Abstract: TH-PO1154
Role and Mechanism of Mitochondria-Associated Endoplasmic Reticulum (MAM) in P2X7R-Induced Kidney Inflammation and Fibrosis
Session Information
- CKD: Mechanisms, AKI, and Beyond - 1
November 06, 2025 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 2303 CKD (Non-Dialysis): Mechanisms
Authors
- Zhang, Qunzi, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University Department of Radiology, Shanghai, China
- He, Li, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University Department of Radiology, Shanghai, China
- Cao, Aili, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University Department of Radiology, Shanghai, China
- Fan, Ying, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University Department of Radiology, Shanghai, China
- Wang, Niansong, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University Department of Radiology, Shanghai, China
Background
Recent studies indicate that the activation of P2X7R induces renal inflammation, and the abnormal structure of mitochondria-associated endoplasmic membranes (MAMs) is an important pathological basis in the progression of renal fibrosis，but the exactly mechanism remains unclear. We test whether P2X7R exacerbates renal fibrosis through MAMs-mediated NLRP3 inflammasome activation.
Methods
In vivo, adenine-induced CKD models were generated using male P2X7Rfl/flGgt1-Cre(+) mice (conditional knockout, CKO) and littermate control mice. A438079, a P2X7R antagonist, was administered orally. We collected and analyzed kidney samples, urine and serum.
In vitro, human HK2 cells were exposed to adenine, and then regulated P2X7R, VDAC with inhibitors, siRNAs and mutant plasmids. MAMs formation, mitochondrial dynamics, NLRP3 inflammasome, and inflammatory cytokine levels (IL-1β, IL-18) were evaluated.
Results
In CKD mice, adenine increased renal P2X7R expression, impaired renal function, aggravated tubular inflammation and mitochondrial dysfunction. yet, genetic P2X7R ablation or pharmacological inhibition with A438079 attenuated these pathological changes, concomitant with reduced MAMs formation and suppressed NLRP3 inflammasome activation.
In vitro, HK2 cells exposed to adenine exhibited increased P2X7R accompanied by elevated MAMs production, altered mitochondrial dynamics and NLRP3-driven cytokine release. Inhibited P2X7R downregulate the formation of MAMs, which decrease the NLRP3 inflammasome activation , whereas upregulated P2X7R aggravated these mitochondrial perturbations. Moreover, partly through MAMs-related pathway, activation of P2X7R regulated NLRP3 inflammasome，which is required for the progression of renal inflammation. Our work found that the inhibition of P2X7R ameliorated mitochondrial dysfunction in renal fibrosis partly through MAMs-related signaling pathway.
Conclusion
The results suggest a novel mechanism linking P2X7R to impair mitochondrial quality control during tubular injury in the pathogenesis of renal inflammation and suggest MAMs-related pathway may may represent a therapeutic strategy to mitigate CKD progression.