Intermittent hypoxia in rat enhancing peritoneal membrane thickening through HIF-1α-induced cytokines in peritoneum
Wasin Manuprasert,1 Asada Leelahavanichkul,4 Sirigul Kanjanabuch,1 Preecha Ruangvejvorachai,2 Krissanapong Manotham,6 Sompol Sanguanrungsirikul,3 Talerngsak Kanjanabuch1,5,7
1 Center of Excellence in Kidney Metabolic Disorders,
2 Department of Pathology,
3 Department of Physiology,
4 Department of Microbiology, and
5 Division of Nephrology, Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
6 Molecular and Cell Biology Unit, Department of Medicine, Lerdsin General Hospital, Bangkok, Thailand
7 PD Excellence Center, King Chulalongkorn Memorial Hospital, Bangkok, Thailand
Abstract
Background: Due to the high prevalence of both obstructive sleep apnea syndrome (OSA) and end-stage renal disease (ESRD), the co-existence of both conditions in peritoneal dialysis is demonstrated. Because OSA-induced chronic intermittent hypoxia is well-known, the hypoxia might worsen peritoneal membrane.
Objective: We tested the influence of chronic intermittent hypoxia upon peritoneal membrane in a Sprague-Dawley rat model.
Methods: Normal saline or 3.86% glucose peritoneal dialysis fluid (PDF) were intra-peritoneally administered twice a day as negative (NSS group) and positive controls (PDF group), respectively. Intermittent hypoxia was induced by using a hypoxic chamber with 10% O2 for 8 hours a day plus twice-daily NSS injection (IH group).
Results: At 12 weeks of the experiments, high serum TNF-α and IL-6 (but not IL-10) with normal renal and liver functions were demonstrated in the IH group (but not the PDF group). In parallel, local cytokines (TNF-α, IL-6, and IL-10 in peritoneal membrane) and peritoneal membrane thickness were increased whereas peritoneal membrane hypoxia (hypoxyprobeTM and hypoxia-inducible factor-1α; HIF-1α) was induced in both PDF and IH groups (more prominent in the PDF group). However, the increased vascular density in submesothelial area was established only in the PDF group.
Conclusion: Intermittent hypoxia model induced local peritoneal membrane inflammation and enhanced peritoneal membrane thickness, at least in part, through a mechanism of hypoxia-induced HIF-1α. Although peritoneal membrane alterations from PDF were more prominent than intermittent hypoxia, the combination between intermittent hypoxia with PDF utilization might facilitate peritoneal membrane failure, which will need more study.
Key words: Peritoneal dialysis, peritoneal membrane, sleep apnea syndrome, intermittent hypoxia, HIF-1α, peritoneal inflammation,