Inhibition of Endothelial BRD4 Alleviates Lupus Nephritis partly through Interacting with FLI-1

Bromodomain 4 (BRD4) could be a therapeutic target in various diseases. We sought to investigate its role in lupus nephritis (LN) progression and explore whether targeting BRD4 could serve as a therapeutic approach for LN.

BRD4 expression in renal cells was evaluated by immunofluorescence. Inhibition of endothelial BRD4 in mice was conducted by using BRD4 shRNA-AAV targeting endothelial cells (ECs). Mouse lupus models were MRL/Lpr mice. Human glomerular ECs (GECs) coupled with RNA-seq, ChIP-PCR, and protein-protein interaction assays were performed to define underlying mechanisms.

BRD4 expression was increased in renal ECs in patients with LN and in mouse lupus models. BET inhibitor NHWD870 treatment greatly improved the features of LN in MRL/Lpr mice as evidenced by reduced lesions, IgG and C3 deposition, immune infiltration, and improved ultrastructural morphology in renal tissues. BRD4 shRNA-AAV treatment robustly ameliorated the hallmark features of LN in Lpr mice including proteinuria, histological and ultrastructural morphology of kidney and IgG and C3 deposition and immune infiltration in kidney in MRL/Lpr mice. Elevated BRD4 led to changes in many pathways linked to LN and promoted permeability and immune responses in GECs, which were associated with its interaction with FLI-1. BRD4 shRNA-AAV treatment attenuated FLI-1 expression in MRL/Lpr mice. BRD4 and FLI-1 were colocalized in renal ECs and FLI-1 expression was elevated in patients with LN.

Elevated BRD4 in ECs is involved in LN pathogenesis, which was partly associated with its interaction with FLI-1. Targeting endothelial BRD4 could be a therapeutic strategy for LN.