Abstract: TH-PO485
High Throughput Sequencing of Human Kidney Tissue Implicates FRMD3 as Important in the Pathogenesis of Progressive CKD
Session Information
- CKD: Mechanisms - I
November 07, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 2103 CKD (Non-Dialysis): Mechanisms
Authors
- Doyle, Ross P., University College Dublin, Dublin, Ireland
- McEvoy, Caitriona M., University Health Network, Toronto, Toronto, Ontario, Canada
- Brennan, Eoin P., University College Dublin, Dublin, Wilton, Ireland
- Conlon, Peter J., Beaumont Hospital, Dublin 9, Co Dublin, Ireland
- Sadlier, Denise M., University College Dublin, Dublin, Wilton, Ireland
- Godson, Catherine, The Conway Institute of Biomolecular and Biomedical, Belfield, Dublin, Wilton, Ireland
Background
The global health concern of Chronic Kidney Disease (CKD) is enhanced by the struggle to predict future disease events, particularly progression to End Stage Kidney Disease (ESKD). We examined the transcriptional profile of human kidney biopsies, aiming to provide insight into the mechanisms of progressive CKD. We evaluated the potential role of the candidate gene FRMD3in CKD progression.
Methods
RNA extracted from kidney biopsy tissue was sequenced using high throughput techniques and gene expression correlated with clinical variables, eGFR and percentage tubulointerstitial fibrosis (%TIF) on kidney biopsy. We identified genes which were differentially expressed in patients experiencing progressive CKD (doubling of serum creatinine or reaching ESKD). Analyses were adjusted for age and sex of the patients, and with a FDR cut-off of <0.05. Using established cellular models we examined the impact of knock-down of the gene FRMD3in human kidney epithelial cells and podocytes.
Results
We examined gene expression in discovery (n=24) and validation cohorts (n=23) and identified a subset of genes which correlated with the clinical variables, eGFR and %TIF, and were associated with CKD progression. Pathways of inflammation and immune system function are heavily represented in our dataset . FRMD3 expressionwas consistently associated with worse kidney disease, with lower expression seen in patients with higher %TIF and lower eGFR, and in patients with progressive CKD.
FRMD3 knockdown enhances the fibrotic responses to TGF-β1, including loss of E-cadherin, upregulation of N-cadherin and CTGF in human kidney epithelial cells, and exaggerated loss of podocin in immortalised human podocytes.
Conclusion
Inflammatory cell signaling pathways are driving forces in CKD progression. Loss of FRMD3 is associated with more severe kidney disease and CKD progression.
Funding
- Private Foundation Support