Universität zu Köln

Zhang, Yu, Wang, Yang, Zheng, Guoxun, Liu, Yang, Li, Jinhong, Huang, Huihui, Xu, Chunhua, Zeng, Yelin, Zhang, Xiaoyi, Qin, Jinzhong, Dai, Chunsun, Hambrock, Harald O., Hartmann, Ursula, Feng, Bo, Mak, Kingston Kinglun, Liu, Youhua ORCID: 0000-0002-4740-805X, Lan, Hui-Yao, Huang, Yu ORCID: 0000-0002-1277-6784, Zheng, Zhi-Hua and Xia, Yin ORCID: 0000-0003-0315-7532 (2022). Follistatin-like 1 (FSTL1) interacts with Wnt ligands and Frizzled receptors to enhance Wnt/beta-catenin signaling in obstructed kidneys in vivo. J. Biol. Chem., 298 (7). AMSTERDAM: ELSEVIER. ISSN 1083-351X

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Abstract

Follistatin (FS)-like 1 (FSTL1) is a member of the FS-SPARC (secreted protein, acidic and rich in cysteine) family of secreted and extracellular matrix proteins. The functions of FSTL1 have been studied in heart and lung injury as well as in wound healing; however, the role of FSTL1 in the kidney is largely unknown. Here, we show using single-cell RNA-Seq that Fstl1 was enriched in stromal cells in obstructed mouse kidneys. In addition, immunofluorescence demonstrated that FSTL1 expression was induced in fibro-blasts during kidney fibrogenesis in mice and human patients. We demonstrate that FSTL1 overexpression increased renal fibrosis and activated the Wnt/beta-catenin signaling pathway, known to promote kidney fibrosis, but not the transforming growth factor beta (TGF-beta), Notch, Hedgehog, or Yes-associated protein (YAP) signaling pathways in obstructed mouse kidneys, whereas inhibition of FSTL1 lowered Wnt/beta-catenin signaling. Importantly, we show that FSTL1 interacted with Wnt ligands and the Frizzled (FZD) receptors but not the coreceptor lipoprotein receptor-related protein 6 (LRP6). Specifically, we found FSTL1 interacted with Wnt3a through its extracellular calcium-binding (EC) domain and von Willebrand factor type C-like (VWC) domain, and with FZD4 through its EC domain. Furthermore, we show that FSTL1 increased the association of Wnt3a with FZD4 and promoted Wnt/beta-catenin signaling and fibrogenesis. The EC domain interacting with both Wnt3a and FZD4 also enhanced Wnt3a signaling. Therefore, we conclude that FSTL1 is a novel extracellular enhancer of the Wnt/beta-catenin pathway.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Zhang, Yu UNSPECIFIED UNSPECIFIED UNSPECIFIED Wang, Yang UNSPECIFIED UNSPECIFIED UNSPECIFIED Zheng, Guoxun UNSPECIFIED UNSPECIFIED UNSPECIFIED Liu, Yang UNSPECIFIED UNSPECIFIED UNSPECIFIED Li, Jinhong UNSPECIFIED UNSPECIFIED UNSPECIFIED Huang, Huihui UNSPECIFIED UNSPECIFIED UNSPECIFIED Xu, Chunhua UNSPECIFIED UNSPECIFIED UNSPECIFIED Zeng, Yelin UNSPECIFIED UNSPECIFIED UNSPECIFIED Zhang, Xiaoyi UNSPECIFIED UNSPECIFIED UNSPECIFIED Qin, Jinzhong UNSPECIFIED UNSPECIFIED UNSPECIFIED Dai, Chunsun UNSPECIFIED UNSPECIFIED UNSPECIFIED Hambrock, Harald O. UNSPECIFIED UNSPECIFIED UNSPECIFIED Hartmann, Ursula UNSPECIFIED UNSPECIFIED UNSPECIFIED Feng, Bo UNSPECIFIED UNSPECIFIED UNSPECIFIED Mak, Kingston Kinglun UNSPECIFIED UNSPECIFIED UNSPECIFIED Liu, Youhua UNSPECIFIED orcid.org/0000-0002-4740-805X UNSPECIFIED Lan, Hui-Yao UNSPECIFIED UNSPECIFIED UNSPECIFIED Huang, Yu UNSPECIFIED orcid.org/0000-0002-1277-6784 UNSPECIFIED Zheng, Zhi-Hua UNSPECIFIED UNSPECIFIED UNSPECIFIED Xia, Yin UNSPECIFIED orcid.org/0000-0003-0315-7532 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-692693
DOI:	10.1016/j.jbc.2022.102010
Journal or Publication Title:	J. Biol. Chem.
Volume:	298
Number:	7
Date:	2022
Publisher:	ELSEVIER
Place of Publication:	AMSTERDAM
ISSN:	1083-351X
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language BONE-MORPHOGENETIC PROTEIN; FIBROBLAST ACTIVATION; URETERAL OBSTRUCTION; PROMOTES ARTHRITIS; TGF-BETA; INJURY; ACTIVIN; BINDING; MECHANISMS; EXPRESSION Multiple languages Biochemistry & Molecular Biology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/69269