar T (2012) Defining a tissue stem cell-driven Runx1/Stat3 signalling axis in epithelial cancer. EMBO J 31(21):4124–4139. https://doi.org/10.1038/emboj.2012.270

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Zhou T, Luo M, Cai W, Zhou S, Feng D, Xu C, Wang H (2018) Runt-related transcription factor 1 (RUNX1) promotes TGF-beta-induced renal tubular epithelial-to-mesenchymal transition (EMT) and renal fibrosis through the PI3K subunit p110delta. EBioMedicine 31:217–225. https://doi.org/10.1016/j.ebiom.2018.04.023

    Article  PubMed  PubMed Central  Google Scholar 

  18. Gu X, Mallipattu SK, Guo Y, Revelo MP, Pace J, Miller T, Gao X, Jain MK, Bialkowska AB, Yang VW, He JC, Mei C (2017) The loss of Kruppel-like factor 15 in Foxd1(+) stromal cells exacerbates kidney fibrosis. Kidney Int 92(5):1178–1193. https://doi.org/10.1016/j.kint.2017.03.037

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Zhang B, Liu P, Zhou Y, Chen Z, He Y, Mo M, Dai G, Xia W, Du Y, Liu Y, Chen X (2019) Dihydroartemisinin attenuates renal fibrosis through regulation of fibroblast proliferation and differentiation. Life Sci 223:29–37. https://doi.org/10.1016/j.lfs.2019.03.020

    Article  CAS  PubMed  Google Scholar 

  20. Nogueira A, Pires MJ, Oliveira PA (2017) Pathophysiological mechanisms of renal fibrosis: a review of animal models and therapeutic strategies. vivo (Athens, Greece) 31(1):1–22. https://doi.org/10.21873/invivo.11019

    Article  CAS  Google Scholar 

  21. Yang L, Yuan H, Yu Y, Yu N, Ling L, Niu J, Gu Y (2019) Epidermal growth factor receptor mimotope alleviates renal fibrosis in murine unilateral ureteral obstruction model. Clin Immun (Orlando, Fla) 205:57–64. https://doi.org/10.1016/j.clim.2019.05.014

    Article  CAS  Google Scholar 

  22. Chen B (2019) The miRNA-184 drives renal fibrosis by targeting HIF1AN in vitro and in vivo. Int Urol Nephrol 51(3):543–550. https://doi.org/10.1007/s11255-018-2025-4

    Article  CAS  PubMed  Google Scholar 

  23. Rudnicki M, Perco P, B DH, Leierer J, Heinzel A, Muhlberger I, Schweibert N, Sunzenauer J, Regele H, Kronbichler A (2016) Renal microRNA- and RNA-profiles in progressive chronic kidney disease. 46 (3):213–226. 10.1111/eci.12585

  24. Li J, Kong X, Jiang S, Liao W, Zhang Z, Song J, Liang Y, Zhang W (2019) miR-627/HMGB1/NF-kappaB regulatory loop modulates TGF-beta1-induced pulmonary fibrosis. J Cell Biochem 120(3):2983–2993. https://doi.org/10.1002/jcb.27038

    Article  CAS  PubMed  Google Scholar 

  25. Meng XM, Nikolic-Paterson DJ, Lan HY (2014) Inflammatory processes in renal fibrosis. Nature Rev Nephrol 10(9):493–503. https://doi.org/10.1038/nrneph.2014.114

    Article  CAS  Google Scholar 

  26. Luo X, Ding L, Xu J, Chegini N (2005) Gene expression profiling of leiomyoma and myometrial smooth muscle cells in response to transforming growth factor-beta. Endocrinology 146(3):1097–1118. https://doi.org/10.1210/en.2004-1377

    Article  CAS  PubMed  Google Scholar 

  27. Marcher A-B, Bendixen SM, Terkelsen MK, Hohmann SS, Hansen MH, Larsen BD, Mandrup S, Dimke H, Detlefsen S, Ravnskjaer K (2019) Transcriptional regulation of Hepatic Stellate Cell activation in NASH. Sci Rep 9(1):2324–2324. https://doi.org/10.1038/s41598-019-39112-6

    Article  PubMed  PubMed Central  Google Scholar 

  28. Kim W, Barron DA, San Martin R, Chan KS, Tran LL, Yang F, Ressler SJ, Rowley DR (2014) RUNX1 is essential for mesenchymal stem cell proliferation and myofibroblast differentiation. Proc Natl Acad Sci USA 111(46):16389–16394. https://doi.org/10.1073/pnas.1407097111

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

Not applicable.

Author information

Authors and Affiliations

  1. Department of Nephrology, Hubei Province, Wuhan No. 1 Hospital, 215# Zhongshan Avenue, Wuhan, 430022, China

    Li Cheng, Can Tu, Yonglong Min, Da He, Sheng Wan & Fei Xiong

Authors
  1. Li Cheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Can Tu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yonglong Min
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Da He
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Sheng Wan
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Fei Xiong
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

LC and FX conceived and designed the experiments, CT and YLM analyzed and interpreted the results of the experiments, DH and SW performed the experiments

Corresponding author

Correspondence to Fei Xiong.

Ethics declarations

Conflict of interest

The authors declare that they have no competing interests, and all authors confirm its accuracy.

Ethics approval

The animal use protocol listed below has been reviewed and approved by the Animal Ethical and Welfaer Committee. Approval No. 2019–802.

Availability of data and materials

All data generated or analyzed during this study are included in this published article.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Cheng, L., Tu, C., Min, Y. et al. MiR-194 targets Runx1/Akt pathway to reduce renal fibrosis in mice with unilateral ureteral obstruction. Int Urol Nephrol 52, 1801–1808 (2020). https://doi.org/10.1007/s11255-020-02544-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11255-020-02544-5

Keywords

Search

Navigation