PDGFβ receptor-targeted delivery of truncated transforming growth factor β receptor type II for improving the in vitro and in vivo anti-renal fibrosis activity via strong inactivation of TGF-β1/Smad signaling pathway.

Bing Wang, Xiaohua Wang, Yixin Dong, Xiaohui Liu, Liming Xu, Yong Liu, Yan Wu, Chuntao Wang, Haifeng Liu

Naunyn-Schmiedeberg's archives of pharmacology 2024 Jan

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Truncated transforming growth factor β receptor type II (tTβRII), serving as a trap for binding excessive transforming growth factor β1 (TGF-β1) by means of competing with wild-type TβRII, is a promising strategy for the treatment of kidney fibrosis. Platelet-derived growth factor β receptor (PDGFβR) is highly expressed in interstitial myofibroblasts in kidney fibrosis. This study identified the interaction between a novel tTβRII variant Z-tTβRII (PDGFβR-specific affibody ZPDGFβR fused to the N-terminus of tTβRII) and TGF-β1. Moreover, Z-tTβRII highly targeted to TGF-β1-activated NIH3T3 cells and UUO-induced fibrotic kidney, but less to normal cells, tissues, and organs. Furthermore, Z-tTβRII significantly inhibited cell proliferation and migration, and reduced fibrosis markers expression and phosphorylation level of Smad2/3 in activated NIH3T3 cells. Meanwhile, Z-tTβRII markedly alleviated the kidney histopathology and fibrotic responses, and inhibited the TGF-β1/Smad signaling pathway in UUO mice. Besides, Z-tTβRII showed good safety performance in the treatment of UUO mice. In conclusion, these results demonstrated that Z-tTβRII may be a potential candidate for a targeting therapy on renal fibrosis due to the high potential of fibrotic kidney-targeting and strong anti-renal fibrosis activity. © 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.

Citation

Bing Wang, Xiaohua Wang, Yixin Dong, Xiaohui Liu, Liming Xu, Yong Liu, Yan Wu, Chuntao Wang, Haifeng Liu. PDGFβ receptor-targeted delivery of truncated transforming growth factor β receptor type II for improving the in vitro and in vivo anti-renal fibrosis activity via strong inactivation of TGF-β1/Smad signaling pathway. Naunyn-Schmiedeberg's archives of pharmacology. 2024 Jan;397(1):237-252