The Notch γ-secretase inhibitor ameliorates kidney fibrosis via inhibition of TGF-β/Smad2/3 signaling pathway activation

Xiao, Zhao; Zhang, Jing; Peng, Xiaogang; Dong, Yanjun; Jia, Lixin; Li, Huihua; Du, Jie

doi:10.1016/j.biocel.2014.08.009

Cited by 70 publications

(66 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Spironolactone does not affect basal collagen expression, so it is a safe antifibrotic agent [24]. Consistent with these findings, low or high doses of spironolactone could prevent myocardial fibrosis in rats with unilateral renal ischemia or hyperaldosteronism [13].…”

Section: Discussionsupporting

confidence: 73%

“…The Notch γ-secretase inhibitor ameliorates kidney fibrosis via inhibition of TGF-β/Smad2/3 signaling pathway activation [24]. Signaling crosstalk between Notch and TGF-β pathways was demonstrated in the early induction of Hey1 expression in Smad3-dependent and Notchindependent or delayed Notch-dependent pathways [8].…”

Section: Discussionmentioning

confidence: 99%

“…Signaling crosstalk between Notch and TGF-β pathways was demonstrated in the early induction of Hey1 expression in Smad3-dependent and Notchindependent or delayed Notch-dependent pathways [8]. Notch signaling is involved in the corneal EndMT process [24]. Notch/Jagged signaling is essential for endothelial function and may contribute to EndMT in embryogenesis and cancer [10].…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Protective Effect of Spironolactone on Endothelial-to-Mesenchymal Transition in HUVECs via Notch Pathway

Chen

Cai

Zhou

et al. 2015

Cell Physiol Biochem

View full text Add to dashboard Cite

Background: Fibrosis results in excessive buildup of extracellular matrix proteins along with abnormalities in structure and is partly derived by a process involving transforming growth factor β (TGF-β) called endothelial-to-mesenchymal transition (EndMT). We investigated whether the aldosterone receptor-blocker spironolactone could abrogate TGF-β-induced fibrosis in EndMT and the underlying mechanism. Methods: Human umbilical vein endothelial cells (HUVECs) were divided into 5 groups for treatment: blank; vehicle control; TGF-β (10 ng/ml); spironolactone (1 μM)+TGF-β; and spironolactone+TGF-β+DAPT (10 μM). Cell chemotaxis was assayed by transwell assay. The expression of CD31 and vimentin was determined by Immunofluorescence staining and western blot analysis. Notch1 protein level was detected by western blot analysis. Results: Spironolactone significantly prevented TGF-β-stimulated EndMT by down-regulate vimentin and up-regulate CD31 in HUVECs (p<0.01).It inhibited cell migration during EndMT (p<0.01). The protective effect of spironolactone against EndMT could be attenuated by blocking the Notch signal pathway with DAPT (p<0.01). Notch signaling was activated and cross-interacted with TGF-β and spironolactone in regulating EndMT in HUVECs and reversed the spironolactone-related signaling by abrogating the antifibrotic actions with decreased Notch1 protein expression (p<0.01). Conclusion: Spironolactone may have a protective role in TGF-β-induced EndMT in HUVECs mediated by the Notch signal pathway.

show abstract

Section: Discussionsupporting

confidence: 73%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Protective Effect of Spironolactone on Endothelial-to-Mesenchymal Transition in HUVECs via Notch Pathway

Chen

Cai

Zhou

et al. 2015

Cell Physiol Biochem

View full text Add to dashboard Cite

show abstract

“…Synthesis of the Amine-SecrI (11), Ac-γ-Glu-SecrI (13a), and H-γ-Glu-SecrI (13b) a a Reagents and conditions: (a) bis(4-nitrophenyl)carbonate, i-Pr 2 NEt in CH 2 Cl 2 , rt, 90%; (b) N-BOC-ethylenediamine, Et 3 N in CH 2 Cl 2 , 0°C to rt, 93%; (c) 4 M HCl in dioxane in CH 2 Cl 2 , 0°C to rt, 96%; (d) for 12a, Ac-Glu(OSU)-OBzl, Et 3 N in DMF, 0°C to rt, 83%; for 12b, BOC-Glu-OtBu, 1-hydroxy-7-azabenzotriazole, Et 3 N and EDCI in DMF, 0°C to rt, quantitative; (e) for 13a, H 2 /Pd−C 10%, in dioxane and MeOH, rt, 82%; for 13b, 4 M HCl in dioxane in CH 2 Cl 2 , 0°C to rt, 82%. endothelial cells which express very high levels of APA and γ-GT activities 44 were evaluated for liberating active inhibitors SecrI (8) or amine-SecrI (11) (Figure 2A). The EC219 and HK2 cells, but not the HEK293 cells, were able to release the amine-SecrI (11) from the H-α-Glu-SecrI (15b) into the extracellular space, but not the free inhibitor 8, in a pattern involving APA activity.…”

