Inhibition of proliferation-linked signaling cascades with atractylenolide I reduces myofibroblastic phenotype and renal fibrosis

Renal fibrosis is a frequent axis contributing to the occurrence of end-stage nephropathy. Previously, it has been reported that atractylenolide I (ATL-1), a natural compound extracted from Atractylodes macrocephala, has anticancer and antioxidant effects. However, the renal anti-fibrotic effects of action remain unclear. In this study, the anti-fibrotic effects of ATL-1 were examined in fibroblasts, tubular epithelial cells (TECs) triggered by TGF-beta 1 in vitro, and using a unilateral ureteral obstruction (UUO) mouse model in vivo. We found that ATL-1 represses the myofibroblastic phenotype and fibrosis development in UUO kidneys by targeting the fibroblast-myofibroblast differentiation (FMD), as well as epithelial-mesenchymal transition (EMT). The anti-fibrotic effects of ATL-1 were associated with reduced cell growth in the interstitium and tubules, leading to suppression of the proliferation-linked cascades activity consisting of JAK2/STAT3, PI3K/Akt, p38 MAPK, and Wnt/beta-catenin pathways. Besides, ATL-1 treatment repressed TGF-beta 1-triggered FMD and the myofibroblastic phenotype in fibroblasts by antagonizing the activation of proliferation-linked cascades. Likewise, TGF-beta 1-triggered excessive activation of the proliferation-linked signaling in TECs triggered EMT. The myofibroblastic phenotype was repressed by ATL-1. The anti-fibrotic and anti-proliferative effects of ATL-1 were linked to the inactivation of Smad2/3 signaling, partially reversing FMD, as well as EMT and the repression of the myofibroblastic phenotype. Thus, the inhibition of myofibroblastic phenotype and fibrosis development in vivo and in vitro through proliferation-linked cascades of ATL-1 makes it a prospective therapeutic bio-agent to prevent renal fibrosis.

Automated summary

The study demonstrated that ATL-1 inhibits the myofibroblastic phenotype and fibrosis development in the kidneys by targeting fibroblast-myofibroblast differentiation and epithelial-mesenchymal transition. This anti-fibrotic effect of ATL-1 is associated with the inhibition of proliferation-linked cascades signaling pathways.