Skip to main content
Log in

Peritoneal dialysis fluid activates calcium signaling and apoptosis in mesothelial cells

  • Original Paper
  • Published:
Apoptosis Aims and scope Submit manuscript

Abstract

A larger diffusion of peritoneal dialysis (PD) is limited by the progressive deterioration of the dialysis membrane structure and function, characterized in vitro and in vivo by mesothelial cell loss and closely related to the use of bioincompatible dialysis solutions. The apoptosis rate of rat and human mesothelial cells incubated in commercial PD fluid (PDF, 4.25 g/dL dextrose) became significant as early as 1 h after PDF addition and reached a plateau at 4–5 h. This pattern was unchanged after exposure to 1.5 g/dL dextrose PDF or freshly prepared PDF, indicating that effects were independent on the dextrose strength and manufacturing procedures but strictly dependent on PDF composition. Molecular studies revealed that PDF exposure inactivated the physiological volume recovery from hypertonic shrinkage, accompanied by an abnormal Ca2+ signaling: a progressive intracellular Ca2+ ([Ca2+]i) rise resulting from an increased Ca2+ entry. PDF also affected cytoskeleton integrity: early dissolution of actin filaments occurred well before the appearance of typical apoptosis features. Lastly, the PDF dependent apoptosis was almost completely prevented by the contemporary Ca2+ concentration decrease and K+ addition. This study suggests that the PDF dependent apoptosis arises from the extreme volume perturbations in mesothelial cells, turned out unable to regulate their volume back once exposed to a hyperosmolal medium containing high Ca2+ levels in the absence of K+, such PDF.

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

Access this article

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
Fig. 7
Fig. 8
Fig. 9

Similar content being viewed by others

Abbreviations

PDF:

Peritoneal dialysis fluid

RM-4:

Rat mesothelial cells

HPMC:

Human peritoneal mesothelial cells

GDP:

Glucose degradation products

FCS:

Fetal calf serum

References

  1. Asari A, Iles-Smith H, Chen YC, Naderer OJ, Johnson MA, Yuen GJ, Otto V, Dunn JA, Gokal R (2007) Pharmacokinetics of lamivudine in subjects receiving peritoneal dialysis in end-stage renal failure. Br J Clin Pharmacol 64(6):738–744

    PubMed  CAS  Google Scholar 

  2. Hirahara I, Kusano E, Yanagiba S, Miyata Y, Ando Y, Muto S, Asano Y (2006) Peritoneal injury by methylglyoxal in peritoneal dialysis. Perit Dial Int 26:380–392

    PubMed  CAS  Google Scholar 

  3. Witowski J, Jörres A (2009) Peritoneal dialysis: a biological membrane with a non biological fluid. Contrib Nephrol 163:27–34

    Article  PubMed  CAS  Google Scholar 

  4. Sitter T, Sauter M (2005) Impact of glucose in peritoneal dialysis: saint or sinner? Perit Dial Int 25(5):415–425

    PubMed  CAS  Google Scholar 

  5. Srivastava S, Hildebrand S, Fan SL (2011) Long-term follow-up of patients randomized to biocompatible or conventional peritoneal dialysis solutions show no difference in peritonitis or technique survival. Kidney Int 80(9):986–991

    Article  PubMed  CAS  Google Scholar 

  6. Yáñez-Mó M, Lara-Pezzi E, Selgas R, Ramírez-Huesca M, Domínguez-Jiménez C, Jiménez-Heffernan JA, Aguilera A, Sánchez-Tomero JA, Bajo MA, Alvarez V, Castro MA, del Peso G, Cirujeda A, Gamallo C, Sánchez-Madrid F, López-Cabrera M (2003) Peritoneal dialysis and epithelial-to-mesenchymal transition of mesothelial cells. N Engl J Med 348(5):403–413

    Article  PubMed  Google Scholar 

  7. Duan S, Yu J, Liu Q, Wang Y, Pan P, Xiao L, Ling G, Liu F (2011) Epithelial-to-mesenchymal transdifferentiation of peritoneal mesothelial cells mediated by oxidative stress in peritoneal fibrosis rats. Zhong Nan Da Xue Xue Bao Yi Xue Ban 36(1):34–43

    PubMed  CAS  Google Scholar 

  8. Gotloib L, Shostak A, Wajsbrot V, Kushnier R (1999) High glucose induces a hypertrophic, senescent mesothelial cell phenotype after long in vivo exposure. Nephron 82(2):164–173

    Article  PubMed  CAS  Google Scholar 

  9. Catalan MP, Subirá D, Reyero A, Selgas R, Ortiz-Gonzalez A, Egido J, Ortiz A (2003) Regulation of apoptosis by lethal cytokines in human mesothelial cells. Kidney Int 64(1):321–330

    Article  PubMed  CAS  Google Scholar 

  10. Grynkiewicz G, Poenie M, Tsien RY (1985) A new generation of Ca2+ indicators with greatly improved fluorescence properties. J Biol Chem 260(6):3440–3450

