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Updated: Oct 9, 2025
Ischemia-reperfusion Model of Acute Kidney Injury and Post Injury Fibrosis in Mice
Published on: August 9, 2013
NFAT inhibitor 11R-VIVIT ameliorates mouse renal fibrosis after ischemia-reperfusion-induced acute kidney injury
Zhi-Yong Xie1,2, Wei Dong2, Li Zhang2
1The Second School of Clinical Medicine, Southern Medical University, Guangzhou, 510515, China.
Abstract:
Acute kidney injury (AKI) with maladaptive tubular repair leads to renal fibrosis and progresses to chronic kidney disease (CKD). At present, there is no curative drug to interrupt AKI-to-CKD progression. The nuclear factor of the activated T cell (NFAT) family was initially identified as a transcription factor expressed in most immune cells and involved in the transcription of cytokine genes and other genes critical for the immune response. NFAT2 is also expressed in renal tubular epithelial cells (RTECs) and podocytes and plays an important regulatory role in the kidney. In this study, we investigated the renoprotective effect of 11R-VIVIT, a peptide inhibitor of NFAT, on renal fibrosis in the AKI-to-CKD transition and the underlying mechanisms. We first examined human renal biopsy tissues and found that the expression of NFAT2 was significantly increased in RTECs in patients with severe renal fibrosis. We then established a mouse model of AKI-to-CKD transition using bilateral ischemia-reperfusion injury (Bi-IRI). The mice were treated with 11R-VIVIT (5 mg/kg, i.p.) on Days 1, 3, 10, 17 and 24 after Bi-IRI. We showed that the expression of NFAT2 was markedly increased in RTECs in the AKI-to-CKD transition. 11R-VIVIT administration significantly inhibited the nuclear translocation of NFAT2 in RTECs, decreased the levels of serum creatinine and blood urea nitrogen, and attenuated renal tubulointerstitial fibrosis but had no toxic side effects on the heart and liver. In addition, we showed that 11R-VIVIT administration alleviated RTEC apoptosis after Bi-IRI. Consistently, preapplication of 11R-VIVIT (100 nM) and transfection with NFAT2-targeted siRNA markedly suppressed TGFβ-induced HK-2 cell apoptosis in vitro. In conclusion, 11R-VIVIT administration inhibits IRI-induced NFAT2 activation and prevents AKI-to-CKD progression. Inhibiting NFAT2 may be a promising new therapeutic strategy for preventing renal fibrosis after IR-AKI.
Insights
A novel peptide inhibitor, 11R-VIVIT, shows promise in preventing the progression from acute kidney injury (AKI) to chronic kidney disease (CKD). By inhibiting nuclear factor of activated T cells 2 (NFAT2), it reduces renal fibrosis and cell apoptosis without adverse effects.
Area of Science:
- Nephrology
- Molecular Biology
- Pharmacology
Background:
- Acute kidney injury (AKI) can lead to maladaptive repair, resulting in renal fibrosis and progression to chronic kidney disease (CKD).
- Currently, no effective drugs exist to halt the AKI-to-CKD transition.
- Nuclear factor of activated T cells 2 (NFAT2) is implicated in kidney disease and is upregulated in renal tubular epithelial cells (RTECs) during fibrosis.
Purpose of the Study:
- To investigate the renoprotective effects of 11R-VIVIT, a peptide inhibitor of NFAT, on renal fibrosis during the AKI-to-CKD progression.
- To elucidate the underlying mechanisms of 11R-VIVIT's action in preventing kidney fibrosis.
Main Methods:
- Analysis of human renal biopsy tissues to assess NFAT2 expression in patients with severe renal fibrosis.
- Establishment of a mouse model of AKI-to-CKD transition using bilateral ischemia-reperfusion injury (Bi-IRI).
- Treatment of mice with 11R-VIVIT post-Bi-IRI and in vitro experiments using HK-2 cells with TGFβ stimulation.
Main Results:
- NFAT2 expression was significantly increased in RTECs of patients with severe renal fibrosis and in the mouse AKI-to-CKD model.
- 11R-VIVIT treatment inhibited NFAT2 nuclear translocation, reduced serum creatinine and blood urea nitrogen levels, and attenuated tubulointerstitial fibrosis in mice.
- 11R-VIVIT alleviated RTEC apoptosis in vivo and suppressed TGFβ-induced HK-2 cell apoptosis in vitro, with no observed cardiotoxicity or hepatotoxicity.
Conclusions:
- 11R-VIVIT administration effectively inhibits ischemia-reperfusion injury-induced NFAT2 activation, thereby preventing the progression of AKI to CKD.
- Targeting NFAT2 with inhibitors like 11R-VIVIT represents a promising therapeutic strategy for mitigating renal fibrosis following ischemic AKI.
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