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 11 R-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.11 R-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 11 R-VIVIT administration alleviated RTEC apoptosis after Bi-IRI.Consistently,preapplication of 11 R-VIVIT(100 nM)and transfection with NFAT2-targeted siRNA markedly suppressed TGFβ-induced HK-2 cell apoptosis in vitro.In conclusion,11 R-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.

Zhi-yong Xie;Wei Dong;Li Zhang;Meng-jie Wang;Zhen-meng Xiao;Yu-hua Zhang;Wan-xin Shi;Ying Huang;Yan Yang;Cui-li Li;Lei Fu;Xing-chen Zhao;Rui-zhao Li;Zhi-lian Li;Yuan-han Chen;Zhi-ming Ye;Shuang-xin Liu;Zheng Dong;Xin-ling Liang

The Second School of Clinical Medicine,Southern Medical University,Guangzhou 510515,China;Division of Nephrology,Guangdong Provincial People's Hospital,Guangdong Academy of Medical Sciences,Guangzhou 510080,China;School of Medicine,South China University of Technology,Guangzhou 510006,China;Department of Cellular Biology and Anatomy,Medical College of Georgia at Augusta University,Augusta,GA,USA;Department of Medical Research,Charlie Norwood Veterans Affairs Medical Center,Augusta,GA,USA

中国药理学报（英文版）

[1]Zhi-yong Xie;Wei Dong;Li Zhang;Meng-jie Wang;Zhen-meng Xiao;Yu-hua Zhang;Wan-xin Shi;Ying Huang;Yan Yang;Cui-li Li;Lei Fu;Xing-chen Zhao;Rui-zhao Li;Zhi-lian Li;Yuan-han Chen;Zhi-ming Ye;Shuang-xin Liu;Zheng Dong;Xin-ling Liang-.NFAT inhibitor 11R-VIVIT ameliorates mouse renal fibrosis after ischemia-reperfusion-induced acute kidney injury)[J].中国药理学报（英文版）,2022(08):2081-2093

11R,maladaptive,renoprotective,preapplication

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