Abstract: Ph.D. ; Kidney fibrosis is a final common pathway of progressive chronic kidney disease and is characterized by the increase of interstitial fibroblasts and myofibroblasts, and the excessive production and accumulation of extracellular matrix (ECM) proteins, such as collagens and fibronectins, within the kidney. The Wnt family of ligands controls a variety of cellular activities. Wnt/β-catenin signalling in the kidney is silent in normal adults, but it is reactivated in tubular cells, pericytes, fibroblasts and macrophages in injured kidneys. Wnt/β-catenin signaling has been found to promote renal fibrosis by facilitating partial tubular epithelial-mesenchymal transition (EMT)/dedifferentiation, and promoting myofibroblast differentiation, proliferation and function. Follistatin-like 1 (FSTL1) is a secreted glycoprotein and comprises a follistatin domain and an extracellular calcium-binding (EC) domain. The functions of FSTL1 have been studied in heart injury, lung development and fibrosis, arthritis, and wound healing. However, the role of FSTL1 in kidney is largely unknown. In the present study, we showed that FSTL1 expression in the kidney was dramatically increased 1, 3, and 7 days after unilateral ureteral obstruction (UUO), while it was not changed by bilateral ischemia/reperfusion (I/R) and cisplatin nephrotoxicity in mice. Immunofluorescent staining showed that FSTL1 was expressed in fibroblasts in the kidneys with UUO. Overexpression of FSTL1 in vivo aggravated renal fibrosis after UUO, as indicated by increased expression of α-SMA, fibronectin and collagen I. Immunoprecipitation assay (IP) demonstrated that FSTL1 interacted with various Wnt ligands in vitro, both caonical and non-canonical, including Wnt1, Wnt2, Wnt3a, Wnt4, Wnt5a, Wnt7a, Wnt8a, Wnt8b, Wnt9a, and Wnt10b, which are concurrently increased in fibrotic kidneys after UUO. In addition, FSTL1 further upregulated the β-catenin responsive 8× TOPFlash luciferase reporter activity induced by canonical Wnt ligands in mIMCD3, HEK293T, and NRK-49F ...
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