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Article

Hypoxia‑inducible adrenomedullin ameliorates the epithelial-to-mesenchymal transition in human proximal tubular epithelial cells

  • Authors:
    • Tiechui Zhu
    • Jun Yang
    • Xiangdong Liu
    • Lianyun Zhang
    • Jie  Zhang
    • Yongtao Wang
    • Haijun Ma
    • Zhenhui Ren
  • View Affiliations / Copyright

    Affiliations: Department of Nephrology, First Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan 453100, P.R. China
  • Pages: 3760-3766
    |
    Published online on: January 13, 2015
       https://doi.org/10.3892/mmr.2015.3189
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Abstract

Renal tubular epithelial cells can enter the epithelial‑to‑mesenchymal transition (EMT) in response to chronic hypoxia. EMT is a process which involves the phenotypic conversion of epithelial cells, that is believed to have an important role in renal fibrosis. However, the underlying mechanisms of the involvement of EMT in renal fibrosis remain to be elucidated. Adrenomedullin (AMD) has been implicated in renal fibrosis and is induced by hypoxia. The aims of the present study were to determine whether ADM signaling was active in human proximal tubular epithelial cells cultured under hypoxic conditions, and to observe the activity of ADM during EMT. The expression levels of ADM were significantly increased, in a time‑dependent manner, in HK‑2 and HKC human proximal tubular epithelial cells, cultured under hypoxic conditions. Overexpression of exogenous ADM was accompanied by increased expression levels of the epithelial markers E‑cadherin and tight junction protein‑1, and decreased expression levels of the mesenchymal markers vimentin and α‑smooth muscle actin, during hypoxia. Knock‑down of ADM expression by small hairpin RNA, or co‑administration of an ADM peptide inhibitor, in HK‑2 cells significantly exacerbated hypoxia‑induced EMT, as compared to the lack of effect observed in the untransfected controls. ADM was shown to suppress EMT by inhibiting the activation of extracellular signal‑regulated kinase (ERK), and this effect was prevented by the ERK activator apigenin. The results of the present study suggest that ADM has an important role in promoting EMT in hypoxic human proximal tubular epithelial cells. ADM may therefore represent a novel therapeutic target in the treatment of injured kidneys.
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1 

Klahr S and Morrissey J: Progression of chronic renal disease. Am J Kidney Dis. 41:S3–S7. 2003. View Article : Google Scholar : PubMed/NCBI

2 

Owen WF Jr: Patterns of care for patients with chronic kidney disease in the United States: dying for improvement. J Am Soc Nephrol. 14:S76–S80. 2003. View Article : Google Scholar : PubMed/NCBI

3 

Coresh J, Selvin E, Stevens LA, et al: Prevalence of chronic kidney disease in the United States. JAMA. 298:2038–2047. 2007. View Article : Google Scholar : PubMed/NCBI

4 

Centers for Disease Control and Prevention. Prevalence of chronic kidney disease and associated risk factors - United States, 1999–2004. MMWR Morb Mortal Wkly Rep. 56:161–165. 2007.

5 

Liu Y: Renal fibrosis: new insights into the pathogenesis and therapeutics. Kidney Int. 69:213–217. 2006. View Article : Google Scholar : PubMed/NCBI

6 

Strutz F and Zeisberg M: Renal fibroblasts and myofibroblasts in chronic kidney disease. J Am Soc Nephrol. 17:2992–2998. 2006. View Article : Google Scholar : PubMed/NCBI

7 

Nath KA: Tubulointerstitial changes as a major determinant in the progression of renal damage. Am J Kidney Dis. 20:1–17. 1992. View Article : Google Scholar : PubMed/NCBI

8 

Nangaku M: Chronic hypoxia and tubulointerstitial injury: a final common pathway to end-stage renal failure. J Am Soc Nephrol. 17:17–25. 2006. View Article : Google Scholar

9 

Nangaku M and Eckardt KU: Hypoxia and the HIF system in kidney disease. J Mol Med (Berl). 85:1325–1330. 2007. View Article : Google Scholar

10 

Zeisberg M and Kalluri R: The role of epithelial-to-mesenchymal transition in renal fibrosis. J Mol Med (Berl). 82:175–181. 2004. View Article : Google Scholar

11 

Manotham K, Tanaka T, Matsumoto M, et al: Transdifferentiation of cultured tubular cells induced by hypoxia. Kidney Int. 65:871–880. 2004. View Article : Google Scholar : PubMed/NCBI

12 

Higgins DF, Kimura K, Bernhardt WM, et al: Hypoxia promotes fibrogenesis in vivo via HIF-1 stimulation of epithelial-to-mesenchymal transition. J Clin Invest. 117:3810–3820. 2007.PubMed/NCBI

13 

Sun S, Ning X, Zhang Y, et al: Hypoxia-inducible factor-1alpha induces Twist expression in tubular epithelial cells subjected to hypoxia, leading to epithelial-to-mesenchymal transition. Kidney Int. 75:1278–1287. 2009. View Article : Google Scholar : PubMed/NCBI

