Key Points

Upregulation of Bmpr2 was identified as a central cause of glomerular endothelial cell activation and injury in lupus nephritis.Glomerular endothelial cells with elevated Bmpr2 expression promoted inflammatory differentiation of macrophages.C5a mediated the increase in Bmpr2 expression in glomerular endothelial cells.

Background

Lupus nephritis, a severe complication of SLE, is closely associated with the abnormal activation of glomerular endothelial cells. Despite its significance, the core mechanisms underlying glomerular endothelial cell activation remain elusive.

Methods

We performed single-nucleus RNA sequencing (snRNA-seq) on kidney tissues from lupus nephritis patients and mouse models to investigate transcriptional alterations in glomerular endothelial cells and validated our findings in two lupus nephritis models: pristane-induced lupus nephritis and murphy roths large/lpr mice. Genetically modified mice and cultured cells were used to further validate the key discoveries.

Results

Bmpr2 was identified as a critical regulator, showing significant upregulation in glomerular endothelial cells from both lupus nephritis patients and mouse models. Elevated Bmpr2 expression correlated with enhanced glomerular endothelial cell proliferation and migration and increased expression of adhesion molecules (Vcam1, Icam1). BMPR2 activated SMA- and MAD-related proteins-dependent pathways, leading to the upregulation of downstream targets ID1 and ID3, thereby promoting glomerular endothelial cell hyperactivation. Bmpr2 overexpression amplified glomerular endothelial cell proliferation and migration, whereas inhibition of inhibitor of DNA binding signaling by 4-[6-[4-[2-(4-Morpholinyl)ethoxy]phenyl]pyrazolo[1,5-a]pyrimidin-3-yl]quinoline (DMH2) or endothelial-specific Bmpr2 knockout attenuated these effects. Moreover, targeting BMPR2 signaling reduced the infiltration of CD86+ macrophages into lupus nephritis kidneys. Coculture experiments confirmed that Bmpr2-activated glomerular endothelial cells promoted macrophage differentiation into an inflammatory phenotype. Complement component C5a was identified as a critical upstream inducer of Bmpr2 in glomerular endothelial cells, and inhibition of C5a signaling with the C5aR1 antagonist PMX-53 effectively suppressed Bmpr2 upregulation.

Conclusions

These findings highlight BMPR2 as a key regulator of glomerular endothelial cell injury and macrophage-mediated inflammation in lupus nephritis. Targeting BMPR2 or its upstream activators, such as C5a, effectively treated and improved lupus nephritis.