Kidney Week

Abstract: SA-PO0162

Mechanism of PI4KA/PI4P Axis Regulation of Lysosome-Dependent Cell Death in the Progression of Oxalate Nephropathy and the Therapeutic Potential of Hydroxychloroquine

Session Information

• AKI: Mechanisms - 3
  November 08, 2025 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

• 103 AKI: Mechanisms

Authors

• Xu, Yanfang, Department of Nephrology, Blood Purification Research Center, the First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian, China

Yanfang Xu, MD, PhD

• Chen, Zhimin, Department of Nephrology, Blood Purification Research Center, the First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian, China

Zhimin Chen, MD

• Xie, Jingzhi, Department of Nephrology, Blood Purification Research Center, the First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian, China

Jingzhi Xie, MD

• Yue, Chen, Department of Nephrology, Blood Purification Research Center, the First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian, China

Chen Yue, MSc

Background

Oxalate nephropathy (ON) is a renal disorder caused by oxalate deposition, leading to tubular epithelial cell death, inflammation, and fibrosis. ON progression is linked to lysosomal membrane permeabilization (LMP), which activates cell death pathways. Phosphatidylinositol 4-kinase alpha (PI4KA) regulates lysosomal stability through PI4P production. In ON models, PI4KA downregulation results in lysosomal damage and promotes tubular epithelial cell death. This study examines PI4KA’s role in ON progression, focusing on its regulation of lysosomal stability and cell death.

Methods

A chronic oxalate nephropathy mouse model was established with an oxalate-rich diet. Kidney tissues were collected at 0, 7, 14 and 25 days for single-cell RNA sequencing (ScRNA-seq). PI4KA expression was assessed via qPCR and Western blot. A Pi4ka knockout mouse model （Pi4ka^fl/flKsp^Cre-ERT2）was used to evaluate the impact of PI4KA deletion on tubular injury, inflammation, and cell death. Flow cytometry and immunofluorescence were employed to detect apoptosis, pyroptosis, necroptosis, and ferroptosis. The effect of hydroxychloroquine (HCQ) on LMP and cell death induced by PI4KA deletion was also assessed.

Results

In the ON model, PI4KA expression was significantly downregulated, correlating with tubular injury. Pi4ka^fl/flKsp^Cre-ERT2mice exhibited severe renal dysfunction, tubular dilation, necrosis, and inflammation, along with increased cell death and activation of multiple cell death pathways. PI4KA deletion caused disturbances in calcium homeostasis, increased ROS production, and lipid peroxidation. HCQ alleviated LMP and cell death induced by PI4KA deletion, restoring oxidative stress and calcium balance, improving lysosomal function, and reducing cathepsin release. HCQ also improved kidney function and reduced tissue damage in the ON model.

Conclusion

PI4KA downregulation destabilizes lysosomal membranes, triggering LMP and cell death pathways, exacerbating tubular injury in ON. HCQ modulates lysosomal stability, mitigating oxidative stress, calcium overload, and LMP, thus delaying ON progression. These findings offer a novel therapeutic strategy for ON through lysosomal stabilization.

Digital Object Identifier (DOI)

• doi: 10.1681/ASN.2025azjdcrqw