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

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.

Identification and validation of immune-related biomarkers and potential regulators and therapeutic targets for diabetic kidney disease

“…And FGF1 treatment can prevent the development of DKD by inhibiting the activation of inflammatory signaling cascades such as nuclear factor-κB and c-Jun N-terminal kinases signaling [ 24 ]. Meanwhile, FGF1 treatment can also increase insulin sensitization, maintain normoglycemia, and prevent diabetic complications [ 25 ]. Similarly, FGF9 can induce ERK and AKT phosphorylation and cAMP-response element binding protein and nuclear factor erythroid-derived 2-like 2 (Nrf2) activation to play the antioxidative function [ 26 ] and cardioprotective effect [ 27 ].…”

Celastrol attenuates renal injury in 5/6 nephrectomized rats via inhibiting epithelial–mesenchymal transition and transforming growth factor-β1/Smad3 pathway

“…28 End-stage renal disease and glomerular fibrosis are linked to podocyte EMT, and TGF-β1/Smad3 signaling contributes to EMT in podocytes. 29,30 Celastrol protected podocytes from EMT, increased nephrin and NEPH1 expression, enhanced the foot process fusion rate, and reduced proteinuria.…”

Unraveling the Multifaceted Roles of Extracellular Vesicles: Insights into Biology, Pharmacology, and Pharmaceutical Applications for Drug Delivery

“…Indeed, tubular epithelial cell EVs loaded with functional cargoes such as chemokines, TGF-β1, CCL2 mRNA, and osteopontin transferred these cargoes to interstitial macrophages, aggravating kidney damage [ 145 ]. In kidney diseases such as IgA nephropathy [ 147 ] and diabetic kidney disease [ 148 ], increased inflammation leads to cellular oxidative damage. The spread of inflammation between tubules and renal interstitium may lead to significant kidney damage.…”