Follistatin-like 1 (FSTL1) interacts with Wnt ligands and Frizzled receptors to enhance Wnt/β-catenin signaling in obstructed kidneys in vivo

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 fibroblasts during kidney fibrogenesis in mice and human patients. We demonstrate that FSTL1 overexpression increased renal fibrosis and activated the Wnt/β-catenin signaling pathway, known to promote kidney fibrosis, but not the transforming growth factor β (TGF-β), Notch, Hedgehog, or Yes-associated protein (YAP) signaling pathways in obstructed mouse kidneys, whereas inhibition of FSTL1 lowered Wnt/β-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/β-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/β-catenin pathway. 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 fibroblasts during kidney fibrogenesis in mice and human patients. We demonstrate that FSTL1 overexpression increased renal fibrosis and activated the Wnt/β-catenin signaling pathway, known to promote kidney fibrosis, but not the transforming growth factor β (TGF-β), Notch, Hedgehog, or Yes-associated protein (YAP) signaling pathways in obstructed mouse kidneys, whereas inhibition of FSTL1 lowered Wnt/β-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/β-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/β-catenin pathway. Kidney fibrosis is the final common pathway of progressive chronic kidney diseases (CKDs) and is characterized by the increase of interstitial fibroblasts and myofibroblasts, and the excessive production and accumulation of extracellular matrix proteins, such as collagens and fibronectins (Fns), within the kidney (1Duffield J.S. Cellular and molecular mechanisms in kidney fibrosis.J. Clin. Invest. 2014; 124: 2299-2306Crossref PubMed Scopus (442) Google Scholar, 2Meng X.M. Nikolic-Paterson D.J. Lan H.Y. TGF-beta: the master regulator of fibrosis.Nat. Rev. Nephrol. 2016; 12: 325-338Crossref PubMed Scopus (1938) Google Scholar, 3Humphreys B.D. Mechanisms of renal fibrosis.Annu. Rev. Physiol. 2018; 80: 309-326Crossref PubMed Scopus (536) Google Scholar, 4Zhou D. Liu Y. Renal fibrosis in 2015: understanding the mechanisms of kidney fibrosis.Nat. Rev. Nephrol. 2016; 12: 68-70Crossref PubMed Scopus (145) Google Scholar). Kidney injury activates several critical signaling pathways, including the transforming growth factor beta (TGF-β), Wnt, Notch, Hedgehog, and Yes-associated protein (YAP) pathways, which collectively promote renal fibrogenesis (3Humphreys B.D. Mechanisms of renal fibrosis.Annu. Rev. Physiol. 2018; 80: 309-326Crossref PubMed Scopus (536) Google Scholar). The Wnt family of ligands controls a variety of cellular activities. Dysregulation of Wnt signaling has been implicated in human diseases, including tissue fibrosis and tumorigenesis. Wnts signal through the Frizzled (FZD) family of proteins as receptors, and low-density lipoprotein receptor–related proteins 5 and 6 (LRP-5 and LRP-6) as coreceptors, to stabilize β-catenin, which translocates into the nuclei to stimulate the transcription of Wnt target genes (5Gammons M. Bienz M. Multiprotein complexes governing Wnt signal transduction.Curr. Opin. Cell Biol. 2018; 51: 42-49Crossref PubMed Scopus (130) Google Scholar, 6Semenov M.V. Habas R. Macdonald B.T. He X. SnapShot: noncanonical Wnt signaling pathways.Cell. 2007; 131: 1378Abstract Full Text PDF PubMed Scopus (266) Google Scholar). Wnt/β-catenin signaling has been found to promote renal fibrosis by increasing fibroblast differentiation, proliferation, and activity (7Surendran K. Schiavi S. Hruska K.A. Wnt-dependent beta-catenin signaling is activated after unilateral ureteral obstruction, and recombinant secreted frizzled-related protein 4 alters the progression of renal fibrosis.J. Am. Soc. 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Welborn J. et al.Paracrine Wnt1 drives interstitial fibrosis without inflammation by tubulointerstitial cross-Talk.J. Am. Soc. Nephrol. 