Role of sphingosine 1-phosphate signalling in tissue fibrosis

Donati, Chiara; Cencetti, Francesca; Bernacchioni, Caterina; Vannuzzi, Valentina; Bruni, Paola

doi:10.1016/j.cellsig.2020.109861

Cited by 27 publications

(16 citation statements)

References 174 publications

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“…Fibrosis is a disorder that can occur in several various organs characterized by aberrant, excessive production and accumulation of extracellular matrix (ECM) in the tissues 24 – 26 . Fibroblast and myofibroblast are the main effector cells responsible for tissue fibrotic changes and overproduction of ECM proteins, e.g., types I and III collagens, fibronectin 27 .…”

Section: Introductionmentioning

confidence: 99%

Effects of secretome derived from macrophages exposed to calcium oxalate crystals on renal fibroblast activation

et al. 2021

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The association between kidney stone disease and renal fibrosis has been widely explored in recent years but its underlying mechanisms remain far from complete understanding. Using label-free quantitative proteomics (nanoLC-ESI-LTQ-Orbitrap MS/MS), this study identified 23 significantly altered secreted proteins from calcium oxalate monohydrate (COM)-exposed macrophages (COM-MP) compared with control macrophages (Ctrl-MP) secretome. Functional annotation and protein-protein interactions network analysis revealed that these altered secreted proteins were involved mainly in inflammatory response and fibroblast activation. BHK-21 renal fibroblasts treated with COM-MP secretome had more spindle-shaped morphology with greater spindle index. Immunofluorescence study and gelatin zymography revealed increased levels of fibroblast activation markers (α-smooth muscle actin and F-actin) and fibrotic factors (fibronectin and matrix metalloproteinase-9 and -2) in the COM-MP secretome-treated fibroblasts. Our findings indicate that proteins secreted from macrophages exposed to COM crystals induce renal fibroblast activation and may play important roles in renal fibrogenesis in kidney stone disease.

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Section: Introductionmentioning

confidence: 99%

Effects of secretome derived from macrophages exposed to calcium oxalate crystals on renal fibroblast activation

et al. 2021

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“…In peptide VII, a strong H-bond was formed between the amide proton of Asn 7 and the carbonyl oxygen of D-Tic 4 (2.8 Å), while the distance between the Cα atoms of these amino residues measured 5.7 Å. The above data suggest regular β-turns for both peptides V and VII, comprised of Asn 7 and L-or D-Tic 4 residues (Table 3).…”

Section: Molecular Dynamics Simulationsmentioning

confidence: 69%

“…The middle conformations of V and VII were compared by superimposing their Gly 1 -Arg 2 -Pro 3 residues, which adopt a similar backbone orientation (Figure 8). Most strikingly, this spatial superimposition revealed that the Asp 5 -Ala 6 -Asn 7 residues with β-turn-like motifs are located on opposite sides of the plane defined by the L-or D-Tic residue, because of the conformational constraints existing in the Tic 4 residue. This difference in the orientation of the Asp 5 -Ala 6 -Asn 7 residues folding in a β-turn-like motif may explain, in structural terms, the selective S1P 3 antagonism of V and VII in comparison to the unselective antagonist KRX-725-II.…”

Section: Molecular Dynamics Simulationsmentioning

confidence: 88%

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Antagonizing S1P3 Receptor with Cell-Penetrating Pepducins in Skeletal Muscle Fibrosis

Corvino

Cerqua

Bianco

et al. 2021

IJMS

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S1P is the final product of sphingolipid metabolism, which interacts with five widely expressed GPCRs (S1P1-5). Increasing numbers of studies have indicated the importance of S1P3 in various pathophysiological processes. Recently, we have identified a pepducin (compound KRX-725-II) acting as an S1P3 receptor antagonist. Here, aiming to optimize the activity and selectivity profile of the described compound, we have synthesized a series of derivatives in which Tyr, in position 4, has been substituted with several natural aromatic and unnatural aromatic and non-aromatic amino acids. All the compounds were evaluated for their ability to inhibit vascular relaxation induced by KRX-725 (as S1P3 selective pepducin agonist) and KRX-722 (an S1P1-selective pepducin agonist). Those selective towards S1P3 (compounds V and VII) were also evaluated for their ability to inhibit skeletal muscle fibrosis. Finally, molecular dynamics simulations were performed to derive information on the preferred conformations of selective and unselective antagonists.

