PPARγ Mediates the Anti-Epithelial-Mesenchymal Transition Effects of FGF1ΔHBS in Chronic Kidney Diseases via Inhibition of TGF-β1/SMAD3 Signaling

Dezhong Wang; Tianyang Zhao; Yushuo Zhao; Yuan Yin; Yuli Huang; Zizhao Cheng; Beibei Wang; Sidan Liu; Minling Pan; Difei Sun; Zengshou Wang; Guanghui Zhu

doi:10.3389/fphar.2021.690535

PPARγ Mediates the Anti-Epithelial-Mesenchymal Transition Effects of FGF1^ΔHBS in Chronic Kidney Diseases via Inhibition of TGF-β1/SMAD3 Signaling

Front Pharmacol. 2021 Jun 3:12:690535. doi: 10.3389/fphar.2021.690535. eCollection 2021.

Authors

Dezhong Wang^{1

2}, Tianyang Zhao³, Yushuo Zhao⁴, Yuan Yin⁴, Yuli Huang³, Zizhao Cheng³, Beibei Wang³, Sidan Liu³, Minling Pan¹, Difei Sun¹, Zengshou Wang⁴, Guanghui Zhu^{2

4}

Affiliations

¹ Institute of Life Sciences and Engineering Laboratory of Zhejiang Province for Pharmaceutical Development of Growth Factors, Wenzhou University, Wenzhou, China.
² The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
³ School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China.
⁴ The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.

Abstract

Podocytes are essential components of the glomerular basement membrane. Epithelial-mesenchymal-transition (EMT) in podocytes results in proteinuria. Fibroblast growth factor 1 (FGF1) protects renal function against diabetic nephropathy (DN). In the present study, we showed that treatment with an FGF1 variant with decreased mitogenic potency (FGF1^ΔHBS) inhibited podocyte EMT, depletion, renal fibrosis, and preserved renal function in two nephropathy models. Mechanistic studies revealed that the inhibitory effects of FGF1^ΔHBS podocyte EMT were mediated by decreased expression of transforming growth factor β1 via upregulation of PPARγ. FGF1^ΔHBS enhanced the interaction between PPARγ and SMAD3 and suppressed SMAD3 nuclei translocation. We found that the anti-EMT activities of FGF1^ΔHBS were independent of glucose-lowering effects. These findings expand the potential uses of FGF1^ΔHBS in the treatment of diseases associated with EMT.

Keywords: FGF1; PPARγ; chronic kidney disease; epithelial-mesenchymal transition; fibrosis.