scholarly journals A Tight Control of Non-Canonical TGF-β Pathways and MicroRNAs Downregulates Nephronectin in Podocytes

Cells ◽  
2022 ◽  
Vol 11 (1) ◽  
pp. 149
Author(s):  
Nina Sopel ◽  
Alexandra Ohs ◽  
Mario Schiffer ◽  
Janina Müller-Deile
Keyword(s):  
Intracellular Signaling ◽  
Matrix Protein ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Fine Tuning ◽  
Extracellular Matrix Protein ◽  
Glomerular Filtration Barrier ◽  
Glomerular Diseases ◽  
Filtration Barrier ◽  
Canonical Pathways

Nephronectin (NPNT) is an extracellular matrix protein in the glomerular basement membrane that is produced by podocytes and is important for the integrity of the glomerular filtration barrier. Upregulated transforming growth factor β (TGF-β) and altered NPNT are seen in different glomerular diseases. TGF-β downregulates NPNT and upregulates NPNT-targeting microRNAs (miRs). However, the pathways involved were previously unknown. By using selective inhibitors of the canonical, SMAD-dependent, and non-canonical TGF-β pathways, we investigated NPNT transcription, translation, secretion, and regulation through miRs in podocytes. TGF-β decreased NPNT mRNA and protein in cultured human podocytes. TGF-β-dependent regulation of NPNT was meditated through intracellular signaling pathways. Under baseline conditions, non-canonical pathways predominantly regulated NPNT post-transcriptionally. Podocyte NPNT secretion, however, was not dependent on canonical or non-canonical TGF-β pathways. The canonical TGF-β pathway was also dispensable for NPNT regulation after TGF-β stimulation, as TGF-β was still able to downregulate NPNT in the presence of SMAD inhibitors. In contrast, in the presence of different non-canonical pathway inhibitors, TGF-β stimulation did not further decrease NPNT expression. Moreover, distinct non-canonical TGF-β pathways mediated TGF-β-induced upregulation of NPNT-targeting miR-378a-3p. Thus, we conclude that post-transcriptional fine-tuning of NPNT expression in podocytes is mediated predominantly through non-canonical TGF-β pathways.

scholarly journals Suppressive Effects of Sulforaphane on TGFBIp-mediated Sepsis

2017 ◽  
Vol 12 (10) ◽  
pp. 1934578X1701201 ◽  
Author(s):  
In-Chul Lee ◽  
Jong-Sup Bae
Keyword(s):  
Endothelial Cells ◽  
Matrix Protein ◽  
Transforming Growth Factor ◽  
Inflammatory Responses ◽  
Inflammatory Diseases ◽  
Umbilical Vein ◽  
Cecal Ligation ◽  
Transforming Growth Factor Β ◽  
Extracellular Matrix Protein ◽  
Experimental Sepsis

Sulforaphane (SFN) is produced when the enzyme myrosinase transforms glucoraphanin upon damage to the plant such as from chewing and effective in preventing carcinogenesis, diabetes, and inflammatory responses. Transforming growth factor β-induced protein (TGFBIp) is an extracellular matrix protein whose expression in several cell types is greatly increased by TGF-β. TGFBIp is released by human umbilical vein endothelial cells (HUVECs) and functions as a mediator of experimental sepsis. We hypothesized that SFN could reduce TGFBIp-mediated severe inflammatory responses in human endothelial cells and mice. Here, we investigated the anti-septic effects and underlying mechanisms of SFN against TGFBIp-mediated septic responses. SFN effectively inhibited lipopolysaccharide-induced release of TGFBIp and suppressed TGFBIp-mediated septic responses. In addition, SFN suppressed cecal ligation and puncture (CLP)-induced sepsis lethality and pulmonary injury. In conclusion, SFN suppressed TGFBIp-mediated and CLP-induced septic responses. Therefore, SFN could be a potential therapeutic agent for treatment of various severe vascular inflammatory diseases via inhibition of the TGFBIp signaling pathway.