2016; 27: 781-790Crossref PubMed Scopus (92) Google Scholar, 13Xiao L. Zhou D. Tan R.J. Fu H. Zhou L. Hou F.F. et al.Sustained activation of Wnt/beta-catenin signaling drives AKI to CKD progression.J. Am. Soc. Nephrol. 2016; 27: 1727-1740Crossref PubMed Scopus (169) Google Scholar, 14Zhou D. Fu H. Zhang L. Zhang K. Min Y. Xiao L. et al.Tubule-derived Wnts are required for fibroblast activation and kidney fibrosis.J. Am. Soc. Nephrol. 2017; 28: 2322-2336Crossref PubMed Scopus (84) Google Scholar, 15Feng Y. Ren J. Gui Y. Wei W. Shu B. Lu Q. et al.Wnt/beta-Catenin-promoted macrophage alternative activation to kidney fibrosis.J. Am. Soc. Nephrol. 2018; PubMed Scopus Google Scholar). Follistatin (FS)-like 1 (FSTL1) is a secreted which was as a M. J. A. T. K. a mouse of a of of which to a J. PubMed Scopus Google Scholar). FSTL1 to the FS-SPARC (secreted protein, acidic and rich in cysteine) family of proteins the of both extracellular calcium–binding (EC) domain and domain. including have that the of family and to and protein T. K. Y. H. K. H. protein is PubMed Scopus Google Scholar, S. C. H. T. S. et of to a of protein and its and in S. A. PubMed Scopus Google Scholar, of activity and S. A. PubMed Scopus Google Scholar, Y. A. H. A. M. A. activity of and is and for and PubMed Scopus Google Scholar, Y. A. H. of and growth and factor by and PubMed Scopus Google Scholar, Y. The of in and 2009; PubMed Scopus Google but not A.P. and of the Biol. 2016; PubMed Scopus Google Scholar). FSTL1 was also to to proteins J. M. T. M. X. K. of a protein the and its PubMed Scopus Google Scholar, M. K. S. Y. T. et protein is a for of with J. PubMed Scopus Google Scholar, Y. Y. M. Zhang L. X. J. et 1 is a protein 4 signaling in mouse lung S. A. 2011; PubMed Scopus Google Scholar, Y. Y. Li L. Li X. X. Y. et 1 fibrosis in PubMed Scopus Google has with and In FSTL1 was found to the of lung by signaling during lung Y. Y. M. Zhang L. X. J. et 1 is a protein 4 signaling in mouse lung S. A. 2011; PubMed Scopus Google fibrogenesis by signaling in fibroblasts Y. Y. Li L. Li X. X. Y. et 1 fibrosis in PubMed Scopus Google Scholar). the that FSTL1 interacted with the and promoted the signaling Y. Y. Li L. Li X. X. Y. et 1 fibrosis in PubMed Scopus Google have been by a which to show the of FSTL1 with and the of signaling by FSTL1 S. K. S. Y. et 1 promotes fibroblast activation and the heart 2016; PubMed Scopus Google Scholar, S. Li C. Liu X. W. W. et protein 1 of matrix and expression in and Cell Physiol. 2018; PubMed Scopus Google Scholar, X. W. Zhou X. Zeng A. et signaling pathway in in PubMed Scopus Google Scholar). In addition, FSTL1 has been found to several pathways including the protein extracellular and protein pathways in and Y. K. Y. K. 1 is factor that is secreted by the PubMed Scopus Google Scholar, Y. K. R. Y. T. et of 1 injury in PubMed Scopus Google Scholar, M. K. B. K. Y. et 1 functions to S. A. 2011; PubMed Scopus Google Scholar, Y. K. A. C. Y. et a secreted protein, promotes and in tissue through a Biol. Full Text Full Text PDF PubMed Scopus Google Scholar, Y. K. A. S. Y. et functions as a FSTL1 Biol. Full Text Full Text PDF PubMed Scopus Google Scholar). The functions of FSTL1 have been studied in heart injury S. K. S. Y. et 1 promotes fibroblast activation and the heart 2016; PubMed Scopus Google Scholar, Y. K. Y. K. 1 is factor that is secreted by the PubMed Scopus Google Scholar, Y. K. R. Y. T. et of 1 injury in PubMed Scopus Google Scholar, M. K. B. K. Y. et 1 functions to S. A. 2011; PubMed Scopus Google Scholar, K. V. C. M. M. S. et FSTL1 the PubMed Scopus Google lung and fibrosis Y. Y. M. Zhang L. X. J. et 1 is a protein 4 signaling in mouse lung S. A. 2011; PubMed Scopus Google Scholar, Y. Y. Li L. Li X. X. Y. et 1 fibrosis in PubMed Scopus Google T. D. J. R. et is a novel PubMed Scopus Google Scholar, R. protein 1 promotes by 2009; PubMed Scopus Google Scholar, Y. L. R. FSTL1 promotes in mice by PubMed Scopus Google and wound S. K. D.P. et expression