title: Lefty-1 alleviates TGF-β1-induced fibroblast-myofibroblast transdifferentiation in NRK-49F cells.
abstract: Fibroblast activation and proliferation are important for fibroblast-myofibroblast transdifferentiation, a crucial process in the pathological changes that define renal interstitial fibrosis. The left-right determination factor (Lefty) is an important cytokine of the transforming growth factor (TGF)-β family, with two variants, Lefty-1 and Lefty-2, in mice. Lefty has diverse functions, such as the regulation of embryonic development, the inhibition of TGF-β1 signaling, and the suppression of tumor activity. However, whether Lefty-1 influences fibroblast activation and proliferation, and consequently prevents fibroblast-myofibroblast transdifferentiation, remains unclear. This study aimed to investigate whether Lefty-1 can attenuate TGF-β1-induced fibroblast-myofibroblast transdifferentiation in normal rat kidney interstitial fibroblast cells (NRK-49F), as well as the mechanisms underlying any effects. Results showed that the typical fibroblast cell morphology of NRK-49F cells was altered after TGF-β1 treatment and that Lefty-1 significantly prevented this change in a dose-dependent manner. Further analyses demonstrated decreased proliferating cell nuclear antigen, cyclin D1, collagen I(A1), alpha-smooth muscle actin, and fibronectin expression. Lefty-1 further induced remarkable reductions in TGF-β1-induced Smad3 and mitogen-activated protein kinase-10/c-Jun N-terminal kinase (JNK-3) signaling, and enhanced expression of the antifibrotic factor bone morphogenetic protein (BMP)-5. However, without TGF-β1, Lefty-1 had no effect on Smad3, JNK-3, and BMP-5 activation and fibroblast-myofibroblast transdifferentiation. Taken together, these findings indicate that Lefty-1 can alleviate TGF-β1-mediated activation and the proliferation of fibroblasts. Furthermore, Lefty-1 may prevent fibroblast-myofibroblast transdifferentiation in part via modulations of Smad3, JNK-3, and BMP-5 activities in the TGF-β/BMP signaling pathway.
authors: Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, People's Republic of China.
authors: Lijun
authors: L
authors: Zhang
authors: Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, People's Republic of China.
authors: Jie
authors: J
authors: Zhang
authors: Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, People's Republic of China.
authors: Changgeng
authors: C
authors: Xu
authors: Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, People's Republic of China.
authors: Xiangjun
authors: X
authors: Zhou
authors: Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, People's Republic of China.
authors: Wei
authors: W
authors: Wang
authors: Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, People's Republic of China.
authors: Renping
authors: R
authors: Zheng
authors: Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, People's Republic of China.
authors: Wei
authors: W
authors: Hu
authors: Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, People's Republic of China.
authors: Pin
authors: P
authors: Wu
mesh_terms: D000818:Animals; D055417:Bone Morphogenetic Protein 5 / Q000378:metabolism; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects*; D048430:Cell Shape / Q000187:drug effects; D054338:Cell Transdifferentiation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism; D005355:Fibrosis; D005786:Gene Expression Regulation; D055458:Left-Right Determination Factors / Q000494:pharmacology*; D048057:Mitogen-Activated Protein Kinase 10 / Q000378:metabolism; D058628:Myofibroblasts / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D051900:Smad3 Protein / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology*
chemical_list: C000603843:BMP5 protein, rat; D055417:Bone Morphogenetic Protein 5; D055458:Left-Right Determination Factors; C111386:Lefty1 protein, mouse; D011994:Recombinant Proteins; D051900:Smad3 Protein; C497787:Smad3 protein, rat; C508961:Tgfb1 protein, mouse; D053773:Transforming Growth Factor beta1; D048057:Mitogen-Activated Protein Kinase 10
keywords: Lefty-1; NRK-49F; fibroblast; myofibroblast; transdifferentiation