2. Academic Validation
  3. Inhibition of TRPC6 suppressed TGFβ-induced fibroblast-myofibroblast transdifferentiation in renal interstitial NRK-49F cells

Inhibition of TRPC6 suppressed TGFβ-induced fibroblast-myofibroblast transdifferentiation in renal interstitial NRK-49F cells

  • Exp Cell Res. 2022 Oct 4;421(1):113374. doi: 10.1016/j.yexcr.2022.113374.
Shan Jiang 1,  Lifei Gu 2,  Yixin Hu 1,  Younan Ren 1,  Zhao Yang 1,  Chengzhi Chai 1,  Boyang Yu 1,  Haitao Ge 3,  Zhengyu Cao 4,  Fang Zhao 5
Affiliations

Affiliations

  • 1 State Key Laboratory of Natural Medicines and Jiangsu Provincial Key Laboratory for TCM Evaluation and Translational Development, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, 211198, China.
  • 2 State Key Laboratory of Natural Medicines and Jiangsu Provincial Key Laboratory for TCM Evaluation and Translational Development, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, 211198, China; NMPA Key Laboratory for Quality Research and Evaluation of Traditional Chinese Medicine, Shenzhen Institute for Drug Control, Shenzhen, Guangdong, 518057, China.
  • 3 Jiangsu Suzhong Pharmaceutical Group Co., Ltd., Taizhou, Jiangsu, 225500, China.
  • 4 State Key Laboratory of Natural Medicines and Jiangsu Provincial Key Laboratory for TCM Evaluation and Translational Development, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, 211198, China. Electronic address: zycao@cpu.edu.cn.
  • 5 State Key Laboratory of Natural Medicines and Jiangsu Provincial Key Laboratory for TCM Evaluation and Translational Development, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, 211198, China. Electronic address: zhaofang0927@cpu.edu.cn.
PMID: 36206825 DOI: 10.1016/j.yexcr.2022.113374
Abstract

Renal fibrosis is a global health concern with limited curative treatment. Canonical transient receptor potential channel 6 (TRPC6), a nonselective cation channel, has been shown to regulate the renal fibrosis in murine models. However, the molecular mechanism is unclear. Fibroblast-myofibroblast transdifferentiation is one of the critical steps in the progression of renal fibrosis. In the present study, we demonstrate that transforming growth factor (TGF)-β1 exposure significantly increases the TRPC6 expression in renal interstitial fibroblast NRK-49F cells. Pharmacological inhibition of TRPC6 and knockdown of Trpc6 by siRNA alleviate TGF-β1-increased expression levels of α-smooth muscle actin (α-SMA) and collagen I, two key markers of myofibroblasts. Although direct activation of TRPC6 by 1-oleoyl-2-acetyl-sn-glycerol (OAG) does not affect the expression of α-SMA and collagen I, OAG potentiates TGF-β1-induced fibroblast-myofibroblast transdifferentiation. Further study demonstrates that TGF-β1 exposure increases the phosphorylation level of p38 and Yes-associated protein (YAP) translocation into the nuclei. Inhibition of p38 and YAP decreases TGF-β1-enhanced TRPC6 and α-SMA expression. In conclusion, we demonstrate that TRPC6 is a key regulator of TGF-β1-induced fibroblast-myofibroblast transdifferentiation and provides the mechanism of how TGF-β1 exposure regulates TRPC6 expression in NRK-49F fibroblasts.

Keywords

Renal fibrosis; TRPC6; Transdifferentiation; YAP; p38 MAPK.

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