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<p>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 an immune checkpoint molecule and highly expressed in macrophages, in attenuating IR-induced renal injury. Using genetic deficiency animal&#xa0;models, we demonstrate that both&#xa0;VISTA deficient&#xa0;(<i>Vsir</i><sup>−/−</sup>) mice&#xa0;and macrophages-specific VISTA knockout (<i>Vsir</i><sup>fl/fl</sup><i>Lyz2</i><sup>Cre</sup>) mice&#xa0;exhibited significantly exacerbated renal dysfunction and histopathological damage post-IR injury. Mechanistically, hypoxia-inducible factor-1α&#xa0;(HIF-α), as a transcriptional regulator, induced VISTA expression in macrophages post IR injury. VISTA deficiency in macrophages reprogrammed these cells toward a pro-inflammatory phenotype via promoting&#xa0;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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月6日

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  • Cuidi Xu,
  • Juntao Chen,
  • Siyue Chen,
  • Lifei Liang,
  • Hao Zeng,
  • Pingbao Zhang,
  • Xuanchuan Wang,
  • Tongyu Zhu,
  • Cheng Yang,
  • Ruiming Rong

摘要

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 an immune checkpoint molecule and highly expressed in macrophages, in attenuating IR-induced renal injury. Using genetic deficiency animal models, we demonstrate that both VISTA deficient (Vsir−/−) mice and macrophages-specific VISTA knockout (Vsirfl/flLyz2Cre) mice exhibited significantly exacerbated renal dysfunction and histopathological damage post-IR injury. Mechanistically, hypoxia-inducible factor-1α (HIF-α), as a transcriptional regulator, induced VISTA expression in macrophages post IR injury. VISTA deficiency in macrophages reprogrammed these cells toward a pro-inflammatory phenotype via promoting 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.