VISTA attenuates ischemia reperfusion-induced renal injury and fibrosis by macrophage polarization reprogramming

Renal ischemia reperfusion (IR) injury is one of the major causes of acute kidney injury (AKI) and may contribute to the development of chronic kidney disease. However, the precise immunological mediators orchestrating these pathophysiological processes remain poorly defined. In the present study, we investigate the protective role of the V-domain Ig suppressor of T cell activation (VISTA), which is and immune checkpoint molecule and highly expressed in macrophages, in attenuating IR-induced renal injury. Using genetic deficiency models, we demonstrate that miace lacking VISTA ( Vsir ^−/− ) and macrophages-specific VISTA knockout ( Vsir ^fl/fl Lyz2 ^Cre ) exhibited significantly exacerbated renal dysfunction and histopathological damage post-IR injury. Mechanistically, hypoxia-inducible factor-1α, as a transcriptional regulator, induced VISTA expression in macrophages post IR injury. VISTA deficiency in macrophages reprogramed these cells toward a pro-inflammatory phenotype via NF-κB nuclear translocation, which amplified Th1 differentiation through IL-12 upregulation while simultaneously suppressing regulatory T cell expansion. Notably, neutralizing IL-12 activity rescued renal injury in VISTA-deficient mice, underscoring its role as a key effector in this pathway. Therapeutically, exogenous VISTA administration attenuated renal inflammation, fibrosis, and functional impairment, highlighting its direct renoprotective capacity. Therefore, VISTA emerges as a sentinel checkpoint protein that balances macrophage polarization and T cell immunity during AKI.