Perit Dial Int
29(Supplement_2):
45-48
2009
© 2009 International Society for Peritoneal Dialysis
Part 2: Cellular and Molecular Biology of the Peritoneum
and Peritoneal Dialysis |
TAMING APOPTOSIS IN PERITONEAL DIALYSIS
Beatriz Santamaria1,
Alvaro Conrado Ucero1,
Alberto Benito–Martin1,
Rafael Selgas2,
Marta Ruiz–Ortega3,
Ana B. Sanz1,
Jesús Egido1 and
Alberto Ortiz1,a
Dialysis Unit,1 Fundación Jiménez
Díaz, Universidad Autónoma de Madrid, Instituto Reina
Sofía de Investigación Nefrológica; Servicio de
Nefrología,2 Hospital Universitario La Paz;
Laboratory of Cellular Biology in Renal Diseases,3
Universidad Autónoma de Madrid, Madrid, Spain
Correspondence to: A. Ortiz, Unidad de Diálisis, Fundación
Jiménez Díaz, Av Reyes Católicos 2, 28040 Madrid, Spain.
aortiz{at}fjd.es
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ABSTRACT
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Excessive, insufficient, or untimely apoptosis may result in disorders
of cell numbers. Peritoneal demesothelization is an example of disease by
decreased cell number; untimely leukocyte apoptosis impairs peritoneal
defense. Conventional peritoneal dialysis solutions accelerate neutrophil
apoptosis. Glucose degradation products such as 3,4-dideoxyglucosone-3-ene
(3,4-DGE) decisively contribute to apoptosis induced by these solutions, in
both leukocytes and mesothelial cells and in both culture and peritoneal
dialysis patients. Pan-caspase inhibition retards neutrophil apoptosis and
improves peritoneal clearance of Staphylococcus aureus in animal
models. However, regulation of apoptosis in mesothelial cells is more complex
than in leukocytes, and caspase inhibitors may not be the optimal drugs to
modulate apoptosis in these cells. In this regard, Bax antagonistic peptides
protect mesothelial cells from 3,4-DGE. In addition, novel molecular targets
have been identified. Short-term modulation of apoptosis may be useful to
accelerate recovery and to prevent irreversible peritoneal injury following
peritonitis.
KEY WORDS: Apoptosis; caspases; Bax; Bcl-xL; mesothelial; peritonitis.
Apoptosis is an active mode of cell death under molecular control (cell
suicide) that contributes to the removal of unwanted and harmful cells and
maintains homeostasis of cell numbers
(1–3).
However, excessive, insufficient, or untimely apoptosis may result in disease.
Apoptosis is usually a response to the cell microenvironment
(1–3).
Cell survival requires the presence of extracellular survival factors and the
absence of lethal factors. The two main pathways for apoptosis are ligation of
plasma membrane death receptors ("extrinsic" pathway) and
perturbation of intracellular homeostasis by cell stressors
("intrinsic" pathway). In the extrinsic pathway, ligation of death
receptors, leads to proximity-induced activation of initiator caspases-8 and
-10. The intrinsic pathway involves intracellular organelles, the most
important being the mitochondria. Sentinel activator "BH3-only
proteins" activate Bax and/or Bak, which oligomerize at the
mitochondria, permeabilizing the outer mitochondrial membrane and releasing
proapoptotic factors, such as cytochrome c, that promote caspase-dependent and
- independent apoptosis. Cytochrome c facilitates the oligomerization of
Apaf-1 and caspase-9 in the apoptosome, resulting in activation of caspase-9.
Activated initiator caspases cleave and activate effector caspases such as
caspase-3 and caspase-7, resulting in widespread proteolysis and commitment to
cell death.
Signaling cross talk exists between the intrinsic and extrinsic pathways.
Cells in which engagement of death receptors results in limited caspase-8
activation require recruitment of the mitochondrial pathway to amplify the
cell death signal (type II cells). Caspase-8 truncates Bid to yield tBid,
which translocates to mitochondria and recruits the intrinsic pathway. Other
pathways for apoptosis are activated by additional receptors, endoplasmic
reticulum or lysosomal stress, and DNA damage. In fact, there are
stimulus-specific and cell-specific pathways, the understanding of which may
help tailor apoptosis modulation strategies to specific clinical
situations.
