Human Peritoneal Mesothelial Cell Death Induced by High-Glucose Hypertonic Solution Involves Ca2+ and Na+ Ions and Oxidative Stress with the Participation of PKC/NOX2 and PI3K/Akt Pathways

Abstract

Chronic peritoneal dialysis (PD) therapy is equally efficient as hemodialysis while providing greater patient comfort and mobility. Therefore, PD is the treatment of choice for several types of renal patients. During PD, a high-glucose hyperosmotic (HGH) solution is administered into the peritoneal cavity to generate an osmotic gradient that promotes water and solutes transport from peritoneal blood to the dialysis solution. Unfortunately, PD has been associated with a loss of peritoneal viability and function through the generation of a severe inflammatory state that induces human peritoneal mesothelial cell (HPMC) death. Despite this deleterious effect, the precise molecular mechanism of HPMC death as induced by HGH solutions is far from being understood. Therefore, the aim of this study was to explore the pathways involved in HGH solution-induced HPMC death. HGH-induced HPMC death included influxes of intracellular Ca2+ and Na+. Furthermore, HGH-induced HPMC death was inhibited by antioxidant and reducing agents. In line with this, HPMC death was induced solely by increased oxidative stress. In addition to this, the cPKC/NOX2 and PI3K/Akt intracellular signaling pathways also participated in HGH-induced HPMC death. The participation of PI3K/Akt intracellular is in agreement with previously shown in rat PMC apoptosis. These findings contribute toward fully elucidating the underlying molecular mechanism mediating peritoneal mesothelial cell death induced by high-glucose solutions during peritoneal dialysis.

TRP Channels as Sensors of Bacterial Endotoxins

“…Early ROS production depends on TLR4, Nox2 and Nox4 and, is suggested to be mediated by PLC/cPKC and PI3-K pathways [ 169 ]. Interestingly, TRPM4 is a Ca 2+ -activated channel [ 171 ] and early ROS production is preceded by Ca 2+ influx [ 172 ]. The origin of the intracellular Ca 2+ increase prompting these pathways remains elusive.…”

Mitochondrial Dysfunction Plays a Relevant Role in Pathophysiology of Peritoneal Membrane Damage Induced by Peritoneal Dialysis

“…In fact, the presence of free radicals in the effluent is associated with technique failure in stable PD patients [ 13 , 14 ]. Previous studies have demonstrated that glucose-rich and/or acidic hypertonic PD solutions could be associated with higher levels of oxidative stress [ 15 , 16 , 17 , 18 ]. The PD-related oxidative process can be modulated by drug treatments used in these patients [ 19 , 20 ].…”

Regimen-related Mortality Risk in Patients Undergoing Peritoneal Dialysis Using Hypertonic Glucose Solution: A Retrospective Cohort Study

“…In light of our main findings, the following points briefly clarify our hypothesis. First, the destruction of peritoneal mesothelial cells has been reported in previous studies, and in particular, it has found to be higher after exposure to 4.2% dextrose [ 3 , 25 ]. Kang et al [ 26 ] found that various incremental ranges in glucose concentrations, including 30, 60, and 90 mmol/L, caused 2.3-, 3.6-, and 4.0-fold increases in the induced fibrosis factor, respectively.…”