of and FSTL1 a in wound 2013; PubMed Scopus Google Scholar, M. M. C. S. et and a pathway 2017; PubMed Scopus Google Scholar). In to a role of FSTL1 in the lung Y. Y. Li L. Li X. X. Y. et 1 fibrosis in PubMed Scopus Google heart M. K. B. K. Y. et 1 functions to S. A. 2011; PubMed Scopus Google and et fibrosis by FSTL1 expression and J. 20: Scopus Google the kidney implicated and of FSTL1 in kidney injury and fibrosis L. L. 1 renal expression in J. Physiol. Physiol. PubMed Scopus Google Scholar, S. K. R. Y. M. T. et 1 renal injury in a Am. Soc. Nephrol. PubMed Scopus Google Scholar). In the we found that FSTL1 promoted kidney activity was with the Wnt but not the pathway. FSTL1 to Wnt ligands and receptors, increased the of Wnt ligands to receptors to Wnt/β-catenin signaling. We Fstl1 in of Fstl1 was in the kidney with ureteral is a mouse of kidney fibrosis as a of renal interstitial fibrosis and Int. 2009; Full Text Full Text PDF PubMed Scopus Google Scholar). We Fstl1 expression in using the for C. J. D.J. A. et single-cell in progression and of kidney Am. Soc. Nephrol. PubMed Scopus Google Scholar). RNA-Seq of the renal that Fstl1 expression was induced by Fstl1 was also found to increased in in RNA-Seq A. C. C. et of mouse of renal fibrosis molecular in kidney 2016; PubMed Scopus Google Scholar). and that Fstl1 and protein and in the kidney increased 1 to after We the for Fstl1 the single-cell RNA-Seq the renal of C. J. D.J. A. et single-cell in progression and of kidney Am. Soc. Nephrol. PubMed Scopus Google and found that Fstl1 was enriched in cells Fstl1 in cells was found and increased In Fstl1 in cells not enriched by FSTL1 was found in interstitial cells in with for and whereas was not in FSTL1 was not in and and cells FSTL1 was with the fibroblast growth factor beta We also FSTL1 expression in with or which renal fibrosis not and found of FSTL1 with and We FSTL1 was induced by kidney injury and protein of FSTL1 in the kidney not by for and Fstl1 and protein increased in after with the and that FSTL1 expression was not or by or the role of FSTL1 in kidney we FSTL1 in through or into mice after and mice the FSTL1 overexpression in the of mice with and type in increased in mice with mice immunofluorescence also in the for and by FSTL1 overexpression in that renal fibrosis was by FSTL1 of the factor and not by FSTL1 overexpression that FSTL1 promoted fibroblast activation and fibrosis in kidneys. FSTL1 was found to Y. Y. Li L. Li X. X. Y. et 1 fibrosis in PubMed Scopus Google and Y. Y. M. Zhang L. X. J. et 1 is a protein 4 signaling in mouse lung S. A. 2011; PubMed Scopus Google both of which in kidney fibrosis (3Humphreys B.D. Mechanisms of renal fibrosis.Annu. Rev. Physiol. 2018; 80: 309-326Crossref PubMed Scopus (536) Google Scholar). and not by FSTL1 overexpression in not by FSTL1 The S. J. C. Li Y. et controls kidney fibrosis Biol. 2018; Scopus Google B. K.A. et pathway activation during kidney J. Full Text Full Text PDF PubMed Scopus Google Scholar, H. Zhou D. S. Zhou L. He W. Nie J. et signaling and promotes renal fibrosis.J. Am. Soc. Nephrol. PubMed Scopus Google and Wnt W. Dai C. Li Y. Zeng G. Monga S.P. Liu Y. Wnt/beta-catenin signaling promotes renal interstitial fibrosis.J. Am. Soc. Nephrol. 2009; 20: 765-776Crossref PubMed Scopus (468) Google pathways also promote kidney the of and not by FSTL1 a of Wnt pathway activation J. G. T. Bienz M. et and promotes 2007; PubMed Scopus Google β-catenin, and induced by and by FSTL1 overexpression Therefore, the Wnt/β-catenin pathway was activated by FSTL1 overexpression in kidneys. and protein in not by FSTL1 that FSTL1 not noncanonical Wnt signaling in obstructed kidneys. the role of FSTL1 in the Wnt pathway, we FSTL1 into mice after and 6 but not the and not and of FSTL1 lowered and but not the and the of and and that FSTL1 promoted the Wnt/β-catenin pathway and and noncanonical Wnt pathways in obstructed kidneys. FSTL1 Wnt we the or mouse and human FSTL1 