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Fluorofenidone protects against renal fibrosis by inhibiting STAT3 tyrosine phosphorylation

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Abstract

Signaling through the Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway, especially JAK2/STAT3, is involved in renal fibrosis. Fluorofenidone (FD), a novel pyridone agent, exerts anti-fibrotic effects in vitro and in vivo. Herein, we sought to investigate whether FD demonstrates its inhibitory function through preventing JAK2/STAT3 pathway. In this study, we examined the effect of FD on activation of rat renal interstitial fibroblasts, glomerular mesangial cells (GMC), and expression of JAK2/STAT3. Moreover, we explored the histological protection effects of FD in UUO rats, db/db mice, and phosphorylation of JAK2/STAT3 cascade. Our studies found that pretreatment with FD resulted in blockade of activation of fibroblast and GMC manifested by fibronectin (FN) and α-smooth muscle actin (α-SMA) protein expression and decline of STAT3 tyrosine phosphorylation induced by IL-6 or high glucose. In unilateral ureteral obstruction rats and a murine model of spontaneous type 2 diabetes (db/db mice), treatment with FD blocked the expression of FN and α-SMA, prevented renal fibrosis progression, and attenuated STAT3 activation. However, FD administration did not interfere with JAK2 activation both in vivo and in vitro. In summary, the molecular mechanism by which FD exhibits renoprotective effects appears to involve the inhibition of STAT3 phosphorylation.

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Acknowledgments

This project was supported by the Doctoral Foundation of the Ministry of Education of China (Grant No. 20120162130001), by the National Natural Science Foundation of China (Grant No. 81273575) to Dr Li-Jian Tao, and by the National Natural Science Foundation for Distinguished Young Scholars of China (Grant No. 81300610) to Dr Qiong-jing Yuan.

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Authors and Affiliations

  1. Division of Nephrology, Department of Internal Medicine, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China

    Juan Tang, Chun-yan Liu, Miao-miao Lu, Jing Zhang, Wen-juan Mei, Yan-yun Xie, Ling Huang, Zhang-zhe Peng, Qiong-jing Yuan & Li-jian Tao

  2. Division of Pathology, Hunan University of Chinese Medicine, Changsha, 410208, Hunan, China

    Chun-yan Liu

  3. Division of Endocrinology, Xiangya Third Hospital, Central South University, Changsha, 410013, Hunan, China

    Wen-jun Yang

  4. Division of Nephrology, Xiangya Third Hospital, Central South University, Changsha, 410013, Hunan, China

    Ji-shi Liu

  5. Department of Medical Chemistry, School of Pharmacy, Central South University, Changsha, 410008, Hunan, China

    Gao-yun Hu

  6. State Key Laboratory of Medical Genetics of China, Central South University, Changsha, Hunan, China

    Li-jian Tao

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  1. Juan Tang
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Correspondence to Li-jian Tao.

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Tang, J., Liu, Cy., Lu, Mm. et al. Fluorofenidone protects against renal fibrosis by inhibiting STAT3 tyrosine phosphorylation. Mol Cell Biochem 407, 77–87 (2015). https://doi.org/10.1007/s11010-015-2456-5

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