Abstract: TH-PO940
Translational Medicine in CKD: Therapeutic Targeting of p-Cresyl Sulfate Triggered Nonspecific ROS in Uremic Lung Injury
Session Information
- Molecular Mechanisms of CKD - I
October 25, 2018 | Location: Exhibit Hall, San Diego Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 1903 CKD (Non-Dialysis): Mechanisms
Author
- Chang, Jia-Feng, En Chu Kong Hospital, New Taipei City, Taiwan
Background
p-Cresyl sulfate (PCS) exerts pro-inflammatory, pro-oxidant, and pro-apoptotic effects on multi-cell systems. Nonetheless, mechanisms and therapies of PCS induced uremic lung injury (ULI) in chronic kidney disease (CKD) remain unclear.
Methods
We analyzed pleural effusions from CKD and non-CKD patients with respiratory distress for uremic toxins, hydroxyl radicals, and chemotactic cytokines. From bedside to bench, cell viability and inflammatory signaling pathways with reactive oxygen species (ROS) were investigated in PCS-treated human alveolar cell model. To mimic human diseases, CKD-ULI mouse model was developed with quantitative comparison of immunostaining and morphometric approach.
Results
Pleural effusions exhibit higher expressions of PCS/ indoxyl sulphate/ hydroxyl radicals/ IL-5/ IL-6/ IL-8/ IL-10/ ENA-78/ MDC/ THPO/ VEGF and leukocyte recruitment with proteinaceous leak in CKD patients. In vitro, PCS promotes alveolar cell death, cPLA2/COX-2 expression, and NADPH oxidase/mitochondria activation-related ROS burst. Intracellular ROS burst is abrogated by non-specific antioxidant (N-acetyl cysteine, NAC), inhibitors of NADPH oxidase and mitochondria-targeted superoxide scavenger. However, only NAC protects against PCS-induced cell death. In vivo, expressions of cPLA2/ COX2/ 8-OHdG, dust cells, recruited leukocytes, alveolar space, plasmatic leakages and interstitial edema increase in lung tissues of CKD-ULI mice, and NAC pretreatment ameliorates ULI and alveolar cell death.
Conclusion
PCS impairs alveolar-capillary integrity through triggering intracellular ROS burst, activating downstream PG pathways, cell death, and recruiting leukocytes to release ROS and multiplex chemoattractants. Our translational research resolves puzzling mechanisms of CKD-ULI, proving that PCS and nonspecific ROS serve as potential therapeutic targets.
Mechanisms of CKD-ULI
Funding
- Private Foundation Support