scholarly journals Identification of the growth factor–binding sequence in the extracellular matrix protein MAGP-1

2020 ◽  
Vol 295 (9) ◽  
pp. 2687-2697 ◽  
Author(s):  
Thomas J. Broekelmann ◽  
Nicholas K. Bodmer ◽  
Robert P. Mecham
Keyword(s):  
Extracellular Matrix ◽  
Growth Factor ◽  
Matrix Protein ◽  
Transforming Growth Factor ◽  
Cultured Cells ◽  
Transforming Growth Factor Β ◽  
Bmp Signaling ◽  
Extracellular Matrix Protein ◽  
Surface Plasmon Resonance Analysis ◽  
Factor Binding

Microfibril-associated glycoprotein-1 (MAGP-1) is a component of vertebrate extracellular matrix (ECM) microfibrils that, together with the fibrillins, contributes to microfibril function. Many of the phenotypes associated with MAGP-1 gene inactivation are consistent with dysregulation of the transforming growth factor β (TGFβ)/bone morphogenetic protein (BMP) signaling system. We have previously shown that full-length MAGP-1 binds active TGFβ-1 and some BMPs. The work presented here further defines the growth factor–binding domain of MAGP-1. Using recombinant domains and synthetic peptides, along with surface plasmon resonance analysis to measure the kinetics of the MAGP-1–TGFβ-1 interaction, we localized the TGFβ- and BMP-binding site in MAGP-1 to a 19-amino acid–long, highly acidic sequence near the N terminus. This domain was specific for binding active, but not latent, TGFβ-1. Growth factor activity experiments revealed that TGFβ-1 retains signaling activity when complexed with MAGP-1. Furthermore, when bound to fibrillin, MAGP-1 retained the ability to interact with TGFβ-1, and active TGFβ-1 did not bind fibrillin in the absence of MAGP-1. The absence of MAGP was sufficient to raise the amount of total TGFβ stored in the ECM of cultured cells, suggesting that the MAGPs compete with the TGFβ large latent complex for binding to microfibrils. Together, these results indicate that MAGP-1 plays an active role in TGFβ signaling in the ECM.

Transforming growth factor-β–induced protein (TGFBIp/β ig-h3) activates platelets and promotes thrombogenesis

Blood ◽  
2009 ◽  
Vol 114 (25) ◽  
pp. 5206-5215 ◽  
Author(s):  
Ha-Jeong Kim ◽  
Pan-Kyung Kim ◽  
Sang Mun Bae ◽  
Hye-Nam Son ◽  
Debraj Singh Thoudam ◽  
...  
Keyword(s):  
Pulmonary Embolism ◽  
Growth Factor ◽  
Platelet Activation ◽  
Matrix Protein ◽  
Transforming Growth Factor ◽  
Thrombus Formation ◽  
Transforming Growth Factor Β ◽  
Extracellular Matrix Protein ◽  
Type I

Abstract Transforming growth factor-β–induced protein (TGFBIp)/βig-h3 is a 68-kDa extracellular matrix protein that is functionally associated with the adhesion, migration, proliferation, and differentiation of various cells. The presence of TGFBIp in platelets led us to study the role of this protein in the regulation of platelet functions. Upon activation, platelet TGFBIp was released and associated with the platelets. TGFBIp mediates not only the adhesion and spread of platelets but also activates them, resulting in phosphatidylserine exposure, α-granule secretion, and increased integrin affinity. The fasciclin 1 domains of TGFBIp are mainly responsible for the activation of platelets. TGFBIp promotes thrombus formation on type I fibrillar collagen under flow conditions in vitro and induces pulmonary embolism in mice. Moreover, transgenic mice, which have approximately a 1.7-fold greater blood TGFBIp concentration, are significantly more susceptible to collagen- and epinephrine-induced pulmonary embolism than wild-type mice. These results suggest that TGFBIp, a human platelet protein, plays important roles in platelet activation and thrombus formation. Our findings will increase our understanding of the novel mechanism of platelet activation, contributing to a better understanding of thrombotic pathways and the development of new antithrombotic therapies.