14 

Kitamura K, Kangawa K, Kawamoto M, et al: Adrenomedullin: a novel hypotensive peptide isolated from human pheochromocytoma. Biochem Biophys Res Commun. 192:553–560. 1993. View Article : Google Scholar : PubMed/NCBI

15 

Hinson JP, Kapas S and Smith DM: Adrenomedullin, a multifunctional regulatory peptide. Endocr Rev. 21:138–167. 2000.PubMed/NCBI

16 

Chen L, Qiu JH, Zhang LL and Luo XD: Adrenomedullin promotes human endothelial cell proliferation via HIF-1α. Mol Cell Biochem. 365:263–273. 2012. View Article : Google Scholar : PubMed/NCBI

17 

Eto Y, Shimosawa T, Nitta K, Nihei H and Maruyama N: Interaction between adrenomedullin and angiotensin II in DNA synthesis and extracellular matrix accumulation in cultured rat kidney interstitial cells. Clin Exp Nephrol. 6:7–12. 2002. View Article : Google Scholar

18 

Nagae T, Mori K, Mukoyama M, et al: Adrenomedullin inhibits connective tissue growth factor expression, extracellular signal-regulated kinase activation and renal fibrosis. Kidney Int. 74:70–80. 2008. View Article : Google Scholar : PubMed/NCBI

19 

Norman JT, Clark IM and Garcia PL: Hypoxia promotes fibrogenesis in human renal fibroblasts. Kidney Int. 58:2351–2366. 2000. View Article : Google Scholar : PubMed/NCBI

20 

Leonard MO, Cottell DC, Godson C, Brady HR and Taylor CT: The role of HIF-1 alpha in transcriptional regulation of the proximal tubular epithelial cell response to hypoxia. J Biol Chem. 278:40296–40304. 2003. View Article : Google Scholar : PubMed/NCBI

21 

Rudnicki M, Eder S, Perco P, et al: Gene expression profiles of human proximal tubular epithelial cells in proteinuric nephropathies. Kidney Int. 71:325–335. 2007. View Article : Google Scholar

22 

Wang S, de Caestecker M, Kopp J, Mitu G, Lapage J and Hirschberg R: Renal bone morphogenetic protein-7 protects against diabetic nephropathy. J Am Soc Nephrol. 17:2504–2512. 2006. View Article : Google Scholar : PubMed/NCBI

23 

Ogita T, Hashimoto E, Yamasaki M, et al: Hypoxic induction of adrenomedullin in cultured human umbilical vein endothelial cells. J Hypertens. 19:603–608. 2001. View Article : Google Scholar : PubMed/NCBI

24 

Oehler MK, Norbury C, Hague S, Rees MC and Bicknell R: Adrenomedullin inhibits hypoxic cell death by upregulation of Bcl-2 in endometrial cancer cells: a possible promotion mechanism for tumour growth. Oncogene. 20:2937–2945. 2001. View Article : Google Scholar : PubMed/NCBI

25 

Nguyen SV and Claycomb WC: Hypoxia regulates the expression of the adrenomedullin and HIF-1 genes in cultured HL-1 cardiomyocytes. Biochem Biophys Res Commun. 265:382–386. 1999. View Article : Google Scholar : PubMed/NCBI

26 

Rudnicki M, Perco P, Enrich J, et al: Hypoxia response and VEGF-A expression in human proximal tubular epithelial cells in stable and progressive renal disease. Lab Invest. 89:337–346. 2009. View Article : Google Scholar : PubMed/NCBI

27 

Sato K, Imai T, Iwashina M, Marumo F and Hirata Y: Secretion of adrenomedullin by renal tubular cell lines. Nephron. 78:9–14. 1998. View Article : Google Scholar : PubMed/NCBI

28 

Shah KG, Rajan D, Jacob A, et al: Attenuation of renal ischemia and reperfusion injury by human adrenomedullin and its binding protein. J Surg Res. 163:110–117. 2010. View Article : Google Scholar : PubMed/NCBI

29 

Zavadil J, Bitzer M, Liang D, et al: Genetic programs of epithelial cell plasticity directed by transforming growth factor-beta. Proc Natl Acad Sci USA. 98:6686–6691. 2001. View Article : Google Scholar : PubMed/NCBI

30 

Jechlinger M, Grunert S, Tamir IH, et al: Expression profiling of epithelial plasticity in tumor progression. Oncogene. 22:7155–7169. 2003. View Article : Google Scholar : PubMed/NCBI

31 

Bajpai S, Feng Y, Wirtz D and Longmore GD: β-Catenin serves as a clutch between low and high intercellular E-cadherin bond strengths. Biophys J. 105:2289–2300. 2013. View Article : Google Scholar : PubMed/NCBI

32 

Horster MF, Braun GS and Huber SM: Embryonic renal epithelia: induction, nephrogenesis, and cell differentiation. Physiol Rev. 79:1157–1191. 1999.PubMed/NCBI

