The BPIFA2 - LRP5 axis orchestrates mitochondrial dysfunction to mediate kidney injury in lupus nephritis

Kidney injury, particularly the processes of inflammation and fibrosis, is a critical pathological feature of Lupus nephritis (LN). BPI fold-containing family A member 2 (BPIFA2), a recently identified parotid gland secretory protein, serves as an early biomarker for acute kidney injury (AKI) and has been shown to promote AKI development. However, the role of BPIFA2 in regulating LN remains largely unclear. In this study, we detected significant BPIFA2 expression in renal tubular epithelial cells of LN patients and animal models, which was strongly correlated with the degree of renal injury. Specifically, targeted knockdown of BPIFA2 in renal tubular epithelial cells significantly alleviated renal tubular injury in LN mice, while its overexpression exacerbated the injury. Mechanistically, under LN conditions, we found that BPIFA2 interacted with low density lipoprotein receptor-related protein 5 (LRP5) in HK-2 cells, resulting in mitochondrial dysfunction and ultimately leading to renal tubular injury. Collectively, our findings not only reveal a novel regulatory mechanism of renal tubular injury in LN but also suggest BPIFA2 as a promising therapeutic target for mitigating LN-associated kidney injury.