A Synthetic Peptide from Transforming Growth Factor-β<sub>1</sub>Type III Receptor Inhibits NADPH Oxidase and Prevents Oxidative Stress in the Kidney of Spontaneously Hypertensive Rats

Baltanás, Ana; Miguel-Carrasco, José L.; José, Gorka San; Cebrián, Carolina; Moreno, María U.; Dotor, Javier; Borrás‐Cuesta, Francisco; López, Begoña; González, Arantxa; Dı́ez, Javier; Fortuño, Ana; Zalba, Guillermo

doi:10.1089/ars.2012.4653

Cited by 22 publications

(21 citation statements)

References 48 publications

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“…EGFR-via transactivation-has the potential to mediate signaling of non-EGFR ligands and thereby serve as a heterologous transducer of cellular signaling. EGFR transactivation in cardiac cells has been observed following stimulation with several vasoactive substances and well-known inducers of cardiomyocyte hypertrophy such as AngII, phenylephrine, endothelin-1 and aldosterone [32][33][34][35]. In CFs, β-adrenergic receptor-dependent changes in cytokine expression are also predominantly mediated through an EGFR-sensitive manner [36].…”

Section: Discussionmentioning

confidence: 99%

“…HB-EGF is known to induce cell activation in various cell types, including cardiac cells via transactivation of EGFR. In CFs and cardiomyocytes, it has been demonstrated that cellular signaling induced by inflammatory agonists and proteases, closely related to cardiac remodeling, is dependent upon HB-EGF shedding and subsequent EGFR activation [33,38,39]. Therefore, further approaches, such as knockdown EGFR or HB-EGF expression, might be considered to be future strategies for validating the results obtained with pharmacological interventions.…”

Section: Discussionmentioning

confidence: 99%

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Secreted Phospholipase A2-IIA Modulates Transdifferentiation of Cardiac Fibroblast through EGFR Transactivation: An Inflammation–Fibrosis Link

Martín

Gutiérrez

Cordova

et al. 2020

Cells

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Secreted phospholipase A 2 -IIA (sPLA 2 -IIA) is a pro-inflammatory protein associated with cardiovascular disorders, whose functions and underlying mechanisms in cardiac remodelling are still under investigation. We herein study the role of sPLA 2 -IIA in cardiac fibroblast (CFs)-to-myofibroblast differentiation and fibrosis, two major features involved in cardiac remodelling, and also explore potential mechanisms involved. In a mice model of dilated cardiomyopathy (DCM) after autoimmune myocarditis, serum and cardiac sPLA 2 -IIA protein expression were found to be increased, together with elevated cardiac levels of the cross-linking enzyme lysyl oxidase (LOX) and reactive oxygen species (ROS) accumulation. Exogenous sPLA 2 -IIA treatment induced proliferation and differentiation of adult rat CFs. Molecular studies demonstrated that sPLA 2 -IIA promoted Src phosphorylation, shedding of the membrane-anchored heparin-binding EGF-like growth factor (HB-EGF) ectodomain and EGFR phosphorylation, which triggered phosphorylation of ERK, P70S6K and rS6. This was also accompanied by an up-regulated expression of the bone morphogenic protein (BMP)-1, LOX and collagen I. ROS accumulation were also found to be increased in sPLA 2 -IIA-treated CFs. The presence of inhibitors of the Src/ADAMs-dependent HB-EGF shedding/EGFR pathway abolished the CF phenotype induced by sPLA 2 -IIA. In conclusion, sPLA 2 -IIA may promote myofibroblast differentiation through its ability to modulate EGFR transactivation and signalling as key mechanisms that underlie its biological and pro-fibrotic effects.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Secreted Phospholipase A2-IIA Modulates Transdifferentiation of Cardiac Fibroblast through EGFR Transactivation: An Inflammation–Fibrosis Link

Martín

Gutiérrez

Cordova

et al. 2020

Cells

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“…Hemodialysis and CKD patients manifest impaired mitochondrial respiration indicative of dysregulated aerobic metabolism and increased oxidative stress . NADPH oxidases (NOX) family has been significantly induced during renal injury, and reduced NOX activity is associated with renal protection in pre‐clinical models of CKD . Nox1, Nox2, and Nox4, which are expressed in both human and rodent kidneys, have a central role in mediating oxidative stress in CKD .…”

Section: Discussionmentioning

confidence: 99%

“…29 NADPH oxidases (NOX) family has been significantly induced during renal injury, and reduced NOX activity is associated with renal protection in pre-clinical models of CKD. 30,31 Nox1, Nox2, and Nox4, which are expressed in both human and rodent kidneys, have a central role in mediating oxidative stress in CKD. 32 These studies suggest that oxidative stress, involving various reactive oxygen and nitrogen species, exerts a promoted role in the progress of CKD development.…”

Section: Fgf1 Treatment Suppressed Diabetes-induced Er Stress and Umentioning

confidence: 99%

Reduction of cellular stress is essential for Fibroblast growth factor 1 treatment for diabetic nephropathy

