Skip to main content
SpringerLink
Log in

Okadaic acid stimulates caspase-like activities and induces apoptosis of cultured rat mesangial cells

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

Abstract

Glomerular mesangial cells play an important role in the development of glomerulosclerosis. Mesangial cell apoptosis has been shown to be involved in different stages of development of glomerulonephritis. The aim of the present study was to evaluate the effect of inhibition of serine/threonine phosphatases by okadaic acid, a shell fish toxin, on rat mesangial cell apoptosis and to examine the molecular mechanisms particularly the role of caspases. Okadaic acid significantly induced mesangial cell apoptosis, as measured by an increase in cytoplasmic nucleosome-associated DNA fragmentation. The induction of apoptosis was dependent on protein synthesis, because cyclohexamide, a protein synthesis inhibitor, blocked okadaic acid-induced apoptosis. In addition, okadaic acid stimulated caspase activities (as measured by caspase substrate peptide hydrolysis) in cultured rat mesangial cells at different time points. After 12 h treatment, okadaic acid caused a modest increase in caspase-8 (IETD-pNAse)(159.3 ± 6.7%) activity, while after 18 h treatment, okadaic acid caused a significant increase in caspase-3 (DEVD-pNAse)(906 ± 245%) activity. Okadaic acid-stimulated caspase-3 activity was inhibited by Z-IETD-FMK (caspase-8 inhibitor) suggesting that the caspase-3 activity is downstream of caspase-8 activity. Both caspase-3 and caspase-8 inhibitors blocked okadaic acid-stimulated apoptosis. These data suggest that inhibition of protein phosphatases by okadaic acid induces apoptosis in rat mesangial cells by activating caspase-3- and -8-like activities and that caspase-3-like activity is downstream of caspase-8-like activity.

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. Klahr S, Schreiner G, Ichikawa I: The progression of renal disease. N Engl J Med 318: 1657-1666, 1988

    PubMed  Google Scholar 

  2. el Nahas AM, Muchaneta-Kubara EC, Essawy M, Soylemezoglu O: Renal fibrosis: Insights into pathogenesis and treatment. Int J Biochem Cell Biol 29: 55-62, 1997

    Article  PubMed  Google Scholar 

  3. Baker AJ, Mooney A, Hughes J, Lombardi D, Johnson RJ, Savill J: Mesangial cell apoptosis: The major mechanism for resolution of glomerular hypercellularity in experimental mesangial proliferative nephritis. J Clin Invest 94: 2105-2116, 1994

    PubMed  Google Scholar 

  4. Sugiyama H, Kashihara N, Makino H, Yamasaki Y, Ota A: Apoptosis in glomerular sclerosis. Kidney Int 49: 103-111, 1996

    PubMed  Google Scholar 

  5. Cohen GM: Caspases: The executioners of apoptosis. Biochem J 326: 1-16, 1997

    PubMed  Google Scholar 

  6. Villa P, Kaufmann SH, Earnshaw WC: Caspases and caspase inhibitors. Trends Biochem Sci 22: 388-393, 1997

    Article  PubMed  Google Scholar 

  7. Nagao M, Shima H, Nakayasu M, Sugimura T: Protein serine/threonine phosphatases as binding proteins for okadaic acid. Mutat Res 333: 173-179, 1995

    PubMed  Google Scholar 

  8. Cohen P, Holmes CF, Tsukitani Y: Okadaic acid: A new probe for the study of cellular regulation. Trends Biochem Sci 15: 98-102, 1990

    Article  PubMed  Google Scholar 

  9. Fujiki H, Suganuma M: Tumor promotion by inhibitors of protein phosphatases 1 and 2A: The okadaic acid class of compounds. Adv Cancer Res 61: 143-194, 1993

    PubMed  Google Scholar 

  10. Song Q, Baxter GD, Kovacs EM, Findik D, Lavin MF: Inhibition of apoptosis in human tumour cells by okadaic acid. J Cell Physiol 153: 550-556, 1992

    Article  PubMed  Google Scholar 

  11. Morimoto Y, Ohba T, Kobayashi S, Haneji T: The protein phosphatase inhibitors okadaic acid and calyculin A induce apoptosis in human osteoblastic cells. Exp Cell Res 230: 181-186, 1997