scholarly journals Targeting TGF-β Signaling in Kidney Fibrosis

2018 ◽  
Vol 19 (9) ◽  
pp. 2532 ◽  
Author(s):  
Yoshitaka Isaka
Keyword(s):  
Intracellular Signaling ◽  
Renal Fibrosis ◽  
Matrix Protein ◽  
Transforming Growth Factor ◽  
Kidney Diseases ◽  
Transforming Growth Factor Β ◽  
Cell Interaction ◽  
Common Pathway ◽  
Kidney Fibrosis ◽  
Fibrotic Diseases

Renal fibrosis is the final common pathway of numerous progressive kidney diseases, and transforming growth factor-β (TGF-β) has an important role in tissue fibrosis by up-regulating matrix protein synthesis, inhibiting matrix degradation, and altering cell-cell interaction. Many strategies targeting TGF-β, including inhibition of production, activation, binding to the receptor, and intracellular signaling, have been developed. Some of them were examined in clinical studies against kidney fibrosis, and some are applied to other fibrotic diseases or cancer. Here, I review the approaches targeting TGF-β signaling in kidney fibrosis.

Abstract 11021: Circulating Cardiac Transforming Growth Factor-β is a Principal Determinant in Inducing Myocardial Hypertrophy in Transgenic Mice Overexpressing Exogenous Hepatic Transforming Growth Factor-β

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Shaukat A Khan ◽  
Takeshi Tsuda
Keyword(s):  
Growth Factor ◽  
Transgenic Mice ◽  
Matrix Protein ◽  
Transforming Growth Factor ◽  
Myocardial Hypertrophy ◽  
Cardiac Fibroblasts ◽  
Mrna Level ◽  
Transforming Growth Factor Β ◽  
Extracellular Matrix Protein ◽  
Potent Growth

Introduction: Transforming growth factor (TGF)-β is a potent growth factor that induces myocardial hypertrophy, but an interaction between circulating and myocardial TGF-β has been poorly understood. An extracellular matrix protein, fibulin-2, mediates exogenous TGF-β-induced endogenous TGF-β up-regulation in isolated cardiac fibroblasts. Hypothesis: Systemic TGF-β-induced myocardial hypertrophy is mediated primarily by enhanced myocardial TGF-β via paracrine fashion. Methods: We created double mutant mice with TGF-β1 over-expressing transgenic mice (TG) and fibulin-2 knockout mice (KO). TG developed myocardial hypertrophy due to excessive circulating hepatic TGF-β. We studied TGF-β dynamics between tissues and circulation during hypertrophic changes. Results: TG/WT developed significant myocardial hypertrophy at 8 weeks compared with non-TG (NTG) groups. Hypertrophy in TG/KO was significantly attenuated compared with TG/WT. Myocardial TGF-β mRNA level was significantly up-regulated in TG/WT compared with TG/KO or NGT groups, so was Smad2 activation, but myocardial TGF-β bioactivity was no different among all four groups. Serum carrier-bound TGF-β was significantly higher in TG/WT than in TG/KO or NTG groups, but free unbound TGF-β level was equally elevated in TG groups compared with NTG groups. Thus, hypertrophy in TG/WT may be attributed to increased serum carrier-bound TGF-β levels, not to either myocardial TGF-β activity or serum unbound TGF-β levels. Endogenous TGF-β mRNA level in kidney and liver was equally increased in TG group compared with NTG group, and was comparable in all 4 groups in lung, suggesting fibulin-2 was not involved in TGF-β-induced TGF-β synthesis in kidney, liver, or lung. Conclusions: Hepatic TGF-β-induced-myocardial TGF-β up-regulation was mediated by fibulin-2. In TG/WT, up-regulated myocardial TGF-β was mainly secreted into circulation as a soluble carrier-bound form and did not directly induce hypertrophy via paracrine fashion. It is this circulating endogenous myocardial TGF-β rather than transgene-induced hepatic TGF-β that is responsible for myocardial hypertrophy in TG/WT. Heart is a major endocrine organ in secreting circulating endogenous TGF-β in inducing myocardial hypertrophy.

