PDGF receptor-targeted delivery of truncated transforming growth factor receptor type II for improving the in vitro and in vivo anti-renal fibrosis activity via strong inactivation of TGF-1/Smad signaling pathway

Truncated transforming growth factor beta receptor type II ( tT beta RII), serving as a trap for binding excessive transforming growth factor beta 1 (TGF-beta 1) by means of competing with wild-type T beta RII, is a promising strategy for the treatment of kidney fibrosis. Platelet-derived growth factor beta receptor (PDGF beta R) is highly expressed in interstitial myofibroblasts in kidney fibrosis. This study identified the interaction between a novel tT beta RII variant Z-tT ss RII (PDGF beta R-specific affibody-Z(PDGF beta R) fused to the N-terminus of tT beta RII) and TGF-beta 1. Moreover, Z-tT beta RII highly targeted to TGF-beta 1-activated NIH3T3 cells and UUO-induced fibrotic kidney, but less to normal cells, tissues, and organs. Furthermore, Z-tT beta RII significantly inhibited cell proliferation and migration, and reduced fibrosis markers expression and phosphorylation level of Smad2/3 in activated NIH3T3 cells. Meanwhile, Z-tT beta RII markedly alleviated the kidney histopathology and fibrotic responses, and inhibited the TGF-beta 1/Smad signaling pathway in UUO mice. Besides, Z-tT beta RII showed good safety performance in the treatment of UUO mice. In conclusion, these results demonstrated that Z-tT beta RII 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.