Acute kidney injury (AKI), often triggered by ischemia-reperfusion (IR) injury during surgeries like transplantation, frequently progresses to irreversible fibrosis and chronic kidney disease (CKD). Despite the central role of immune cells in driving this process, the specific molecular checkpoints that control the transition from harmful inflammation to tissue repair have remained elusive. Now, research from the team of Professors Cheng Yang and Ruiming Rong at Fudan University has identified a critical protective player.
Published in Volume 2, article number 14, of the journal Immunity & Inflammation on March 06, 2026, the study titled "VISTA attenuates ischemia reperfusion-induced renal injury and fibrosis by macrophage polarization reprogramming" reveals that the immune checkpoint molecule VISTA (V-domain Ig suppressor of T cell activation) is a master regulator of kidney immune homeostasis. The team demonstrates that VISTA, predominantly expressed on kidney macrophages, orchestrates a protective response by reprogramming macrophage polarization and restraining pathogenic T cell immunity, opening a new avenue for therapies aimed at blocking the AKI–CKD continuum.
Immune Sentinel Dynamically Expressed in Kidney Injury
Using single-cell RNA sequencing and flow cytometry, the researchers first mapped VISTA expression in the kidney. They found that VISTA is highly expressed on renal macrophages—both resident and infiltrating populations—at levels significantly higher than on T cells or other immune subsets. Notably, VISTA expression followed a distinct biphasic pattern following IR injury: it was rapidly upregulated in the early acute phase (within hours to one day), suggesting an active role in the initial response, but progressively declined during the fibrotic phase (after seven days), coinciding with failed repair. “ This spatiotemporal expression profile positions VISTA as an immune sentinel tasked with balancing immune activation and inflammation resolution during kidney injury, ” Prof. Yang pointed out.
HIF-1α Drives VISTA to Reshape the Immune Microenvironment
To dissect the functional role of VISTA, the team generated both global Vsir knockout mice and mice with a macrophage-specific deletion of Vsir . In both models, VISTA deficiency dramatically exacerbated renal failure, tubular necrosis, and subsequent interstitial fibrosis following IR injury, confirming its non-redundant protective function.
Mechanistically, the study made several key discoveries. First, they identified the transcriptional driver of VISTA upregulation. The hypoxic environment caused by IR injury stabilizes hypoxia-inducible factor 1α (HIF-1α). Using chromatin immunoprecipitation (ChIP–qPCR) and dual-luciferase reporter assays, the team confirmed that HIF-1α binds directly to the Vsir promoter, driving its transcription in macrophages. This establishes a direct link between tissue hypoxia and the activation of this protective immune checkpoint.
Second, they elucidated how VISTA exerts its protective effects. VISTA signaling suppresses the nuclear translocation of NF-κB, a master transcription factor for pro-inflammatory genes. In the absence of VISTA, NF-κB becomes aberrantly activated, driving macrophages toward a pro-inflammatory M1 phenotype and significantly increasing secretion of IL-12.
Third, the study uncovered a critical crosstalk between macrophages and T cells. The excessive IL-12 produced by VISTA-deficient macrophages potently drives the differentiation of naive T cells into IFN-γ-producing Th1 cells, while simultaneously suppressing the expansion of regulatory T cells (Tregs). This macrophage–T cell immune imbalance—characterized by amplified Th1 responses and impaired Treg-mediated suppression—emerges as the core driver of exacerbated kidney injury and failed repair.
Translational Promise: Exogenous VISTA Shows Potent Protection
Critically, the team evaluated the therapeutic potential of targeting this pathway. Administering recombinant VISTA protein to mice at the time of reperfusion significantly attenuated kidney damage. Treated animals showed markedly reduced serum creatinine and blood urea nitrogen levels, diminished tubular necrosis, and less fibrotic area compared to controls.
These results provide compelling proof-of-concept that a VISTA-targeted immunomodulatory strategy can effectively reshape the kidney inflammatory microenvironment, shifting it from a destructive, pro-inflammatory state toward a pro-repair milieu. By simultaneously restraining macrophage-driven inflammation and the downstream pathogenic T cell response, “ this approach offers a promising therapeutic avenue for patients with acute kidney injury, with the potential to prevent long-term fibrotic sequelae and progression to chronic kidney disease, ” Prof. Rong concluded.
About Immunity & Inflammation
Immunity & Inflammation is a newly launched open-access journal co-published by the Chinese Society for Immunology and Springer Nature under the leadership of Editors-in-Chief Prof. Xuetao Cao and Prof. Jules A. Hoffmann. Immunity & Inflammation aims to publish major scientific questions and cutting-edge advances that explore groundbreaking discoveries and insights across the spectrum of immunity and inflammation, from basic science to translational and clinical research.
Website: https://link.springer.com/journal/44466
About Authors
Prof. Cheng Yang from Fudan University
Prof. Yang is the Deputy Director of the Kidney Transplantation Department at Zhongshan Hospital, Fudan University. He serves as a committee member of the Immunotherapy Engineering Branch of the Chinese Society of Biomedical Engineering. Dr. Yang has been recognized through several prestigious talent programs, including the Shanghai Health System New Outstanding Youth Program, the Shanghai Eastern Talent Program (Top Project), and the Shanghai High-level Local University Innovation Team, et al. He has received the Young Investigator Award/Basic Science Award from the American Transplant Society, the International Transplantation Society, and the European Transplant Society, as well as the First Prize of the Shanghai Research Hospital Association Science and Technology Award. His research focuses on the clinical and basic science of kidney transplantation.
Prof. Ruiming Rong from Fudan University
Prof. Rong is a Senior Clinical Professor at Fudan University and Chief Physician in the Department of Urology at Zhongshan Hospital. He is also a Principal Investigator in both the State Key Laboratory of Large Molecule Drugs and the Shanghai Key Laboratory of Organ Transplantation. His research focuses on kidney transplantation and ischemia-reperfusion injury.
Dr. Cuidi Xu from Fudan University
Dr. Xu is a resident physician and clinical postdoctoral fellow at Zhongshan Hospital, Fudan University. Her research focuses on kidney transplantation and ischemia-reperfusion injury.
Funding information
This study was supported by the National Natural Science Foundation of China (82270789 to R. R.; 82370754, 82170765 to C. Y.; 82241213 to T. Z.), and Shanghai Municipal Key Clinical Specialty (shslczdzk05802).
Experimental study
Animals
VISTA attenuates ischemia reperfusion-induced renal injury and fibrosis by macrophage polarization reprogramming
6-Mar-2026
The authors declare no competing interests.