Abstract: SA-OR39
Cytosolic Phospholipase A2: A Drug Target in FSGS
Session Information
- Glomerular Diseases: Trials, Prognostic Markers, and Podocyte Biology
November 06, 2021 | Location: Simulive, Virtual Only
Abstract Time: 04:30 PM - 06:00 PM
Category: Glomerular Diseases
- 1204 Podocyte Biology
Authors
- Erkan, Elif, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States
- Chhaing, Richard, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States
- Potter, Andrew, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States
Background
Focal Segmental Glomerulosclerosis (FSGS) is the most common glomerular cause of end stage kidney disease (ESKD) in children. The refractory nature of FSGS renders treatment of FSGS as one of the most difficult challenges in pediatric nephrology. A significant knowledge gap in understanding the mechanism of progression in FSGS hampers development of successful treatment strategies.
We demonstrated that patients with FSGS present with a distinct urinary lipid profile characterized by increased fatty acids (FA) and lysophosphatidylcholines (LPC), metabolites of cytosolic phospholipase A2 (cPLA2). We propose that LPC and FA incites proinflammatory and proapoptotic response in podoctes and proximal tubule epithelial cells (PTECs). We hypothesize that increased cPLA2 activity induces apoptosis, fibrosis and progression in FSGS by harboring intracellular LPC and FA.
Methods
A bigenic model of FSGS was induced by mutation of Fyn and Cd2ap (Fyn–/–Cd2ap+/–) in podocytes. A second model of FSGS was generated by adriamycin injection in mice. Animals subjected to adriamycin were treated by intraperitoneal cPLA2 inhibitor (AACOCF3-4mM) versus saline for 6 weeks.
Untargeted lipidomics was performed in urine and kidney lysates of FSGS mice by CSH-QTOF MS/MS.
cPLA2 expression in podocytes and PTECs was investigated by RNA sequencing.
Western blotting and immunofluorescence staining was utilized to examine cPLA2 expression.
Results
Lipid profiling revealed increased urinary LPC and FA and increased LPC levels in kidney lysates of FSGS mice reminiscent of human data. FSGS mice kidneys displayed increased cPLA2 activity in podocytes and PTECs. RNA seq data revealed upregulation of cPLA2 in podocytes and PTECs in FSGS mice. Treatment with AACOCF3 decreased proteinuria and ameliorated kidney dysfunction, FSGS pathology and tubulointerstitial fibrosis.
Conclusion
Our data strongly suggest that increased cPLA2 expression contributes to progression of FSGS by harboring production of proinflammatory and propapoptotic lipid metabolites. We propose that upregulated cPLA2 activity leads to podocytes and PTEC damage by perpetuating oxidative injury, apoptosis, inflammation and subsequent fibrosis in FSGS. We postulate that targeting cPLA2 pathway for drug development will improve outcomes in FSGS. Furthermore urinary lipid metabolite profile is a promising biomarker to monitor disease progression and treatment response in FSGS.
Funding
- Commercial Support –