Abstract: TH-PO743
Interleukin (IL)-27-Induced Podocyte Injury in Minimal Change Nephrotic Syndrome (MCNS)
Session Information
- Glomerular Diseases: Podocyte Biology - I
November 02, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1403 Podocyte Biology
Authors
- Chan, Chang-Yien, National University of Singapore Yong Loo Lin School of Medicine, Singapore, Singapore
- Yang, Henry He, Cancer Science Institute of Singapore, Singapore, Singapore
- Zhang, Yaochun, National University of Singapore Yong Loo Lin School of Medicine, Singapore, Singapore
- Lu, Liangjian, Khoo Teck Puat-National University Children’s Medical Institute, National University Health System, Singapore, Singapore
- Teo, Sharon, Khoo Teck Puat-National University Children’s Medical Institute, National University Health System, Singapore, Singapore
- Ng, Kar Hui, National University of Singapore Yong Loo Lin School of Medicine, Singapore, Singapore
- Yap, Hui Kim, National University of Singapore Yong Loo Lin School of Medicine, Singapore, Singapore
Background
We have previously demonstrated that relapse in MCNS was associated with decreased monocyte expression of CD14 and downregulation of proinflammatory cytokines in lipopolysaccharide-stimulated monocytes. This study aimed to identify the dysregulated monokines in disease relapse and subsequently to investigate the proteinuria-inducing mechanism in an experimental rat model and cultured human podocytes.
Methods
Monocytes were isolated from 5 MCNS patients in relapse (MCNSrelapse) and remission (MCNSrem) using monocyte isolation kit II. Monocyte transcription profile was performed using Illumina Human Ref8 chips. Plasma IL-27 levels were measured in 14 MCNS patients in relapse and remission and 20 healthy controls. Experimental rat model was created through electroporation of IL-27 plasmid DNA in Wistar rats. The role of IL-27 in human podocytes was examined through cell RhoA/Rac1 and STAT1/3 activities. Statistical analysis was done using Mann-Whitney test and Wilcoxon signed rank test for paired data.
Results
Monocyte transcriptome in MCNSrelapse involved regulation of IL-1 signaling, RhoGTPases regulation of actin cytoskeleton, toll-interleukin receptor (TIR)-domain-containing adapter-inducing interferon-β (TRIF) and IFN-induction pathways. Analysis of monokine gene expression showed 2.7-fold increase in IL27 expression in MCNSrelapse. Plasma IL-27 levels were also significantly higher in MCNSrelapse (1.56±0.19ng/ml) compared to MCNSrem (0.95±0.13ng/ml) (P<0.05) and controls (0.89±0.14ng/ml) (P≤0.01). Similarly, in an IL-27 overexpression rat model, both 24-hour urine albumin excretion (409±34 vs 251±34µg/24h, P=0.005) and plasma triglyceride levels (36±2 vs 27±2mg/dL, P=0.02) were significantly higher at Day 70, compared to control rats. This was associated with upregulation of glomerular pSTAT3 expression in IL-27 transfected rats. Additionally, IL-27 stimulation in human podocytes resulted in phosphorylation of both STAT1 and STAT3 as well as 1.56-fold increase in activated Rac1 levels.
Conclusion
corroborated in the IL-27 overexpression rat model demonstrating podocyte injury possibly through activation of STAT3 and Rac1 as shown on podocyte culture experiments.
Funding
- Government Support – Non-U.S.