Abstract: FR-PO1045
Inhibition of ATP-Citrate Lyase Improves CKD Through Multiple Mechanisms
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
- O'Neil, Kian S., McMaster University, Hamilton, Ontario, Canada
- Patel, Zeel, McMaster University, Hamilton, Ontario, Canada
- Soomro, Asfia, McMaster University, Hamilton, Ontario, Canada
- Fayyazi, Russta, McMaster University, Hamilton, Ontario, Canada
- Trink, Jackie, McMaster University, Hamilton, Ontario, Canada
- Gao, Bo, McMaster University, Hamilton, Ontario, Canada
- Macdonald, Melissa, McMaster University, Hamilton, Ontario, Canada
- Krepinsky, Joan C., McMaster University, Hamilton, Ontario, Canada
Background
ATP-citrate lyase (ACLY), upregulated in chronic kidney disease (CKD), catalyzes the synthesis of acetyl-coA from citrate. Acetyl-CoA is a vital precursor for lipid synthesis and histone acetylation that regulates gene expression. In kidney cells, ACLY regulates fibrogenic, lipogenic and inflammatory gene expression; its inhibition reduced fibrosis in the unilateral ureteral obstruction (UUO) model. The ACLY metabolic by-product malonyl-coA, however, is also an important inhibitor of fatty acid oxidation (FAO), and defective FAO in proximal tubular epithelial cells (PTEC) is now established as a major contributor to fibrosis. Here we tested the efficacy of a novel ACLY inhibitor (ACLYi) on reducing fibrosis and its potential role in improving FAO in UUO.
Methods
8-week-old male C57BL/6J mice underwent UUO surgery and were treated orally with an ACLY inhibitor (Espervita Therapeutics) for 10 days. Kidneys were assessed by immunohistochemistry, immunoblotting and RNAseq. Effects of ACLYi were tested on the HK2 PTEC cell line and primary renal fibroblast responses to TGFβ1 (5ng/ml, 48h), a cytokine known to promote fibrosis and reduce FAO. Lipid accumulation was assessed by Oil Red O staining and LC/MS analysis.
Results
ACLYi significantly and dose-dependently decreased fibrosis in the UUO model determined by trichrome, PSR, fibronectin and α-smooth muscle actin (SMA) expression. ACLYi decreased macrophage (F4/80) infiltration including that of the profibrotic M2 phenoype marked by CD206. RNAseq analysis showed upregulation of FAO-related hallmark pathways and reduction in inflammation pathways with ACLYi. Defective FAO is known to result in PTEC apoptosis and lipid accumulation. ACLYi reduced both apoptosis, as assessed by the presence of cleaved caspase 3, as well as lipid accumulation, with a particular decrease in cholesteryl esters. In HK2 cells and renal fibroblasts, TGFβ1-induced fibrotic protein expression was inhibited by ACLYi, and lipid accumulation was reduced in PTEC.
Conclusion
ACLYi reduced renal fibrosis, apoptosis and lipid accumulation in UUO mice. ACLYi also prevented profibrotic responses to TGFβ1 in PTEC and fibroblasts. Current studies are ongoing to confirm beneficial effects on restoring FAO.
Funding
- Commercial Support – Espervita Therapeutics