Abstract: FR-PO1004
Farnesoid X Receptor Agonism Prevents Neutrophil Extracellular Traps via Reduced Sphingosine-1-Phosphate in CKD
Session Information
- CKD Mechanisms: From Mendel to Mars
November 03, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 2303 CKD (Non-Dialysis): Mechanisms
Authors
- Jones, Bryce A., Georgetown University Medical Center, Washington, District of Columbia, United States
- Myakala, Komuraiah, Georgetown University Medical Center, Washington, District of Columbia, United States
- Guha, Mahilan, Georgetown University Medical Center, Washington, District of Columbia, United States
- Davidson, Shania Ro'Shea, Howard University College of Arts and Sciences, Washington, District of Columbia, United States
- Adapa, Sharmila, Georgetown University Medical Center, Washington, District of Columbia, United States
- Lopez Santiago, Isabel, Georgetown University Medical Center, Washington, District of Columbia, United States
- Schaffer, Isabel, Georgetown University Medical Center, Washington, District of Columbia, United States
- Wang, Xiaoxin, Georgetown University Medical Center, Washington, District of Columbia, United States
- Rosenberg, Avi Z., Johns Hopkins Medicine, Baltimore, Maryland, United States
- Levi, Moshe, Georgetown University Medical Center, Washington, District of Columbia, United States
Background
Activation of the farnesoid X receptor (FXR) reduces renal inflammation, but the underlying mechanisms remain elusive. Neutrophil extracellular traps (NETs) are webs of DNA formed when neutrophils undergo specialized programmed cell death (NETosis). Sphingosine-1-phosphate (S1P) is a signaling lipid that stimulates NETosis via its receptor on neutrophils. Here, we identify FXR as a negative regulator of kidney NETosis via repressing S1P signaling in male but not female mice.
Methods
We determined the effects of the FXR agonist obeticholic acid (OCA) in mouse models of adenosine phosphoribosyltransferase deficiency and Alport syndrome. We assessed renal NETosis by immunofluorescence in these models and in biopsies from patients with Alport syndrome (6 male, 9 female). We also inhibited de novo sphingosine production in Alport mice to show a causal relationship between S1P signaling and renal NETosis.
Results
Renal FXR activity is greatly reduced in both models, and OCA prevents kidney fibrosis, inflammation, and lipotoxicity. OCA reduces renal neutrophilic inflammation and NETosis in male adenine and Alport mice, but not in female adenine mice. Extensive NETosis was also identified in human Alport kidney biopsies. Kidney sphingosine kinase 1 (Sphk1) expression is increased in mice with kidney disease and reduced by OCA in male but not female mice. Also, Sphk1 expression correlates with NETosis in male but not female mice. Short-term inhibition of sphingosine synthesis reduces neutrophilic inflammation and NETosis.
Conclusion
FXR agonism represses kidney Sphk1 expression in male but not female mice. This inhibits renal S1P signaling, thereby reducing neutrophilic inflammation and NETosis in a sex-dependent manner.
Funding
- NIDDK Support