    PubMed  CAS  Google Scholar 

  11. Witowski J, Bender TO, Wisniewska-Elnur J, Ksiazek K, Passlick-Deetjen J, Breborowicz A, Jörres A (2003) Mesothelial toxicity of peritoneal dialysis fluids is related primarily to glucose degradation products, not to glucose per se. Perit Dial Int 23(4):381–390

    PubMed  CAS  Google Scholar 

  12. Müller-Krebs S, Kihm LP, Zeier B, Gross ML, Deppisch R, Wieslander A, Henle T, Penndorf I, Oh J, Reiser J, Nawroth PP, Zeier M, Schwenger V (2008) Renal toxicity mediated by glucose degradation products in a rat model of advanced renal failure. Eur J Clin Invest 38(5):296–305

    Article  PubMed  Google Scholar 

  13. Gottlieb RA, Nordberg J, Skowronski E, Babior BM (1996) Apoptosis induced in Jurkat cells by several agents is preceded by intracellular acidification. Proc Natl Acad Sci USA 93(2):654–658

    Article  PubMed  CAS  Google Scholar 

  14. Mortier S, Faict D, Schalkwijk CG, Lameire NH, De Vriese AS (2004) Long-term exposure to new peritoneal dialysis solutions: effects on the peritoneal membrane. Kidney Int 66(3):1257–1265

    Article  PubMed  CAS  Google Scholar 

  15. Zareie M, Hekking LH, Welten AG, Driesprong BA, Schadee-Eestermans IL, Faict D, Leyssens A, Schalkwijk CG, Beelen RH, ter Wee PM, van den Born J (2003) Contribution of lactate buffer, glucose and glucose degradation products to peritoneal injury in vivo. Nephrol Dial Transplant 18(12):2629–2637

    Article  PubMed  CAS  Google Scholar 

  16. Lang F (2007) Mechanisms and significance of cell volume regulation. J Am Coll Nutr 26(5 Suppl):613S–623S

    PubMed  CAS  Google Scholar 

  17. Dupont G, Combettes L, Bird GS, Putney JW (2011) Calcium oscillations. Cold Spring Harb Perspect Biol 3:a004226

    Article  PubMed  Google Scholar 

  18. Ekhterae D, Platoshyn O, Krick S, Yu Y, McDaniel SS, Yuan JX (2001) Bcl-2 decreases voltage-gated K+ channel activity and enhances survival in vascular smooth muscle cells. Am J Physiol Cell Physiol 281(1):C157–C165

    PubMed  CAS  Google Scholar 

  19. Bortner CD, Sifre MI, Cidlowski JA (2008) Cationic gradient reversal and cytoskeleton-independent volume regulatory pathways define an early stage of apoptosis. J Biol Chem 283(11):7219–7229

    Article  PubMed  CAS  Google Scholar 

  20. Leadsham JE, Kotiadis VN, Tarrant DJ, Gourlay CW (2010) Apoptosis and the yeast actin cytoskeleton. Cell Death Differ 17(5):754–762

    Article  PubMed  CAS  Google Scholar 

  21. Zhang Y, Shi H, Sun G, Li S, Xu X, Ye C, Li X, Wang S (2011) High glucose induces dysfunction and apoptosis in endothelial cells: is the effect of high glucose persistence more important than concentration? Exp Clin Endocrinol Diabetes 119(4):225–233

    Article  PubMed  CAS  Google Scholar 

  22. Tanabe K, Liu Y, Hasan SD, Martinez SC, Cras-Méneur C, Welling CM, Bernal-Mizrachi E, Tanizawa Y, Rhodes CJ, Zmuda E, Hai T, Abumrad NA, Permutt MA (2011) Glucose and fatty acids synergize to promote B -cell apoptosis through activation of glycogen synthase kinase 3β independent of JNK activation. PLoS ONE 6(4):e18146

    Article  PubMed  CAS  Google Scholar 

  23. Zhivotovsky B, Orrenius S (2011) Calcium and cell death mechanisms: a perspective from the cell death community. Cell Calcium 50(3):211–221

    Article  PubMed  CAS  Google Scholar 

  24. Brown EM (2007) The calcium-sensing receptor: physiology, pathophysiology and CaR-based therapeutics. Subcell Biochem 45:139–167

    Article  PubMed  CAS  Google Scholar 

  25. Lang F, Föller M, Lang K, Lang P, Ritter M, Vereninov A, Szabo I, Huber SM, Gulbins E (2007) Cell volume regulatory ion channels in cell proliferation and cell death. Methods Enzymol 428:209–225

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

In memory of our friend and colleague Vincenzo Calderaro that during the writing of this manuscript has left us prematurely.

Conflict of interest

The authors declare that there are no conflicts of interest.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Lucio Quagliuolo.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Boccellino, M., La Porta, R., Coppola, M. et al. Peritoneal dialysis fluid activates calcium signaling and apoptosis in mesothelial cells. Apoptosis 18, 43–56 (2013). https://doi.org/10.1007/s10495-012-0771-9

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10495-012-0771-9

Keywords

Navigation