Abstract: TH-PO0401
DHCR24 Alleviates Mesangial-Cell Activation and Glomerulosclerosis in Lupus Nephritis by Regulating Cholesterol Accumulation and TLR4/MyD88/NF-κB Signaling
Session Information
- Glomerular Diseases: Autoimmune Diseases
October 22, 2026 | Location: Exhibit Hall A, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1401 Glomerular Diseases: Mechanisms, including Podocyte Biology
Authors
- Zhou, Hua, Department of Nephrology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
- Hao, Xiangnan, Department of Nephrology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
- Luan, Junjun, Department of Nephrology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China
Background
Lupus nephritis (LN), a severe complication of systemic lupus erythematosus, is a leading cause of ESKD, with mesangial cells activation being important factor in glomerular injury. While dyslipidemia is associated with LN, the role of cholesterol metabolism in mesangial cells remains unclear. This study aimed to elucidate the mechanism of 24-dehydrocholesterol reductase (DHCR24), a key cholesterol synthesis enzyme, promotes mesangial cell activation in LN.
Methods
Firstly, bioinformatic analysis of LN patients’ glomerular transcriptomics in renal tissues from patients and mice verified the differetial expression of DHCR24 in both in LN patients and Fcgr2b-/- spontanous LN mice. Secondly, cholesterol levels, proliferation, and fibrosis in human mesangial cells (HMCs) were studied via DHCR24 overexpression or silence, and downstream toll-like receptor 4 (TLR4)/myeloid differentiation primary response 88 (MyD88)/nuclear factor kappaB (NF-κB) pathway. Finally, shDhcr24 was administered to LN mice for intervention in vivo, to explore DHCR24 as potential therapeutic target for LN.
Results
Integrated bioinformatics analysis identified DHCR24 as a top differentially expressed gene, and was validated in LN patient kidney biopsies by qPCR. DHCR24 protein was significantly upregulated in renal tissues from both LN patients and LN mice, positively correlated with severity of LN as reflected by proteinuria, serum creatinine, mesangial cell activation and glomerulosclerosis. DHCR24 overexpression in HMCs increased intracellular cholesterol accumulation, subsequently activated the lipid raft mediated TLR4/ MyD88/ NF-κB pathway, leading to upregulation of mesangial cell activation and fibrosis. Disrupting cholesterol enriched lipid rafts with methyl-β-cyclodextrin abolished DHCR24-induced activation of TLR4/MyD88/NF-κB pathway. Conversely, DHCR24 knockdown reversed TGF-β-induced TLR4/MyD88/NF-κB and mesangial cell activation and fibrosis. Adeno-associated virus-mediated Dhcr24 silencing in LN mice ameliorated proteinuria, reduced glomerular cholesterol deposition, suppressed TLR4 signaling, and alleviated mesangial activation and glomerulosclerosis.
Conclusion
DHCR24 drove LN progression by modulating cholesterol to activate the TLR4/MyD88/NF-κB pathway in mesangial cells, positioning it as a novel therapeutic target for intervening in LN.
Funding
- Government Support – Non-U.S.