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TRPV4 Mediates Cardiac Fibrosis via the TGF-β1/Smad3 Signaling Pathway in Diabetic Rats

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Abstract

Emerging evidence shows that the transient receptor potential vanilloid 4 (TRPV4) channel is involved in fibrosis in many organs. However, its role in diabetic cardiac fibrosis remains unclear. Our aim was to evaluate the expression level of TRPV4 in the diabetic heart and clarify its role in diabetes-induced cardiac fibrosis. A diabetic animal model was induced by a single intraperitoneal injection of streptozotocin into Sprague–Dawley rats. We also investigated cardiac fibroblasts isolated from neonatal Sprague–Dawley rats. TRPV4 expression was significantly upregulated in both diabetic myocardium and cardiac fibroblasts cultured in high-glucose medium. Masson’s trichrome staining revealed that the TRPV4 antagonist HC067047 attenuated the diabetes-induced cardiac fibrosis. Furthermore, HC067047 reduced collagen Ι synthesis and suppressed the transforming growth factor beta 1 (TGF-β1) level as well as the phosphorylation of Smad3 in the diabetic heart. In addition, the TRPV4 antagonist inhibited the proliferation of cardiac fibroblasts, collagen Ι synthesis, and activation of the TGF-β1/Smad3 signaling pathway induced by high-glucose culture medium. Our findings demonstrate that the upregulation of TRPV4 expression mediates diabetic cardiac fibrosis via activation of the TGF-β1/Smad3 signaling pathway.

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Abbreviations

DM:

Diabetes mellitus

TRPV:

Transient receptor potential vanilloid

ECM:

Extracellular matrix

CFs:

Cardiac fibroblasts

STZ:

Streptozotocin

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Acknowledgements

We thank Weifeng Huang for excellent technical assistance and Dr. IC Bruce for reading the manuscript. This research was supported by grants from the National Natural Science Foundation of China (30872716), the Natural Science Foundation of Hubei Province (2015CFB288), and a Health and Family Planning Project in Hubei Province (WJ2015MB171).

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  1. Xiaoli Jia and Chao Xiao have contributed equally to this article.

Authors and Affiliations

  1. Department of Physiology, Medical College of China Three Gorges University, 8 Daxue Road, Yichang, 443002, Hubei, China

    Xiaoli Jia, Chao Xiao, Deqiao Sheng, Mengcheng Yang, Quanyi Cheng, Jing Wu & Shizhong Zhang

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Contributions

XLJ and CX carried out the experiments and drafted the manuscript. DQS was involved in data analysis. MCY, QYC, and JW contributed to conducting the experiments. SZZ conceived the study, reviewed the data, and revised the manuscript. All authors read and approved the final manuscript.

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Correspondence to Shizhong Zhang.

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Jia, X., Xiao, C., Sheng, D. et al. TRPV4 Mediates Cardiac Fibrosis via the TGF-β1/Smad3 Signaling Pathway in Diabetic Rats. Cardiovasc Toxicol 20, 492–499 (2020). https://doi.org/10.1007/s12012-020-09572-8

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