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EVIDENCE FOR A RELEVANT ROLE OF PERITONEAL APOPTOSIS
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Both mesothelial cells and leukocytes are lost through apoptosis during
peritoneal dialysis (PD)
(4–7).
Neutrophils are programmed to die by apoptosis at the site of inflammation,
limiting the inflammatory response. Thus, the percentage of apoptotic effluent
cells increases in the course of peritonitis
(7). However, accelerated
untimely leukocyte apoptosis may compromise peritoneal defense
(7). In this regard, prevention
of neutrophil apoptosis by caspase inhibitors accelerated Staphylococcus
aureus clearance in experimental peritonitis
(4,7).
Chronic long-term PD and acute peritonitis are associated with loss of
mesothelium
(8,9).
Mesothelial cells may detach, die, or undergo epithelial-to-mesenchymal
differentiation, but the relative contribution of these processes to
demesothelization has not been adequately characterized
(6,10).
Only by therapeutically targeting the individual processes in vivo
will we establish their precise contribution. For that, we need to
characterize the molecular mechanisms and identify potential therapeutic
compounds in cell culture models.
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EXOGENOUS LETHAL FACTORS
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Conventional glucose-based PD fluids containing high concentrations of
glucose degradation products (GDPs) are cytotoxic and induce apoptosis in
leukocytes and mesothelial cells
(6,7,11–13).
While high glucose concentrations may induce apoptosis
(14), the GDPs are the main
proapoptotic components in PD solutions
(6,7,15).
Apoptosis is not induced by exogenous glucose, even in the presence of
lactate, or by low-GDP PD solutions, and is not prevented by correcting the pH
(6,7).
Apoptosis kinetics in response to conventional PD solutions differs between
leukocytes and mesothelial cells, suggesting different apoptosis regulation
pathways. The time course is 4 – 24 hours for neutrophils and 48 –
72 hours for mesothelial cells
(6,7,13,15).
3,4-dideoxyglucosone-3-ene (3,4-DGE), the main lethal GDP of conventional
PD solutions, accounts for most of the lethal activity of PD solutions against
neutrophils, peripheral blood mononuclear cells, and mesothelial cells
(6,15–17).
3-4-DGE dose dependently induces apoptosis within the concentration range (25
– 125 µmol/L) found in PD solutions
(6,15,18).
These studies do not exclude the possibility that other GDPs or combinations
of GDPs contribute to cell death. However, the concentrations of other GDPs,
such as 3-deoxyglucosone (3-DG) and methylglyoxal, that induced apoptosis
were, in general, higher than those present in conventional PD fluids
(18–21).
These data are consistent with early reports of GDP cytotoxicity in which the
then known GDPs were not toxic at concentrations found in PD fluids
(22).
In mesothelial cells, both 3,4-DGE and high-GDP high-glucose PD solutions
activate the cell stress pathway that requires Bax and results in
mitochondrial injury (6). The
Bax pathway is also engaged in diabetes and by 3,4-DGE in tubular epithelial
cells (23), suggesting that
therapeutic maneuvers aimed at preserving mesothelial integrity may also
protect kidney cells. Bax is also required for cyclosporine A-induced
apoptosis, but not for acetaminophen cytotoxicity in tubular renal cells
(24,25).
The clinical relevance of these observations is supported by a
crossover-design prospective study in which low-GDP PD solutions displayed
lower total and mesothelial rates of apoptosis in peritoneal effluents than
conventional solutions (6).
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ENDOGENOUS MEDIATORS OF CELL DEATH
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Lethal cytokines belonging to the tumor necrosis factor (TNF) superfamily,
such as TNF, FasL, TRAIL, and TWEAK, may induce apoptosis
(26–29).
During peritonitis, several of them are present in high concentrations in the
peritoneal cavity and they act in concert to promote mesothelial cell
apoptosis (5). The rate of cell
death further increases when PD solutions and inflammatory cytokines coexist.