proteins increased activity in medullary cells a and proteins activity in cells and proteins also promoted activity in human kidney cells and kidney fibroblasts that FSTL1 enhanced signaling in kidney recombinant FSTL1 proteins, we or FSTL1 in enhanced activity induced by protein or by Wnt3a also promoted Wnt/β-catenin signaling induced by and inhibition of FSTL1 expression by Fstl1 activity Fstl1 or and inhibition Wnt3a signaling was by with activation with we in protein increased which by with FSTL1 protein also increased the β-catenin, and induced by Wnt3a and that promoted Wnt/β-catenin FSTL1 overexpression also promoted the expression of and collagens induced by Wnt3a overexpression and Therefore, FSTL1 fibroblast activity in the molecular mechanisms by FSTL1 to Wnt we FSTL1 with We with for several Wnts in that FSTL1 interacted with Wnt1 Wnt3a and FSTL1 and or also found in the cells with and or a the type not with Wnt3a We also FSTL1 and Wnts interacted with in the We with for of FSTL1 and and We FSTL1 using or FSTL1 was to Wnt ligands that the of FSTL1 for was we to FSTL1 using a of and the FSTL1 and recombinant protein or a of and FSTL1 proteins in a and the complexes FSTL1 with of the that was with FSTL1 demonstrate a FSTL1 and FSTL1 of domain and EC domain, by a domain with to the von Willebrand factor type C–like (VWC) domain B. S. K. M. et of of Biol. Full Text Full Text PDF PubMed Scopus Google Scholar). demonstrated that the EC domain, domain, or whereas the domain not and that interacted with the EC and but not the domain that FSTL1 interacted with that Wnt proteins are also that with Wnt ligands through of Wnt We FSTL1 interacted with Wnt The Wnt FZD4 and the coreceptor are in the kidney Li B. S. B.T. et is critical for kidney and S. A. PubMed Scopus Google Scholar, S. Y. C. et is a coreceptor for signaling pathways in and that are by S. A. 2013; PubMed Scopus Google Scholar). We FSTL1 interacted with and in FSTL1 and and FZD4 to and and FSTL1 that not have a with FZD4 FSTL1 also was with using recombinant proteins a and FSTL1 the for FSTL1 we found that FZD4 interacted with the EC domain but not with the and FZD4 interacted with FSTL1 through the EC domain not the FSTL1 and FZD4 4 and for In the of FZD4 and FSTL1 not FSTL1 in the of FZD4 that FSTL1 through and that and a FSTL1 increased the FZD4 and 4 and for and and for In a interacted with and FSTL1 enhanced FSTL1 the association of with FZD4 the we which has been to in Wnt/β-catenin signaling M. K. J. J. D. et of Wnt 2018; Full Text Full Text PDF PubMed Scopus Google Scholar). for of FZD4 by using a et Wnt signaling by S. A. 2018; PubMed Scopus Google Scholar). using that FSTL1 enhanced the and the 4 and 5 with and for collectively show that FSTL1 interacted with Wnts and and promoted Wnt/β-catenin signaling by the of Wnts to We have that the EC domain of FSTL1 interacted with both and FZD4 to the EC domain Wnt signaling. in the EC domain increased activity in The EC domain also promoted Wnt signaling induced by Wnt3a or Wnt3a in cells the that of FSTL1 with Wnts and Wnt signaling. We FSTL1 signaling. proteins activity in cells and or inhibition of FSTL1 not activity in cells FSTL1 also to and expression of and a role of FSTL1 in signaling. In the we that FSTL1 promotes Wnt/β-catenin signaling and kidney FSTL1 has been found to promote fibrosis in the lung Y. Y. Li L. Li X. X. Y. et 1 fibrosis in PubMed Scopus Google heart M. K. B. K. Y. et 1 functions to S. A. 2011; PubMed Scopus Google and et fibrosis by FSTL1 expression and J. 20: Scopus Google Scholar). in the we a role for FSTL1 in the kidney overexpression of FSTL1 increased the expression of the proteins and in and in both and for FSTL1 in human diseases and Y. B. S. R. protein 1 and its role in inflammation and 2014; PubMed Scopus Google Scholar). the in the kidney after FSTL1 overexpression in kidneys. Therefore, the increased fibrosis was not to of and signaling have been to in