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“…This led us to hypothesize that other bioactive molecules in PRP might determine either synergistic or antagonistic effects, with the engagement of different effector/receptor systems in determining the outcome on RMP, probably involving a long‐term modulation of membrane ion channels and/or pumps. In this regard, preliminary experiments in our laboratory showed that sphingosine 1‐phosphate, a bioactive lipid supposed to be released by activated PRP (Hoeferlin et al., 2015) and recognized as a profibrotic agent (Donati et al., 2021), is able to depolarize RMP, possibly antagonizing the effects of VEGF‐A. This is another aspect that certainly deserves further investigation.…”

Section: Discussionmentioning

confidence: 90%

Platelet‐rich plasma affects gap junctional features in myofibroblasts in vitro via vascular endothelial growth factor (VEGF)‐A/VEGF receptor

Sassoli

Garella

Chellini

et al. 2022

Experimental Physiology

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New Findings What is the central question of this study?It is a challenge to discover effective therapies for fibrosis. Increasing evidence supports the antifibrotic potential of platelet‐rich plasma (PRP) as a source of bioactive molecules, such as vascular endothelial growth factor (VEGF)‐A. However, the effects and mechanisms of action of PRP need to be clarified. What is the main finding and its importance?This report clarifies the mechanisms mediating the antifibrotic action of PRP, strengthening the role of VEGF‐A/VEGF receptor, and identifies gap junction currents and connexin 43 as novel targets of this pathway in the fibroblast‐to‐myofibroblast transition induced by the transforming growth factor‐β1. Abstract Despite increasing experimental evidence, the antifibrotic potential of platelet‐rich plasma (PRP) remains controversial, and its mechanisms of action are not fully clarified. This short report extends our previous research on the capability of PRP to prevent the in vitro differentiation of fibroblasts toward myofibroblasts, the key effectors of fibrosis, induced by the profibrotic agent transforming growth factor‐β1 (TGF‐β1). In particular, we focused on the involvement of signalling mediated by vascular endothelial growth factor (VEGF)‐A/VEGF receptor (VEGFR) in the PRP‐induced fibroblast response, highlighting gap junction features. Electrophysiological and morphological analyses revealed that PRP hindered morphofunctional differentiation of both murine NIH/3T3 and human primary adult skin fibroblasts toward myofibroblasts as judged by the analysis of membrane phenomena, α‐smooth muscle actin and vinculin expression and cell morphology. Neutralization of VEGF‐A by blocking antibodies or pharmacological inhibition of VEGFR by KRN633 in TGF‐β1‐treated fibroblasts prevented the PRP‐promoted effects, such as the reduction of voltage‐dependent transjunctional currents in cell pairs and a decreased expression of connexin 43, the typical connexin isoform forming voltage‐dependent connexons. The role of VEGF‐A in inhibiting these events was confirmed by treating TGF‐β1‐stimulated fibroblasts with soluble VEGF‐A. The results obtained when cells were differentiated using KRN633 alone suggest an antagonistic cross‐talk between TGF‐β1 and VEGFR. In conclusion, this study identifies, for the first time, gap junction currents as crucial targets in the VEGF‐A/VEGFR‐mediated antifibrotic pathway and provides new insights into mechanisms behind the action of PRP in preventing differentiation of fibroblasts to myofibroblasts.

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Role of sphingosine 1-phosphate signalling in tissue fibrosis

Cited by 27 publications

References 174 publications

Effects of secretome derived from macrophages exposed to calcium oxalate crystals on renal fibroblast activation

Effects of secretome derived from macrophages exposed to calcium oxalate crystals on renal fibroblast activation

Antagonizing S1P3 Receptor with Cell-Penetrating Pepducins in Skeletal Muscle Fibrosis

Platelet‐rich plasma affects gap junctional features in myofibroblasts in vitro via vascular endothelial growth factor (VEGF)‐A/VEGF receptor

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