    Article  PubMed  Google Scholar 

  12. Li DW, Fass U, Huizar I, Spector A: Okadaic acid-induced lens epithelial cell apoptosis requires inhibition of phosphatase-1 and is associated with induction of gene expression including p53 and bax. Eur J Biochem 257: 351-361, 1998

    Article  PubMed  Google Scholar 

  13. Albrightson CR, Nambi P, Zabko-Potapovich B, Dytko G, Groom T: Effect of thrombin on proliferation, contraction and prostaglandin production of rat glomerular mesangial cells in culture. J Pharmacol Exp Ther 263: 404-412, 1992

    PubMed  Google Scholar 

  14. Yue TL, Wang C, Romanic AM, Kikly K, Keller P, DeWolf WE Jr., Hart TK, Thomas HC, Storer B, Gu JL, Wang X, Feuerstein GZ: Staurosporine-induced apoptosis in cardiomyocytes: A potential role of caspase-3. J Mol Cell Cardiol 30: 495-507, 1998

    Article  PubMed  Google Scholar 

  15. Dimmeler S, Rippmann V, Weiland U, Haendeler J, Zeiher AM: Angiotensin II induces apoptosis of human endothelial cells. Protective effect of nitric oxide. Circ Res 81: 970-976, 1997

    PubMed  Google Scholar 

  16. Ohta T, Kinoshita T, Naito M, Nozaki T, Masutani M, Tsuruo T, Miyajima A: Requirement of the caspase-3/CPP32 protease cascade for apoptotic death following cytokine deprivation in hematopoietic cells. J Biol Chem 272: 23111-23116, 1997

    Article  PubMed  Google Scholar 

  17. Kagaya S, Kitanaka C, Noguchi K, Mochizuki T, Sugiyama A, Asai A, Yasuhara N, Eguchi Y, Tsujimoto Y, Kuchino Y: A functional role for death proteases in s-myc-and c-myc-mediated apoptosis. Mol Cell Biol 17: 6736-6745, 1997

    PubMed  Google Scholar 

  18. Kaushal GP, Singh AB, Shah SV: Identification of gene family of caspases in rat kidney and altered expression in ischemia-reperfusion injury. Am J Physiol 274: F587-F595, 1998

    PubMed  Google Scholar 

  19. DiMari J, Megyesi J, Udvarhelyi N, Price P, Davis R, Safirstein R: Nacetyl cysteine ameliorates ischemic renal failure. Am J Physiol 272: F292-F298, 1997

    PubMed  Google Scholar 

  20. Juo P, Kuo CJ, Reynolds SE, Konz RF, Raingeaud J, Davis RJ, Biemann HP, Blenis J: Fas activation of the p38 mitogen-activated protein kinase signalling pathway requires ICE/CED-3 family proteases. Mol Cell Biol 17: 24-35, 1997

    PubMed  Google Scholar 

  21. Parameswaran N, Nambi P, Hall CS, Brooks DP, Spielman WS: Adrenomedullin decreases extracellular signal-regulated kinase activity through an increase in protein phosphatase-2A activity in mesangial cells. Eur J Pharmacol 388: 133-138, 2000

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Physiology, Michigan State University, East Lansing, MI, USA

    Narayanan Parameswaran & Wiliam S. Spielman

  2. Department of Renal Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, PA, USA

    David P. Brooks & Ponnal Nambi

  3. Women's Health Research Institute, N-2275, Wyeth Pharmaceuticals, N-2275, Collegeville, PA, 19426, USA

    Ponnal Nambi

Authors
  1. Narayanan Parameswaran
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Wiliam S. Spielman
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. David P. Brooks
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ponnal Nambi
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Parameswaran, N., Spielman, W.S., Brooks, D.P. et al. Okadaic acid stimulates caspase-like activities and induces apoptosis of cultured rat mesangial cells. Mol Cell Biochem 260, 7–11 (2004). https://doi.org/10.1023/B:MCBI.0000026041.41078.32

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/B:MCBI.0000026041.41078.32

Search

Navigation