Abstract: FR-PO1197
Critical Role of Lysine-Specific Histone Demethylase 1 in Kidney Inflammation and Fibrosis
Session Information
- CKD: Mechanisms - 2
October 25, 2024 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 2303 CKD (Non-Dialysis): Mechanisms
Authors
- Jiao, Baihai, University of Connecticut School of Medicine, Farmington, Connecticut, United States
- Du, Hao, University of Connecticut School of Medicine, Farmington, Connecticut, United States
- Tran, Melanie, University of Connecticut School of Medicine, Farmington, Connecticut, United States
- Wang, Yanlin, University of Connecticut School of Medicine, Farmington, Connecticut, United States
Background
Chronic kidney disease is characterized by inflammation and fibrosis. Inflammation often triggers fibrosis, and fibrosis is the end result of chronic inflammatory reactions. Kidney inflammation is characterized by inflammatory cell infiltration and activation leading to inflammatory and fibrotic molecule production. However, there is a critical knowledge gap on molecular mechanisms underlying kidney inflammation and fibrosis. In this study, we evaluated the impact of lysine-specific histone demethylase 1 (LSD1) on kidney inflammation and fibrosis.
Methods
To explore the role of LSD1 in kidney inflammation and fibrosis in vivo, we generated mice with tamoxifen inducible deletion of LSD1 using Cre-LoxP strategy. Unilateral ureteral obstruction (UUO) and ischemia-reperfusion injury (IRI) models were used to induce kidney inflammation and fibrosis. Cultured macrophages were used to examine the role of LSD1 in the regulation of macrophage activation in vitro.
Results
LSD1 expression markedly increased in the kidneys following obstructive or ischemic injury. Mice with a tamoxifen-inducible deletion of LSD1 exhibited no significant morphological abnormalities in the kidney. Compared with Cre negative, floxed LSD1 mice, mice with tamoxifen-induced deletion of LSD1 exhibited fewer α-SMA+ myofibroblasts and expressed less α-SMA protein in the kidneys following UUO or IRI. Inducible deletion of LSD1 significantly ameliorated total collagen deposition and ECM protein production in the kidneys in response to UUO or IRI. Real-time RT-PCR showed that the mRNA expression levels of proinflammatory and profibrotic molecules were significantly increased after UUO or IRI, which were significantly reduced in LSD1 deficient mice. Furthermore, the activity of NF-κB signaling was significantly decreased in LSD1-deficient mice following UUO or IRI. In cultured macrophages, inhibition of LSD1 reduced NF-κB signaling activation and proinflammatory and profibrotic molecule expression.
Conclusion
Our study demonstrates that LSD1 is a key regulator of inflammation and renal fibrosis in chronic kidney disease. Targeting LSD1 could provide a novel therapeutic approach to mitigate kidney inflammation and fibrosis and ameliorate the progression of chronic kidney disease.
Funding
- NIDDK Support