scholarly journals Role of LTBP4 in alveolarization, angiogenesis, and fibrosis in lungs

2017 ◽  
Vol 313 (4) ◽  
pp. L687-L698 ◽  
Author(s):  
Insa Bultmann-Mellin ◽  
Katharina Dinger ◽  
Carolin Debuschewitz ◽  
Katharina M. A. Loewe ◽  
Yvonne Melcher ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Matrix Protein ◽  
Transforming Growth Factor ◽  
Elastic Fiber ◽  
Transforming Growth Factor Β ◽  
Matrix Proteins ◽  
Extracellular Matrix Protein ◽  
Elastic Fibers ◽  
Fiber Network

Deficiency of the extracellular matrix protein latent transforming growth factor-β (TGF-β)-binding protein-4 (LTBP4) results in lack of intact elastic fibers, which leads to disturbed pulmonary development and lack of normal alveolarization in humans and mice. Formation of alveoli and alveolar septation in pulmonary development requires the concerted interaction of extracellular matrix proteins, growth factors such as TGF-β, fibroblasts, and myofibroblasts to promote elastogenesis as well as vascular formation in the alveolar septae. To investigate the role of LTBP4 in this context, lungs of LTBP4-deficient ( Ltbp4−/−) mice were analyzed in close detail. We elucidate the role of LTBP4 in pulmonary alveolarization and show that three different, interacting mechanisms might contribute to alveolar septation defects in Ltbp4−/− lungs: 1) absence of an intact elastic fiber network, 2) reduced angiogenesis, and 3) upregulation of TGF-β activity resulting in profibrotic processes in the lung.

Relevant role of PKG in the progression of fibrosis induced by TNF-like weak inducer of apoptosis

2014 ◽  
Vol 307 (1) ◽  
pp. F75-F85 ◽  
Author(s):  
Paloma Martín ◽  
Inés Mora ◽  
M. Alicia Cortes ◽  
Laura Calleros ◽  
Andrea García-Jerez ◽  
...  
Keyword(s):  
Intracellular Signaling ◽  
Matrix Protein ◽  
Transforming Growth Factor ◽  
Mesangial Cells ◽  
Dominant Negative ◽  
Extracellular Matrix Protein ◽  
Potent Inducer ◽  
Ras Pathway ◽  
Expression And Activity

TNF-like weak inducer of apoptosis (TWEAK) is an inflammatory cytokine that activates the FGF-inducible 14 receptor. Both TWEAK and the FGF-inducible 14 receptor are constitutively expressed in the kidney. TWEAK has been shown to modulate several biological responses, such as inflammation, proliferation, differentiation, and apoptosis, that contribute to kidney injury. However, the role of TWEAK in fibrosis and TWEAK-activated intracellular signaling pathways remain poorly understood. We tested the hypothesis that TWEAK can be a potent inducer of renal fibrosis by increasing transforming growth factor (TGF)-β1 expression (a well-known switch in the fibrosis process) through PKG-I downregulation. We showed that in human mesangial cells, TWEAK increased TGF-β1 expression and activity, leading to higher levels of the extracellular matrix protein fibronectin and decreased PKG-I expression and activity via the Ras pathway. PKG-I activation with 8-bromo-cGMP, Ras inactivation with dominant negative Ras, or Ras pathway inhibition with the ERK1/2 inhibitor PD-98059 resulted in the prevention of TWEAK-induced TGF-β1 upregulation. In vivo, exogenous administration of TWEAK to wild-type mice downregulated kidney PKG-I and increased kidney TGF-β1 expression. These effects were blunted in H-Ras knockout mice. Together, these data demonstrate, for the first time, the key role of PKG-I in TGF-β1 induction by TWEAK in kidney cells.

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