The mechanisms leading to death and therapeutic maneuvers that prevent cell
injury in such a complex environment should be explored.
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NEW THERAPEUTIC OPPORTUNITIES
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Cytokines are required for an effective antibacterial defense. In the
clinical setting, TNF-
antagonists have been marred by an increased
rate of severe infections
(30).This suggests that,
during infection, rather than antagonize cytokines we should strive for the
selective therapeutic manipulation of their specific adverse effects that
promote tissue injury, such as parenchymal cell apoptosis.
Caspase inhibition has been used successfully to accelerate recovery from
experimental peritonitis (4).
However, in at least some cell types, caspase inhibition may transform a mild
proapoptotic response to lethal cytokines into an intense necrotic response
(29). Recently, multiple
non-apoptotic caspase actions on cell proliferation and migration that favor
the recovery process have been described
(31,32).
In this regard, the consequences for mesothelial regeneration of caspase
inhibition have not been adequately explored. Other potential maneuvers to
prevent PD solution-induced and lethal cytokine-induced peritoneal cell
apoptosis include Bcl-xL-like peptides, Bax antagonists, and apoptosome
inhibitors
(6,33,34).
Bax antagonists reduced mesothelial cell apoptosis induced by PD solutions
(6). Bcl-xL-like peptides
prevented PD solution-induced apoptosis in cultured leukocytes
(35).
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UNRESOLVED ISSUES
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A clear understanding of the role and regulation of apoptosis in peritoneal
disease has the potential to provide the basis for new therapeutic strategy
designs as well as to improve the biocompatibility of PD fluids. Among the
cellular targets, we might be interested in prolonging mesothelial cell
survival and preventing untimely leukocyte death.
The key to any successful therapeutic manipulation of apoptosis lies in
limiting the interference to the cell type of interest and to a defined time
period. Experimental designs that closely resemble the in vivo
situation, that provide a complex microenvironment in which several cytokines
are present, and that provide evolving dynamic conditions representative of
the different phases of the evolution of peritonitis should be used to
evaluate both prevention of cell death and promotion of regeneration. The
first potential clinical use of apoptosis inhibitors may be as adjuvant
therapy associated with antibiotics in order to accelerate recovery from the
more severe cases of peritonitis. Thus, local intraperitoneal delivery and
short-term treatment will limit any potential unwanted side effects.
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ACKNOWLEDGMENTS
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This work was supported by grants from FIS 06/0046 and ISCIII-RETICS
REDinREN RD 06/0016, MEC (SAF 03/884), Sociedad Espanola de Nefrologia. ABM
and ABS were supported by Fondo de Investigaciones Sanitarias (FIS), ACU and
BS by Fundacion Conchita Rabago, and AO by the Programa de
Intensificación de la Actividad Investigadora in the Sistema Nacional
de Salud of the Instituto de Salud Carlos III and the Agencia "Pedro
Lain Entralgo" of the Comunidad de Madrid and CIFRA S-BIO 0283/2006.
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FOOTNOTES
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a All authors (except JE) belong to REDinREN (Red de Investigación
Renal Española del Instituto de Salud Carlos III, RETICS 06/0016). 
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REFERENCES
|
|---|
- Sanz AB, Santamaria B, Ruiz Ortega M, Egido J, Ortiz A. Mechanisms
of renal apoptosis in health and disease. J Am Soc
Nephrol 2008; 19:1634
-42.[Abstract/Free Full Text]
- Ortiz A. Nephrology Forum: Apoptotic regulatory proteins in renal
injury. Kidney Int 2000;58
: 467-85.[Medline]
- Ortiz A, Catalan MP. Will modulation of cell death increase PD
technique survival? Perit Dial Int 2004;24
: 105-14.[Free Full Text]
- Catalán MP, Esteban J, Subirá D, Egido J, Ortiz A.
