Cyclosporin A indirectly suppresses NK cells activity in renal microvascular inflammation by inducing ubiquitination-dependent degradation of ULBP1

Immune-mediated kidney diseases (IMKD) feature microvascular inflammation (MVI), where natural killer (NK) cells act as key effectors. Although cyclosporine A (CsA) is widely used to suppress immune activation in these conditions, its specific effects on NK cells within the renal microenvironment remain poorly defined. This study aimed to clarify how CsA regulates NK-cell function and to explore the role of endothelial cells in this process. Through bulk and single-cell RNA Sequencing (RNA-seq) datasets from public repositories, we found that activated NK cells were enriched in glomerular lesions and closely associated with glomerular endothelial cells. Co-culture experiments showed that CsA-pretreated endothelium reduced NK-cell activation and cytotoxicity. Further assays revealed that CsA induced ubiquitination-dependent degradation of endothelial UL16-binding protein 1 (ULBP1), an activating ligand for NKG2D, which in turn weakened NK-cell PI3K/Akt signaling and effector function. These results describe a mechanism linking CsA-induced endothelial changes to NK-cell inhibition. In conclusion, our study demonstrates an endothelium-NK cell axis through which cyclosporin A suppresses immune activation in microvascular inflammation. This mechanism advances current understanding of Calcineurin Inhibitor action and may guide dosing and the development of endothelial-targeted therapies in IMKD.

Cyclosporine A; Endothelial cells; Microvascular inflammation; NK cells; ULBP1; Ubiquitination.