tissue fibrosis M. C. proteins as in renal have we after of and PubMed Scopus Google Scholar). FSTL1 was found to signaling in lung cells during lung Y. Y. M. Zhang L. X. J. et 1 is a protein 4 signaling in mouse lung S. A. 2011; PubMed Scopus Google Scholar). et Y. Y. Li L. Li X. X. Y. et 1 fibrosis in PubMed Scopus Google demonstrated that FSTL1 signaling in fibroblasts by interacting with and we that the role of FSTL1 to its role in and signaling. we to in and signaling after overexpression or of FSTL1 in kidneys. In we that FSTL1 signaling but not of FSTL1 overexpression or signaling and its Nie et X. W. Zhou X. Zeng A. et signaling pathway in in PubMed Scopus Google to FSTL1 and FSTL1 and in the or the of in fibroblasts S. K. S. Y. et 1 promotes fibroblast activation and the heart 2016; PubMed Scopus Google Scholar). FSTL1 not in S. Li C. Liu X. W. W. et protein 1 of matrix and expression in and Cell Physiol. 2018; PubMed Scopus Google Scholar). In with and of the FS-SPARC not with A.P. and of the Biol. 2016; PubMed Scopus Google Scholar). a role of FSTL1 in signaling. demonstrate that signaling and signaling not the activity of has been well that Wnt/β-catenin signaling is activated during kidney injury and promotes renal fibrosis (5Gammons M. Bienz M. Multiprotein complexes governing Wnt signal transduction.Curr. Opin. Cell Biol. 2018; 51: 42-49Crossref PubMed Scopus (130) Google Scholar, 6Semenov M.V. Habas R. Macdonald B.T. He X. SnapShot: noncanonical Wnt signaling pathways.Cell. 2007; 131: 1378Abstract Full Text PDF PubMed Scopus (266) Google Scholar, 8He W. Dai C. Li Y. Zeng G. Monga S.P. Liu Y. Wnt/beta-catenin signaling promotes renal interstitial fibrosis.J. Am. Soc. Nephrol. 2009; 20: 765-776Crossref PubMed Scopus (468) Google Scholar, 11Tan R.J. Zhou D. Zhou L. Liu Y. Wnt/beta-catenin signaling and kidney fibrosis.Kidney Int. Suppl. (2011). 2014; 4: 84-90Abstract Full Text Full Text PDF PubMed Scopus (195) Google Scholar). we found that FSTL1 interacted with Wnt including and which are in after FSTL1 also interacted with FZD4 and but not and FSTL1 enhanced the FZD4 and Furthermore, FSTL1 Wnt/β-catenin signaling induced by Wnt ligands in several kidney and promoted fibrogenesis induced by Wnt3a in of FSTL1 increased the expression of β-catenin, β-catenin, and in kidneys, whereas of FSTL1 and FSTL1 pathways, including the Notch, Hedgehog, and pathways, is that is the Wnt pathway that the activity of that FSTL1 promoted the activity in cells and that the activity was by S. Y. C. He Y. Zhang Y. Zhang Q. FSTL1 and in cells signaling Biol. 20: PubMed Scopus Google Scholar). but a role in the FSTL1 and Wnts or to We that FSTL1 interacted with Wnt3a through the EC and and with FZD4 through the EC domain. The EC domain of FSTL1 is by Wnt3a and FSTL1 enhanced the of FZD4 and is that FZD4 and Wnt3a FSTL1 of the EC domain. to the within the EC domain that are required for the with Wnt3a and single-cell RNA-Seq of the renal of and immunofluorescence that FSTL1 was in fibroblasts in in mice and patients. are by a which human with and found that FSTL1 was enriched in fibroblasts and X. H. R. Y. et (FSTL1) is a growth factor that to progression of chronic kidney J. 22: PubMed Scopus Google Scholar). The FSTL1 expression in the kidney is and cellular was not by Therefore, the role of FSTL1 in the kidney unknown. Fstl1 a in the kidney in FSTL1 expression L. L. 1 renal expression in J. Physiol. Physiol. PubMed Scopus Google Scholar). that FSTL1 not for kidney In the was found that FSTL1 AKI induced by FSTL1 a role in has been well that Wnt signaling in kidney injury in AKI but promotes fibrosis in CKD D. Tan R.J. Fu H. Liu Y. Wnt/beta-catenin signaling in kidney injury and a Invest. 