Skip to main content

Advertisement

SpringerLink
Log in

Prohibitin suppresses renal interstitial fibroblasts proliferation and phenotypic change induced by transforming growth factor-β1

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

Prohibitin (PHB), a potential tumor suppressor, has been shown to inhibit cell proliferation by repressing E2F-mediated transcription. But little is known about the role of PHB involved in tubulointerstitial fibrosis (TIF). Here, for the first time, we found PHB protein was positively expressed at normal renal tissues, strongly down-regulated in renal biopsy specimens, and negatively correlated with the expression of alpha-smooth-muscle actin (α-SMA) and with the degrees of tubulointerstitial lesions. Transforming growth factor-β1 (TGF-β1) is the most important profibrotic cytokine in the process of TIF and capable of inducing cell phenotypic change of interstitial fibroblasts characterized by the de novo expression of α-SMA. Confocal microscopy showed majority of PHB is located at cytoplasm as well as at nucleus in rat kidney fibroblasts cell (NRK-49F). As we found that PHB protein and mRNA expression were down-regulated in NRK-49F cells following TGF-β1 stimulation. We used transient transfection to over-express PHB protein and found that cells with increased PHB levels had a significant reduction in the percentage entering cell cycle and abolished de novo expression of α-SMA following TGF-β1 stimulation. Therefore, over-expression of PHB suppresses renal interstitial fibroblasts proliferation and cell phenotypic change induced by TGF-β1, which indicates PHB as a potential therapeutic target to halt the progression of TIF.

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

Similar content being viewed by others

References

  1. Strutz F, Muller GA (1995) On the progression of chronic renal disease Nephron 69: 371–379

    Article  PubMed  CAS  Google Scholar 

  2. Bohle A, Muller GA, Wehrmann M, Mackensen-Haen S, Xiao JC (1996) Pathogenesis of chronic renal failure in the primary glomerulopathies, renal vasculopathies, and chronic interstitial nephritides Kidney Int 54: S2–S9

    CAS  Google Scholar 

  3. Eddy AA (2000) Molecular basis of renal fibrosis Pediatr Nephrol 15:290–301

    Article  PubMed  CAS  Google Scholar 

  4. Negri AL (2004) Prevention of progressive fibrosis in chronic renal diseases: Antifibrotic agents J Nephrol 17: 496–503

    PubMed  CAS  Google Scholar 

  5. Kaneto H, Morrissey J, Klahr S (1993) Increased expression of TGF-b1 mRNA in the obstructed kidney of rats with unilateral uretheral ligation Kidney Int 44: 313–321

    PubMed  CAS  Google Scholar 

  6. Yamamoto T, Noble NA, Miller DE, Border WA (1994) Sustained expression of TGF-b1 underlies development of progressive kidney fibrosis Kidney Int 45: 916–927

    PubMed  CAS  Google Scholar 

  7. Yamamotto T, Nakamura T, Noble NA, Ruoslahti E, Border WA (1993) Expression of transforming growth factor-b is elevated in human and experimental diabetic nephropathy Proc Natl Acad Sci USA 90: 1814–1818

    Article  PubMed  CAS  Google Scholar 

  8. Cuhaci B, Kumar MS, Bloom RD, Pratt B, Haussman G, Laskow DA, Alidoost M, Grotkowski C, Cahill K, Butani L, Sturgill BC, Pankewycz OG (1999) Transforming growth factor-b levels in human allograft chronic fibrosis correlate with the rate of decline in renal function Transplantation 68: 785–790

    Article  PubMed  CAS  Google Scholar 

  9. Badid C, Vincent M, Fouque D, Laville M, Desmouliere A (2001) Myofibroblast: a prognosticmarker and target cell in progressive renal disease Ren Fail 23: 543–549

    Article  PubMed  CAS  Google Scholar 

  10. el Nahas AM, Muchaneta-Kubara EC, Zhang G, Adam A, Goumenos D (1996) Phenotypic modulation of renal cells during experimental and clinical renal scarring Kidney Int 54: S23–S27

    CAS  Google Scholar 

  11. Klahr S, Morrissey J (2002) Obstructive nephropathy and renal fibrosis Am J Physiol 283: F861–F875

    Google Scholar 

  12. De Heer E, Sijpkens YW, Verkade M, den Dulk M, Langers A, Schutrups J, Bruijn JA, van Es LA (2000) Morphometry of interstitial fibrosis Nephrol Dial Transpl 15:72–73

    Article  Google Scholar 

  13. Huang WY, Sun H, Pan XQ, Guo M, Zhang AH, Wu YJ, Huang SM, Chen RH (2003) Screening of genes involved in renal interstitial fibrosis in rats with unilateral ureteral obstruction Chin J Pediatr 41: 855–856

    Google Scholar 

  14. Mishra S, Murphy LC, Nyomba BL, Murphy LJ (2005) PHB: a potential target for new therapeutics TRENDS Mol Med 11: 192–197

    Article  PubMed  CAS  Google Scholar 

  15. Thompson WE, Branch A, Whittaker JA, Lyn D, Zilberstein M, Mayo KE, Thomas K (2001) Characterization of PHB in a newly established rat ovarian granulosa cell line Endocrinology 142: 4076–4085

    Article  PubMed  CAS  Google Scholar 

  16. Nijtmans LG, Artal SM, Grivell LA, Coates PJ (2002) The mitochondrial PHB complex: roles in mitochondrial respiratory complex assembly, ageing and degenerative disease Cell Mol Life Sci 59: 143–155

    Article  PubMed  CAS  Google Scholar 

  17. Artal-Sanz M, Tsang WY, Willems EM, Grivell LA, Lemire BD, van der Spek H, Nijtmans LG (2003) The mitochondrial prohibitin complex is essential for embryonic viability and germline function in Caenorhabditis elegans J Biol Chem 278: 32091–32099

