Skip to main content
SpringerLink
Log in

AngiotensinII induces HuR shuttling by post-transcriptional regulated CyclinD1 in human mesangial cells

  • Published:
Molecular Biology Reports Aims and scope Submit manuscript

    We’re sorry, something doesn't seem to be working properly.

    Please try refreshing the page. If that doesn't work, please contact support so we can address the problem.

Abstract

Abnormal proliferation of human mesangial cells was the earliest pathological character in chronic kidney disease and linked to the accumulation of extracellular matrix and glomerular sclerosis. Multifunctional Angiotensin (AngII) had been emerged as a key player in initiation and progression of fibrogenic processes in kidney. In mesangial cells, treatment with the proliferation stimulus AngII triggered the escalated cyclinD1 expression, where its association with HuR increased dramatically. In our study, it was demonstrated that both in vivo and in vitro HuR redistribution in dysregulated mesangial cell proliferation accompanied by an abundant cyclinD1 expression following the AngII treatment. ActinomycinD experiments revealed that AngII stabilized cyclinD1 mRNA in human mesangial cells via HuR. Furthermore, employing the RIP-Chip assay yielded cyclinD1 mRNA with a higher affinity to HuR in mesangial cells induced by AngII compared with the normal ones in vitro study. Analysis of a cyclinD1 mRNA directly implicated HuR in regulating cyclinD1 production: cyclinD1 translation increased in HuR-shuttling cells induced by AngII and declined in cells in which HuR levels were lowered by RNA interference. We proposed that the release of HuR-bound mRNAs via an AngII–cyclinD1–HuR regulatory axis was implicated in the evolution of proliferative kidney diseases, providing us a novel therapeutic strategy to treat glomerular disease.

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
Fig. 6

Similar content being viewed by others

References

  1. Schlöndorff D, Banas B (2009) The mesangial cell revisited: no cell is an island. J Am Soc Nephrol 20:1179–1187

    Article  PubMed  Google Scholar 

  2. Abboud H (2012) Mesangial cell biology. Exp Cell Res 318:979–985

    Article  CAS  PubMed  Google Scholar 

  3. Rüster C, Wolf G (2006) Renin–angiotensin–aldosterone system and progression of renal disease. J Am Soc Nephrol 17:2985–2991

    Article  PubMed  Google Scholar 

  4. Turner J, Bauer C, Abramowitz M, Melamed M, Hostetter T (2012) Treatment of chronic kidney disease. Kidney Int 81:351–362

    Article  CAS  PubMed  Google Scholar 

  5. Boffa J, Lu Y, Placier S, Stefanski A, Dussaule J et al (2003) Regression of renal vascular and glomerular fibrosis: role of angiotensin II receptor antagonism and matrix metalloproteinases. J Am Soc Nephrol 14:1132–1144

    Article  CAS  PubMed  Google Scholar 

  6. Wolf G, Wenzel U (2004) Angiotensin II and cell cycle regulation. Hypertension 43:693–698

    Article  CAS  PubMed  Google Scholar 

  7. Watanabe G, Lee R, Albanese C, Rainey W, Batlle D et al (1996) Angiotensin II activation of cyclin D1-dependent kinase activity. J Biol Chem 271:22570–22577

    Article  CAS  PubMed  Google Scholar 

  8. Lang S, Hartner A, Sterzel R, Schöcklmann H (2000) Requirement of cyclin D1 in mesangial cell mitogenesis. J Am Soc Nephrol 11:1398–1408

    CAS  PubMed  Google Scholar 

  9. Hong Q, Li C, Xie Y, Lv Y, Liu X et al (2012) Kruppel-like factor-15 inhibits the proliferation of mesangial cells. Cell Physiol Biochem 29:893–904

    Article  CAS  PubMed  Google Scholar 

  10. Keene J (2007) RNA regulons: coordination of post-transcriptional events. Nat Rev Genet 8:533–543

    Article  CAS  PubMed  Google Scholar 

  11. Anderson P (2008) Post-transcriptional control of cytokine production. Nat Immunol 9:353–359

    Article  CAS  PubMed  Google Scholar 

  12. Abdelmohsen K, Gorospe M (2010) Posttranscriptional regulation of cancer traits by HuR. Wiley Interdiscip Rev RNA 1:214–229

    Article  CAS  PubMed  Google Scholar 

  13. Masuda K, Abdelmohsen K, Kim M et al (2011) Global dissociation of HuR–mRNA complexes promotes cell survival after ionizing radiation. EMBO J 30:1040–1053

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Mazan-Mamczarz K, Hagner P, Corl S et al (2008) Post-transcriptional gene regulation by HuR promotes a more tumorigenic phenotype. Global changes in HuR-bound mRNAs and tumor progression. Oncogene 27:6151–6163

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Nowotarski S, Shantz L (2010) Cytoplasmic accumulation of the RNA-binding protein HuR stabilizes the ornithine decarboxylase transcript in a murine nonmelanoma skin cancer model. J Biol Chem 285:31885–31894

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Woo H, Zhou Y, Yi X et al (2009) Regulation of non-AU-rich element containing c-fms proto-oncogene expression by HuR in breast cancer. Oncogene 28:1176–1186

    Article  CAS  PubMed  Google Scholar 

  17. Erkinheimo T, Lassus H, Sivula A et al (2003) Cytoplasmic HuR expression correlates with poor outcome and with cyclooxygenase 2 expression in serous ovarian carcinoma. Cancer Res 63:7591–7594