2016; PubMed Scopus Google Scholar). Therefore, is that FSTL1 Wnt signaling in renal injury during Fstl1 in of renal inflammation and tubulointerstitial fibrosis, whereas expression of FSTL1 renal inflammation and tubulointerstitial fibrosis induced by S. K. R. Y. M. T. et 1 renal injury in a Am. Soc. Nephrol. PubMed Scopus Google Scholar). that FSTL1 and in the and is unknown. a found that FSTL1 to progression of CKD X. H. R. Y. et (FSTL1) is a growth factor that to progression of chronic kidney J. 22: PubMed Scopus Google Scholar). Furthermore, FSTL1 was also found to promote fibrosis in lung Y. Y. Li L. Li X. X. Y. et 1 fibrosis in PubMed Scopus Google M. K. B. K. Y. et 1 functions to S. A. 2011; PubMed Scopus Google and et fibrosis by FSTL1 expression and J. 20: Scopus Google Scholar). a role for In the we Fstl1 mice to In we have demonstrated that FSTL1 is in fibroblasts in kidneys. FSTL1 with Wnts and Wnt/β-catenin signaling by as a protein that Wnts and FSTL1 promotes the Wnt/β-catenin signaling pathway and renal fibrosis FSTL1 as a novel regulator of Wnt/β-catenin signaling. injury and AKI and as by W. B. Y. C. H. et kidney injury by S. A. 2018; PubMed Scopus Google Scholar, H. C. Y. C. Liu W. Y. et protein kidney injury by the pathway in renal Int. 2018; Full Text Full Text PDF PubMed Scopus Google Scholar, W. Li X. Y. X.M. C. B. et expression and in renal Biol. 2013; Full Text Full Text PDF PubMed Scopus Google Scholar). was after as by Xiao et L. Zhou D. Tan R.J. Fu H. Zhou L. Hou F.F. et al.Sustained activation of Wnt/beta-catenin signaling drives AKI to CKD progression.J. Am. Soc. Nephrol. 2016; 27: 1727-1740Crossref PubMed Scopus (169) Google Scholar). or was in and the into the within 5 to after FSTL1 or was into mice a of 5 after 6 after kidney kidney for to interstitial of was using for with for 4 with or and or in as by or with a or and by M. Y. Zhou expression of the secreted 1 is a of to PubMed Scopus Google M. T. W. J. to Frizzled and a role in the of Wnt Cell 2014; PubMed Scopus Google and J. M. K. J. J. D. et of Wnt 2018; Full Text Full Text PDF PubMed Scopus Google and and by M. et Wnt signaling by S. A. 2018; PubMed Scopus Google Scholar). for EC domain, and domain B. S. K. M. et of of Biol. Full Text Full Text PDF PubMed Scopus Google Scholar). for domain and domain using the and and by using and for protein for Wnt ligands L. Zhou D. Tan R.J. Fu H. Zhou L. Hou F.F. et al.Sustained activation of Wnt/beta-catenin signaling drives AKI to CKD progression.J. Am. Soc. Nephrol. 2016; 27: 1727-1740Crossref PubMed Scopus (169) Google or cells and mouse cells in with fibroblasts in with cells in and with in with for Wnt ligands using to the and for the of FSTL1 the Wnt pathway, cells in a or and with in the or the of for Wnt The cells with for the cells for Cell with as in 4 The 4 for 6 with protein or protein proteins to using as the FSTL1 and Wnt ligands in with for with protein 4 with and Cell or 4 and 4 for 6 proteins to using are FSTL1 and or FZD4 and recombinant FSTL1 and proteins to and 4 and with by that been with for the FSTL1 and or with that also been with for the and FSTL1 proteins and by cells with for and the after cells for with Wnt3a in the or the of which also with 1 for with with for 6 and the by for and of to of protein was by and to with Cell Cell Cell Cell Cell Cell Cell Cell 1 or Cell Cell Cell Cell Cell Cell and The using or and cells with a of the a or a or in with with or without with in the or the of for Wnt after the was with with or without or protein, in the or the of protein cells and activity was with the in or as of and Fstl1 cells with or a of was using with transcription was using was using are as of or by by of or to was of of for and of of or for by The of and in with The of The of human kidney was by are within the to The that have of with the of We M. of of and J. of for the and We also and M. for the and and with Y. and Y. X. Y. Y. G. J. H. C. and X. J. C. H. B. K. K. Y. and J. C. H. B. K. K. Y. and Y. Y. G. J. H. C. X. J. C. H. B. K. K. Y. and Y. X. Y. was by was by and and and Y. and the and the of and of Y. and the of and and the and

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