Jiang

et al. 2018

J Cellular Molecular Medi

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Diabetic nephropathy (DN) is one of general and common complication of diabetes, which severely affects the physical and mental health of diabetic patients. Fibroblast growth factor 1 (FGF1), an effective control agent of blood glucose, plays an effective treatment role on diabetes‐induced renal injury. But the specific molecule mechanism underlying it is still unclear. Since induction of cellular stress is the main and common mechanism of diabetes‐induced complication, we hypothesized that reduction of cellular stress is also the molecular mechanism of FGF1 treatment for DN. Here, we have further confirmed that FGF1 significantly ameliorated the diabetes‐induced renal interstitial fibrosis and glomerular damage. The expression levels of collagen and α‐smooth muscle actin (α‐SMA) also dramatically induced in kidney from db/db mice, but these effects were blocked by FGF1 administration. Our mechanistic investigation had further revealed that diabetes significantly induced oxidative stress, nitrosative stress, and endoplasmic reticulum (ER) stress with upregulation of malondialdehyde (MDA), nitrotyrosine level, ER stress makers and downregulation of antioxidant capacity (AOC). FGF1 treatment significantly attenuated the effect of diabetes on cellular stress. We conclude that FGF1‐associated glucose decreases and subsequent reduction of cellular stress is the another potential molecule mechanism underlying FGF1 treatment for DN.

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“…53,54 These peptides have shown an antagonist effect over TGFb-dependent processes in cellular cultures and a strong TGF-b inhibitory effect in different animal models. 23,[55][56][57] PD Fluid Exposure Model in Mice Female C57BL/6 mice between 12 and 16 weeks of age were used in this study (Harlan Interfauna Iberica, Barcelona, Spain). The experimental protocol used was in accordance with the National Institutes of Health Guide for Care and Use of Laboratory Animals and approved by the Animal Ethics Committee of the Centro de Biología Molecular "Severo Ochoa."…”

Section: Reagentsmentioning

confidence: 99%

A Pathogenetic Role for Endothelin-1 in Peritoneal Dialysis-Associated Fibrosis

Busnadiego

Loureiro-Álvarez

Sandoval

et al. 2015

Journal of the American Society of Nephrology

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In patients undergoing peritoneal dialysis (PD), chronic exposure to nonphysiologic PD fluids elicits lowgrade peritoneal inflammation, leading to fibrosis and angiogenesis. Phenotype conversion of mesothelial cells into myofibroblasts, the so-called mesothelial-to-mesenchymal transition (MMT), significantly contributes to the peritoneal dysfunction related to PD. A number of factors have been described to induce MMT in vitro and in vivo, of which TGF-b1 is probably the most important. The vasoconstrictor peptide endothelin-1 (ET-1) is a transcriptional target of TGF-b1 and mediates excessive scarring and fibrosis in several tissues. This work studied the contribution of ET-1 to the development of peritoneal damage and failure in a mouse model of PD. ET-1 and its receptors were expressed in the peritoneal membrane and upregulated on PD fluid exposure. Administration of an ET receptor antagonist, either bosentan or macitentan, markedly attenuated PD-induced MMT, fibrosis, angiogenesis, and peritoneal functional decline. Adenovirus-mediated overexpression of ET-1 induced MMT in human mesothelial cells in vitro and promoted the early cellular events associated with peritoneal dysfunction in vivo. Notably, TGF-b1-blocking peptides prevented these actions of ET-1. Furthermore, a positive reciprocal relationship was observed between ET-1 expression and TGF-b1 expression in human mesothelial cells. These results strongly support a role for an ET-1/TGF-b1 axis as an inducer of MMT and subsequent peritoneal damage and fibrosis, and they highlight ET-1 as a potential therapeutic target in the treatment of PDassociated dysfunction.

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A Synthetic Peptide from Transforming Growth Factor-β₁Type III Receptor Inhibits NADPH Oxidase and Prevents Oxidative Stress in the Kidney of Spontaneously Hypertensive Rats

Abstract: We demonstrate that P144 inhibits NADPH oxidases and prevents oxidative stress in kidneys from hypertensive rats. Our data also suggest that these effects are associated with the renal antifibrotic effect of P144.

Cited by 22 publications

References 48 publications

Secreted Phospholipase A2-IIA Modulates Transdifferentiation of Cardiac Fibroblast through EGFR Transactivation: An Inflammation–Fibrosis Link

Secreted Phospholipase A2-IIA Modulates Transdifferentiation of Cardiac Fibroblast through EGFR Transactivation: An Inflammation–Fibrosis Link

Reduction of cellular stress is essential for Fibroblast growth factor 1 treatment for diabetic nephropathy

A Pathogenetic Role for Endothelin-1 in Peritoneal Dialysis-Associated Fibrosis

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A Synthetic Peptide from Transforming Growth Factor-β1Type III Receptor Inhibits NADPH Oxidase and Prevents Oxidative Stress in the Kidney of Spontaneously Hypertensive Rats

Abstract: We demonstrate that P144 inhibits NADPH oxidases and prevents oxidative stress in kidneys from hypertensive rats. Our data also suggest that these effects are associated with the renal antifibrotic effect of P144.

Cited by 22 publications

References 48 publications

Secreted Phospholipase A2-IIA Modulates Transdifferentiation of Cardiac Fibroblast through EGFR Transactivation: An Inflammation–Fibrosis Link

Secreted Phospholipase A2-IIA Modulates Transdifferentiation of Cardiac Fibroblast through EGFR Transactivation: An Inflammation–Fibrosis Link

Reduction of cellular stress is essential for Fibroblast growth factor 1 treatment for diabetic nephropathy

A Pathogenetic Role for Endothelin-1 in Peritoneal Dialysis-Associated Fibrosis

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Product

Resources

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A Synthetic Peptide from Transforming Growth Factor-β₁Type III Receptor Inhibits NADPH Oxidase and Prevents Oxidative Stress in the Kidney of Spontaneously Hypertensive Rats