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Abstract: TH-PO795

Urinary Lipidomics: A New Biomarker in FSGS

Session Information

Category: Glomerular Diseases

  • 1201 Glomerular Diseases: Fibrosis and Extracellular Matrix

Authors

  • Erkan, Elif, Children's Hospital of Cincinnati, CIncinnati, Ohio, United States
  • Schuh, Meredith Posner, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States
  • Potter, Andrew, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States
  • Potter, Steven, Cincinnati Children's Hospital, Cincinnati, Ohio, United States
Background

Primary focal segmental glomerulosclerosis (FSGS) is the most common glomerular pathology leading to end-stage renal disease in pediatric patient population. The refractory nature of FSGS and a more than 30% recurrence rate after kidney transplantation 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 the development and implementation of successful treatment strategies. We reported an increase in urinary fatty acid (FA) and lysophosphatidylcholine (LPC) levels in patients with FSGS in comparison to patients with minimal change disease (MCD). We hypothesize that phospholipase A2 (PLA2) metabolizes phosphotidylcholine (PC) leading to LPC and FA accumulation causing cellular toxicity in proximal tubule epithelial cells and podocytes contributes to progression in FSGS.

Methods

Mouse model of FSGS was induced by mutation of Fyn and Cd2ap(Fyn–/–Cd2ap+/– ) in podocytes.
Untrageted lipidomics of urine and kidney lysates of FSGS mice was analyzed by CSH-QTOF MS/MS.
Cytosolic PLA2 expression in podocytes and proximal tubule epithelial cells was investigated by RNA sequencing.
Western blotting and immunoflurescence staining was utilized to examine cPLA2 and PLA2 receptor expression in FSGS mice and human kidney biopsy sections with MCD and FSGS.

Results

Untargeted lipidomics of FSGS mice urine demonstrated increased FA and LPC levels reminiscent of human urine samples. Lipidomic analysis of kidney lysate of FSGS mice revealed increased LPC levels. Cytosolic PLA2 and PLA2 receptor expression was increased in the proximal tubule epithelial cells and podocytes by western blotting, immunofluorecence and RNA sequencing in FSGS mice.
Human kidney biopsy sections with FSGS revealed increased cPLA2 and PLA2 receptor expression in proximal tubule epithelial cells and podocytes in comparison to MCD.

Conclusion

We concluded that PLA2 activity is increased in proximal tubule epithelial cells and podocytes in mouse and human FSGS. Moreover urinary detection of PLA2 by products, LPC and FA, renders urinary lipidomics a novel tool for predicting the diagnosis and prognosis of FSGS. We propose that increased levels of circulating PLA2 and cellular levels of cPLA2 leads to accumulation of toxic lipid metabolites and contributes to progression by inducing apoptosis and inflammation in FSGS.

Funding

  • NIDDK Support