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

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

doi:10.3389/fphar.2021.690535

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 (FGF1ΔHBS) inhibited podocyte EMT, depletion, renal fibrosis, and preserved renal function in two nephropathy models. Mechanistic studies revealed that the inhibitory effects of FGF1ΔHBS podocyte EMT were mediated by decreased expression of transforming growth factor β1 via upregulation of PPARγ. FGF1ΔHBS enhanced the interaction between PPARγ and SMAD3 and suppressed SMAD3 nuclei translocation. We found that the anti-EMT activities of FGF1ΔHBS were independent of glucose-lowering effects. These findings expand the potential uses of FGF1ΔHBS in the treatment of diseases associated with EMT.

Highlights

Podocytes are an essential part of the glomerular filtration barrier
hematoxylin and eosin (H&E) staining revealed that mesangial expansion was relieved by FGF1ΔHBS treatment (Figures 1D,E), and renal fibrosis was significantly reduced (Figures 1D–H)
We showed that the inhibitory effects of FGF1ΔHBS on podocyte EMT and renal protection were independent of its glucoselowering activity

Summary

Introduction

Podocytes are an essential part of the glomerular filtration barrier. Their injury leads to several glomerular diseases that develop to end-stage renal disease (ESRD) (Fishel Bartal et al, 2020). The expression of nephrin, podocin, and ZO-1 was decreased during podocyte EMT, resulting in the abnormal glomerular basement membrane (GBM) and fibrosis (He et al, 2011; Choi et al, 2020). Owing to its pivotal role in renal function, podocyte homeostatic regulation is a promising strategy for treating CKD. Transforming growth factor-β1 (TGF-β1) is the most potent EMT inducer, and enhanced expression of TGF-β1 was noted in renal tissues in the context of CKD (Chen et al, 2021).

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Discussion

Conclusion