Inhibition of caspases improves bacterial clearance in experimental
peritonitis. Perit Dial Int 2003;23
: 123-6.[Abstract/Free Full Text]
- Catalan MP, Subirá D, Reyero A, Selgas R, Ortiz A, Egido J,
et al. Regulation of apoptosis by lethal cytokines in human
mesothelial cells. Kidney Int 2003;64
: 321-30.[Medline]
- Santamaría B, Ucero AC, Reyero A, Selgas R, Ruiz-Ortega M,
Catalán M, et al. 3,4-di-deoxyglucosone-3-ene as a mediator of
peritoneal demesothelization. Nephrol Dial Transplant2008; 23:3307
-15.[Abstract/Free Full Text]
- Catalán MP, Reyero A, Egido J, Ortiz A. Acceleration of
neutrophil apoptosis by glucose-containing peritoneal dialysis solutions: role
of caspases. J Am Soc Nephrol 2001;12
: 2442-9.[Abstract/Free Full Text]
- Di Paolo N, Sacchi G. Atlas of peritoneal histology.
Perit Dial Int 2000;20
(Suppl 3):S5
-96.[Abstract]
- Verger C, Luger A, Moore HL, Nolph KD. Acute changes in peritoneal
morphology and transport properties with infectious peritonitis and mechanical
injury. Kidney Int 1983;23
: 823-31.[Medline]
- Yanez-Mo M, Lara-Pezzi E, Selgas R, Ramirez-Huesca M,
Dominguez-Jimenez C, Jimenez-Heffernan JA, et al. Peritoneal dialysis
and epithelial-to-mesenchymal transition of mesothelial cells. N
Engl J Med 2003; 348:403
-13.[Abstract/Free Full Text]
- Witowski J, Wisniewska J, Korybalska K, Bender TO, Breborowicz A,
Gahl GM, et al. Prolonged exposure to glucose degradation products
impairs viability and function of human peritoneal mesothelial cells.
J Am Soc Nephrol 2001;12
: 2434-41.[Abstract/Free Full Text]
- Cendoroglo M, Sundaram S, Groves C, Ucci AA, Jaber BL, Pereira BJ.
Necrosis and apoptosis of polymorphonuclear cells exposed to peritoneal
dialysis fluids in vitro. Kidney Int1997; 52:1626
-34.[Medline]
- Yang AH, Chen JY, Lin YP, Huang TP, Wu CW. Peritoneal dialysis
solution induces apoptosis of mesothelial cells. Kidney
Int 1997; 51:1280
-8.[Medline]
- Ortiz A, Ziyadeh FN, Neilson EG. Expression of apoptosis-regulatory
genes in renal proximal tubular epithelial cells exposed to high ambient
glucose and in diabetic kidneys. J Invest Med1997; 45:50
-6.[Medline]
- Catalan MP, Santamaria B, Reyero A, Ortiz A, Egido J, Ortiz A.
3,4-di-deoxyglucosone-3-ene promotes leukocyte apoptosis. Kidney
Int 2005; 68:1303
-11.[Medline]
- Linden T, Cohen A, Deppisch R, Kjellstrand P, Wieslander A.
3,4-dideoxyglucosone-3-ene (3,4-DGE): a cytotoxic glucose degradation product
in fluids for peritoneal dialysis. Kidney Int2002; 62:697
-703.[Medline]
- Ortiz A, Wieslander A, Linden T, Santamaria B, Sanz A, Justo P,
et al. 3,4-DGE is important for side effects in peritoneal dialysis
what about its role in diabetes. Curr Med Chem2006; 13:2695
-702.[Medline]
- Erixon M, Linden T, Kjellstrand P, Carlsson O, Ernebrant M,
Forsback G, et al. PD fluids contain high concentrations of cytotoxic
GDPs directly after sterilization. Perit Dial Int2004; 24:392
-8.[Abstract/Free Full Text]
- Amore A, Cappelli G, Cirina P, Conti G, Gambaruto C, Silvestro L,
et al. Glucose degradation products increase apoptosis of human
mesothelial cells. Nephrol Dial Transplant2003; 18:677
-88.[Abstract/Free Full Text]
- Boulanger E, Wautier MP, Gane P, Mariette C, Devuyst O, Wautier JL.