    Article  PubMed  CAS  Google Scholar 

  18. Thompson WE, Ramalho-Santos J, Sutovsky P (2003) Ubiquitination of prohibitin in mammalian sperm mitochondria: possible roles in the regulation of mitochondrial inheritance and sperm quality control Biol Reprod 69: 254–260

    Article  PubMed  CAS  Google Scholar 

  19. Jupe ER, Liu XT, Kiehlbauch JL, McClung JK, Dell’Orco TT (1996) The 3′ untranslated region of PHB and cellular immortalization Exp Cell Res 224: 128–135

    Article  PubMed  CAS  Google Scholar 

  20. Wang S, Fusaro G, Paddmanabhan J, Chellappan SP (2002) PHB co-localizes with Rb in the nucleus and recruits N-CoR and HDAC1 for transcriptional repression Oncogene 21: 8388–8396

    Article  PubMed  CAS  Google Scholar 

  21. Joshi B, Ko D, Ordonez-Ercan D, Chellappan SP (2003) A putative coiled-coil domain of prohibitin is sufficient to repress E2F1-mediated transcription and induce apoptosis Biochem Biophys Res Commun 312: 459–466

    Article  PubMed  CAS  Google Scholar 

  22. Fusaro G, Wang S, Chellappan S (2002) Differential regulation of Rb family proteins and prohibitin during camptothecin-induced apoptosis Oncogene 21: 4539–4548

    Article  PubMed  CAS  Google Scholar 

  23. Churg J, Bernstein J, Glassock RJ: In: Renal Disease Classification and atlas of glomerular disease, 2nd edn. Ikagu Shoin, New York, pp. 541–553, 1995

  24. The Chinese Society of Pediatric Nephrology (2001) Clinical classification, diagnosis and treatment of glomerular diseases in children Chin J Pediatr 39: 746–749

    Google Scholar 

  25. Thomas SE, Anderson S, Gordon KL, Oyama TT, Shankland SJ, Johnson RJ (1988) Tubulointerstitial disease in aging: Evidence of underlying peritubular capillary damage, potential role for renal ischemia J Am Soc Nephrol 9: 231–242

    Google Scholar 

  26. Coates PJ, Nenutil R, McGregor A, Picksley SM, Crouch DH, Hall PA, Wright EG (2001) Mammalian PHB proteins respond to mitochondrial stress and decrease during cellular senescence Exp Cell Res 265: 262–273

    Article  PubMed  CAS  Google Scholar 

  27. Gamble SC, Odontiadis M, Waxman J (2004) Androgens target PHB to regulate proliferation of prostate cancer cells Oncogene 23: 2996–3004

    Article  PubMed  CAS  Google Scholar 

  28. Zeisberg M, Strutz F, Muller GA (2001) Renal fibrosis: an update Curr Opin Nephrol Hypertens 10: 315–320

    Article  PubMed  CAS  Google Scholar 

  29. Andrew L, David JA (2004) TGF-β1 signaling and the fibrotic response FASEB 18: 816–827

    Article  CAS  Google Scholar 

  30. Bottinger EP, Bitzer M (2002) TGF-β1 signaling in renal disease J Am Soc Nephrol 13: 2600–2610

    Article  PubMed  Google Scholar 

  31. Moustakas A, Heldin CH (2005) Non-Smad TGF-β1 signals J Cel Sci 118: 3573–3584

    Article  CAS  Google Scholar 

  32. Wang S, Nath N, Adlam M (1999) PHB, a potential tumor suppressor, interacts with RB and regulates E2F function Oncogene 18: 3501–3510

    Article  PubMed  CAS  Google Scholar 

  33. Shinae KK, Nobutake A, Hiroto O (2000) Role of TGF-β in EGF-induced transformation of NRK cells is sustaining high-level EGF-signaling FEBS Lett 466: 160–164

    Article  Google Scholar 

  34. Satoshi O, Shinae KK, Yuko H (1998) Constitutive Association of EGF Receptor with the CrkII-23 Mutant that Inhibits Transformation of NRK Cells by EGF and TGF-β Cell Signal 10: 283–290

    Article  Google Scholar 

  35. Wang S, Nath N, Fusaro G, Chellappan S (1999) Rb and PHB target distinct regions of E2F1for repression and respond to different upstream signals Mol Cell Biol 19: 7447–7460

    PubMed  CAS  Google Scholar 

Download references

Acknowledgment

This study was supported by the grant from National Nature Science Foundation of China (No: 30270619).

Author information

Authors and Affiliations

  1. Department of Nephrology, Children’s Hospital of Fudan University, 183 Feng Lin Road, Shanghai, 200032, P.R. China

    Wei Guo, Hong Xu, Jing Chen, Rui Fu, Hai Mei Liu & Wen Yan Huang

  2. Key Laboratory of Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, Shanghai, P.R. China

    Yong Yang, Jia Wei Jin & Xi Liang Zha

  3. Department of Pathology, Shanghai Medical College, Fudan University, Shanghai, P.R. China

    Zhi Gang Zhang

Authors
  1. Wei Guo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hong Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jing Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yong Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jia Wei Jin
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Rui Fu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Hai Mei Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Xi Liang Zha
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Zhi Gang Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Wen Yan Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Wen Yan Huang.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Guo, W., Xu, H., Chen, J. et al. Prohibitin suppresses renal interstitial fibroblasts proliferation and phenotypic change induced by transforming growth factor-β1. Mol Cell Biochem 295, 167–177 (2007). https://doi.org/10.1007/s11010-006-9286-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11010-006-9286-4

Keywords

Search

Navigation