    CAS  PubMed  Google Scholar 

  18. Lal A, Mazan-Mamczarz K, Kawai T, Yang X, Martindale J et al (2004) Concurrent versus individual binding of HuR and AUF1 to common labile target mRNAs. EMBO J 23:3092–3102

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Doller A, Schlepckow K, Schwalbe H, Pfeilschifter J, Eberhardt W (2010) Tandem phosphorylation of serines 221 and 318 by protein kinase Cδ coordinates mRNA binding and nucleocytoplasmic shuttling of HuR. Mol Cell Biol 30:1397–1410

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Huwiler A, Akool S, Aschrafi A, Hamada F, Pfeilschifter J et al (2003) ATP potentiates interleukin-1 beta-induced MMP-9 expression in mesangial cells via recruitment of the ELAV protein HuR. J Biol Chem 278:51758–51769

    Article  CAS  PubMed  Google Scholar 

  21. Doller A, Gauer S, Sobkowiak E, Geiger H, Pfeilschifter J et al (2009) Angiotensin II induces renal plasminogen activator inhibitor-1 and cyclooxygenase-2 expression post-transcriptionally via activation of the mRNA-stabilizing factor human-antigen R. Am J Pathol 174:1252–1263

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Akhtar J, Wang Z, Zhang ZP, Bi MM (2013) Lentiviral-mediated RNA interference targeting stathmin1 gene in human gastric cancer cells inhibits proliferation in vitro and tumor growth in vivo. J Transl Med 11:212

    Article  PubMed  PubMed Central  Google Scholar 

  23. Zhang P, Cao M, Liu Y, Lv Z, Yang Q et al (2012) PDGF-induced airway smooth muscle proliferation is associated with human antigen R activation and could be weakened by AMPK activation. Mol Biol Rep 39:5819–5829

    Article  CAS  PubMed  Google Scholar 

  24. Ma W, Cheng S, Campbell C, Wright A, Furneaux H (1996) Cloning and characterization of HuR, a ubiquitously expressed Elav-like protein. J Biol Chem 271:8144–8151

    Article  CAS  PubMed  Google Scholar 

  25. Khabar K (2005) The AU-rich transcriptome: more than interferons and cytokines, and its role in disease. J Interferon Cytokine Res 25:1–10

    Article  CAS  PubMed  Google Scholar 

  26. Cok S, Acton S, Morrison A (2003) The proximal region of the 3′-untranslated region of cyclooxygenase-2 is recognized by a multimeric protein complex containing HuR, TIA-1, TIAR, and the heterogeneous nuclear ribonucleoprotein U. J Biol Chem 278:36157–36162

    Article  CAS  PubMed  Google Scholar 

  27. Doller A, Huwiler A, Müller R, Radeke H, Pfeilschifter J et al (2007) Protein kinase C alpha-dependent phosphorylation of the mRNA-stabilizing factor HuR: implications for posttranscriptional regulation of cyclooxygenase-2. Mol Biol Cell 18:2137–2148

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Breving K, Esquela-Kerscher A (2010) The complexities of microRNA regulation: mirandering around the rules. Int J Biochem Cell Biol 42:1316–1329

    Article  CAS  PubMed  Google Scholar 

  29. Moore M (2005) From birth to death: the complex lives of eukaryotic mRNAs. Science 309:1514–1518

    Article  CAS  PubMed  Google Scholar 

  30. Qian Y, Feldman E, Pennathur S et al (2008) From fibrosis to sclerosis: mechanisms of glomerulosclerosis in diabetic nephropathy. Diabetes 57:1439–1445

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Jefferson J, Shankland S, Pichler R (2008) Proteinuria in diabetic kidney disease: a mechanistic viewpoint. Kidney Int 74:22–36

    Article  CAS  PubMed  Google Scholar 

  32. Navarro-González J, Mora-Fernández C, Fuentes MMd, García-Pérez J (2011) Inflammatory molecules and pathways in the pathogenesis of diabetic nephropathy. Nat Rev Nephrol 7:327–340

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

All authors contributed to the scientific conduct of the study, data review and analysis, and manuscript preparation and review. Financial supported by the National Natural Science Foundation of China (Grant 30971381) and Shandong Natural Science Foundation (ZR2009CM043).

Author information

Authors and Affiliations

  1. Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong University, Jingwu Road No. 324, Jinan City, 250021, Shandong, People’s Republic of China

    Yu Che, Chen Bing, Zhang Ruiyu, Wan Qiang & Wang Rong

  2. Department of Respiratory Medicine, Shandong Provincial Hospital Affiliated to Shandong University, Jinan City, 250021, Shandong, People’s Republic of China

    Liu Yi

  3. Department of Thoracic Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan City, 250021, Shandong, People’s Republic of China

    Javed Akhtar

Authors
  1. Yu Che
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Liu Yi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Javed Akhtar
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Chen Bing
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Zhang Ruiyu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Wan Qiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Wang Rong
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Wan Qiang or Wang Rong.

Additional information

Yu Che and Liu Yi contributed equally to this research.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Che, Y., Yi, L., Akhtar, J. et al. AngiotensinII induces HuR shuttling by post-transcriptional regulated CyclinD1 in human mesangial cells. Mol Biol Rep 41, 1141–1150 (2014). https://doi.org/10.1007/s11033-013-2960-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11033-013-2960-1

Keywords

Search

Navigation