Abstract: FR-PO1040
Acyloxyacyl Hydrolase Protects Against Kidney Injury via Inhibition of Tubular CD74-Macrophage Cross-Talk
Session Information
- CKD Mechanisms: Progression, Fibrosis, and Beyond
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
- Wu, Zhenkai, Shanghai Jiao Tong University School of Medicine Affiliated Ninth People's Hospital, Shanghai, China
- Pan, Yu, Shanghai Jiao Tong University School of Medicine Affiliated Ninth People's Hospital, Shanghai, China
- Ding, Feng, Shanghai Jiao Tong University School of Medicine Affiliated Ninth People's Hospital, Shanghai, China
Background
Renal tubulointerstitial fibrosis is the final common pathway in the progression of chronic kidney disease (CKD) to end-stage renal disease (ESRD). Acyloxyacyl hydrolase (AOAH) is expressed in renal tubular epithelial cells and other immune cells. Research shows that AOAH plays a critical role in infections and chronic inflammatory diseases. However, its role in kidney injury and fibrosis is unknown.
Methods
AOAH expression was examined in human and mouse kidneys. Single cell RNA sequencing (scRNA-seq) was performed for kidneys from FA-treated wild type (WT) and Aoah-/- mice. Aoah-/- mice and Aoah-/- mice with overexpression of Aoah in kidney were used to determine its role in kidney injury induced by folic acid (FA), unilateral ureteral obstruction (UUO), and lipopolysaccharide (LPS).
Results
AOAH expression was positively correlated with estimated glomerular filtration rate (eGFR) while negatively correlated with the degree of renal fibrosis in human kidney biopsy tissue. AOAH deletion led to exacerbated kidney injury and fibrosis after FA administration, which was reversed by overexpression of Aoah in kidney. scRNA-seq analysis revealed that Aoah-/- mice exhibited increased subpopulation of proximal tubular epithelial cells (PTECs) expressing CD74, even though total PTECs were decreased compared to WT mice after FA treatment. Finally, exacerbated renal inflammation and fibrosis seen in Aoah-/- mice after kidney injury was attenuated via administration of ISO-1, an inhibitor of macrophage inhibition factor (MIF) and CD74 binding.
Conclusion
AOAH plays a protective role in renal inflammation and fibrosis by inhibiting renal tubular epithelial cells CD74 signaling pathways, which involves tubule-macrophage crosstalk. Targeting kidney AOAH represents a promising strategy to prevent renal fibrosis progression.