The triggering of human peritoneal mesothelial cell apoptosis and oncosis by
glucose and glycoxydation products. Nephrol Dial
Transplant 2004; 19:2208
-16.[Abstract/Free Full Text]
- Welten AG, Schalkwijk CG, ter Wee PM, Meijer S, van den Born J,
Beelen RJ. Single exposure of mesothelial cells to glucose degradation
products (GDPs) yields early advanced glycation end-products (AGEs) and a
proinflammatory response. Perit Dial Int2003; 23:213
-21.[Abstract/Free Full Text]
- Wieslander AP, Andren AH, Nilsson-Thorell C, Muscalu N, Kjellstrand
PT, Rippe B. Are aldehydes in heat-sterilized peritoneal dialysis fluids toxic
in vitro? Perit Dial Int 1995;15
: 348-52.[Abstract]
- Justo P, Sanz AB, Egido J, Ortiz A. 3,4-dideoxyglucosone-3-ene
induces apoptosis in renal tubular epithelial cells.
Diabetes 2005; 54:2424
-9.[Abstract/Free Full Text]
- Justo P, Lorz C, Sanz A, Egido J, Ortiz A. Intracellular mechanisms
of cyclosporin A-induced tubular cell apoptosis. J Am Soc
Nephrol 2003; 14:3072
-80.[Abstract/Free Full Text]
- Lorz C, Justo P, Sanz A, Subira D, Egido J, Ortiz A.
Paracetamol-induced renal tubular injury: a role for ER stress. J
Am Soc Nephrol 2004; 15:380
-9.[Abstract/Free Full Text]
- Ortiz A, Lorz C, Egido J. New kids in the block: the role of FasL
and Fas in kidney damage. J Nephrol 1999;12
: 150-8.[Medline]
- Ortiz A, Gonzalez-Cuadrado S, Bustos C, Alonso J,
Gómez-Guerrero C, López-Armada MJ, et al. Tumor
necrosis factor and glomerular damage. J Nephrol1995; 8:27
-34.
- Lorz C, Benito-Martín A, Boucherot A, Ucero AC, Rastaldi MP,
Henger A, et al. The death ligand TRAIL in diabetic nephropathy.
J Am Soc Nephrol 2008,19
: 904-14.[Abstract/Free Full Text]
- Justo P, Sanz AB, Sanchez-Nino MD, Winkles JA, Lorz C, Egido J,
et al. Cytokine cooperation in renal tubular cell injury: the role of
TWEAK. Kidney Int 2006;70
: 1750-8.[Medline]
- Crum NF, Lederman ER, Wallace MR. Infections associated with tumor
necrosis factor-alpha antagonists. Medicine
(Baltimore) 2005; 84:291
-302.[Medline]
- Li J, Brieher WM, Scimone ML, Kang SJ, Zhu H, Yin H, et
al. Caspase-11 regulates cell migration by promoting
Aip1-cofilin-mediated actin depolymerization. Nat Cell
Biol 2007; 9:276
-86.[Medline]
- Ben MT, Barash H, Kang TB, Kim JC, Kovalenko A, Gross E, et
al. Role of caspase-8 in hepatocyte response to infection and injury in
mice. Hepatology 2007;45
: 1014-24.[Medline]
- Malet G, Martin AG, Orzaez M, Vicent MJ, Masip I, Sanclimens G,
et al. Small molecule inhibitors of Apaf-1-related caspase-3/-9
activation that control mitochondrial-dependent apoptosis. Cell
Death Differ 2006; 13:1523
-32.[Medline]
- Hotchkiss RS, McConnell KW, Bullok K, Davis CG, Chang KC, Schwulst
SJ, et al. TAT-BH4 and TAT-Bcl-xL peptides protect against
sepsis-induced lymphocyte apoptosis in vivo. J Immunol2006; 176:5471
-7.[Abstract/Free Full Text]
- Santamaria B, Benito-Martin A, Ucero AC, Reyero A, Selgas R,
Ruiz-Ortega M, et al. Bcl-xL prevents peritoneal dialysis
solution-induced leukocyte apoptosis. Perit Dial Int2008; 28(Suppl 5):S48
-52.[Abstract/Free Full Text]
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ABSTRACT
EVIDENCE FOR A RELEVANT...