Section: ■ Resultsmentioning

confidence: 99%

Targeted γ-Secretase Inhibition To Control the Notch Pathway in Renal Diseases

et al. 2015

View full text Add to dashboard Cite

Notch is a membrane inserted protein activated by the membrane-inserted γ-secretase proteolytic complex. The Notch pathway is a potential therapeutic target for the treatment of renal diseases but also controls the function of other cells, requiring cell-targeting of Notch antagonists. Toward selective targeting, we have developed the γ-secretase inhibitor-based prodrugs 13a and 15a as substrates for γ-glutamyltranspeptidase (γ-GT) and/or γ-glutamylcyclotransferase (γ-GCT) as well as aminopeptidase A (APA), which are overexpressed in renal diseases, and have evaluated them in experimental in vitro and in vivo models. In nondiseased mice, the cleavage product from Ac-γ-Glu-γ-secretase inhibitor prodrug 13a (γ-GT-targeting and γ-GCT-targeting) but not from Ac-α-Glu-γ-secretase inhibitor prodrug 15a (APA-targeting) accumulated in kidneys when compared to blood and liver. Potential nephroprotective effects of the γ-secretase inhibitor targeted prodrugs were investigated in vivo in a mouse model of acute kidney injury, demonstrating that the expression of Notch1 and cleaved Notch1 could be selectively down-regulated upon treatment with the Ac-γ-Glu-γ-secretase-inhibitor 13a.

show abstract

“…The addition of RLX to TGF-β1-stimulated cells caused a significant decrease in Smad3 phosphorylation, a typical downstream event of TGF-β1 receptor activation, while the treatment with a prevented this effect [22]. Studies also have suggested that spironolactone improved cardiac remodeling by reducing proinflammatory cytokine levels and inhibiting TGF-β and R-Smads expression [23], without affecting basal collagen expression [24]. However, further studies should been done to assess the anti-fibrosis effect of diverse matching schemes and the security of the combined treatment, and to go into more detail on how TGF-β mediate the effects of relaxin and spironolactone on EndMT.…”

Section: Discussionmentioning

confidence: 99%

Anti-Fibrosis Effect of Relaxin and Spironolactone Combined on Isoprenaline-Induced Myocardial Fibrosis in Rats via Inhibition of Endothelial–Mesenchymal Transition

Cai

Chen

et al. 2017

Cell Physiol Biochem

View full text Add to dashboard Cite

Background: The effect of relaxin and spironolactone combined on myocardial fibrosis has not been reported. Thus, we investigated the effect of the combined therapy on isoprenaline-induced myocardial fibrosis and the mechanism. Methods: Rats were injected subcutaneously with isoprenaline to induce myocardial fibrosis and underwent subcutaneous injection with relaxin (2 µg·kg^-1·d^-1) and given a gavage of spironolactone (30 mg·kg^-1·d^-1) alone or combined for 14 days. In vitro, the endothelial–mesenchymal transition was induced with transforming growth factor β (TGF-β) in human umbilical vein endothelial cells (HUVECs) pretreated with relaxin, 200 ng/ml, and/or spironolactone, 1uM. Results: Relaxin and spironolactone used alone or combined improved cardiac function and decreased cardiac weight indices; reduced fibrous tissue proliferation; reduced levels of type I and III collagen; decreased the expression of α–smooth muscle actin (α-SMA) and transforming growth factor-β1 (TGF-β1), and increased the expression of cluster of differentiation-31 (CD31) in rats with isoprenaline-induced myocardial fibrosis. In vitro, compared with TGF-β treatment, relaxin and spironolactone used alone or combined with TGF-β decreased cell mobility, α-SMA and vimentin levels but increased vascular endothelial cadherin (VE-cadherin) and endothelial CD31levels. Especially, combined therapy had more remarkable effect than relaxin and spironolactone used alone both in vitro and in vivo. Conclusion: Relaxin and spironolactone combined affected isoprenaline-induced myocardial fibrosis in rats that the mechanism might be inhibition of the cardiac endothelial–mesenchymal transition.

show abstract

The Notch γ-secretase inhibitor ameliorates kidney fibrosis via inhibition of TGF-β/Smad2/3 signaling pathway activation

Cited by 70 publications

References 35 publications

Protective Effect of Spironolactone on Endothelial-to-Mesenchymal Transition in HUVECs via Notch Pathway

Protective Effect of Spironolactone on Endothelial-to-Mesenchymal Transition in HUVECs via Notch Pathway

Targeted γ-Secretase Inhibition To Control the Notch Pathway in Renal Diseases

Anti-Fibrosis Effect of Relaxin and Spironolactone Combined on Isoprenaline-Induced Myocardial Fibrosis in Rats via Inhibition of Endothelial–Mesenchymal Transition

Contact Info

Product

Resources

About