33 

Zeisberg M, Hanai J, Sugimoto H, et al: BMP-7 counteracts TGF-beta1-induced epithelial-to-mesenchymal transition and reverses chronic renal injury. Nat Med. 9:964–968. 2003. View Article : Google Scholar : PubMed/NCBI

34 

Okada H, Danoff TM, Kalluri R and Neilson EG: Early role of Fsp1 in epithelial-mesenchymal transformation. Am J Physiol. 273:F563–F574. 1997.PubMed/NCBI

35 

Yang J and Liu Y: Dissection of key events in tubular epithelial to myofibroblast transition and its implications in renal interstitial fibrosis. Am J Pathol. 159:1465–1475. 2001. View Article : Google Scholar : PubMed/NCBI

36 

Strutz F, Zeisberg M, Ziyadeh FN, et al: Role of basic fibroblast growth factor-2 in epithelial-mesenchymal transformation. Kidney Int. 61:1714–1728. 2002. View Article : Google Scholar : PubMed/NCBI

37 

Keller C, Kroening S, Zuehlke J, Kunath F, Krueger B and Goppelt-Struebe M: Distinct mesenchymal alterations in N-cadherin and E-cadherin positive primary renal epithelial cells. PLoS One. 7(8): e435842012. View Article : Google Scholar : PubMed/NCBI

38 

Grewal JS, Mukhin YV, Garnovskaya MN, Raymond JR and Greene EL: Serotonin 5-HT2A receptor induces TGF-beta1 expression in mesangial cells via ERK: proliferative and fibrotic signals. Am J Physiol. 276:F922–F930. 1999.PubMed/NCBI

39 

Pat B, Yang T, Kong C, Watters D, Johnson DW and Gobe G: Activation of ERK in renal fibrosis after unilateral ureteral obstruction: modulation by antioxidants. Kidney In. 67:931–943. 2005. View Article : Google Scholar

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Copy and paste a formatted citation
Spandidos Publications style
Zhu T, Yang J, Liu X, Zhang L, Zhang J, Wang Y, Ma H and Ren Z: Hypoxia‑inducible adrenomedullin ameliorates the epithelial-to-mesenchymal transition in human proximal tubular epithelial cells. Mol Med Rep 11: 3760-3766, 2015.
APA
Zhu, T., Yang, J., Liu, X., Zhang, L., Zhang, J., Wang, Y. ... Ren, Z. (2015). Hypoxia‑inducible adrenomedullin ameliorates the epithelial-to-mesenchymal transition in human proximal tubular epithelial cells. Molecular Medicine Reports, 11, 3760-3766. https://doi.org/10.3892/mmr.2015.3189
MLA
Zhu, T., Yang, J., Liu, X., Zhang, L., Zhang, J., Wang, Y., Ma, H., Ren, Z."Hypoxia‑inducible adrenomedullin ameliorates the epithelial-to-mesenchymal transition in human proximal tubular epithelial cells". Molecular Medicine Reports 11.5 (2015): 3760-3766.
Chicago
Zhu, T., Yang, J., Liu, X., Zhang, L., Zhang, J., Wang, Y., Ma, H., Ren, Z."Hypoxia‑inducible adrenomedullin ameliorates the epithelial-to-mesenchymal transition in human proximal tubular epithelial cells". Molecular Medicine Reports 11, no. 5 (2015): 3760-3766. https://doi.org/10.3892/mmr.2015.3189
Copy and paste a formatted citation
x
Spandidos Publications style
Zhu T, Yang J, Liu X, Zhang L, Zhang J, Wang Y, Ma H and Ren Z: Hypoxia‑inducible adrenomedullin ameliorates the epithelial-to-mesenchymal transition in human proximal tubular epithelial cells. Mol Med Rep 11: 3760-3766, 2015.
APA
Zhu, T., Yang, J., Liu, X., Zhang, L., Zhang, J., Wang, Y. ... Ren, Z. (2015). Hypoxia‑inducible adrenomedullin ameliorates the epithelial-to-mesenchymal transition in human proximal tubular epithelial cells. Molecular Medicine Reports, 11, 3760-3766. https://doi.org/10.3892/mmr.2015.3189
MLA
Zhu, T., Yang, J., Liu, X., Zhang, L., Zhang, J., Wang, Y., Ma, H., Ren, Z."Hypoxia‑inducible adrenomedullin ameliorates the epithelial-to-mesenchymal transition in human proximal tubular epithelial cells". Molecular Medicine Reports 11.5 (2015): 3760-3766.
Chicago
Zhu, T., Yang, J., Liu, X., Zhang, L., Zhang, J., Wang, Y., Ma, H., Ren, Z."Hypoxia‑inducible adrenomedullin ameliorates the epithelial-to-mesenchymal transition in human proximal tubular epithelial cells". Molecular Medicine Reports 11, no. 5 (2015): 3760-3766. https://doi.org/10.3892/mmr.2015.3189
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