Angiotensin II in the lesional skin of systemic sclerosis patients contributes to tissue fibrosis via angiotensin II type 1 receptors

Kawaguchi, Yasushi; Takagi, Kae; Hara, Masako; Fukasawa, Chikako; Sugiura, Tomoko; Nishimagi, Emi; Harigai, Masayoshi; Kamatani, Naoyuki

doi:10.1002/art.11364

Cited by 105 publications

(95 citation statements)

References 55 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…16 Recently, evidence has been presented that defined a role of Ang II in stimulation of collagen gene expression and protein turnover in cultured cardiac fibroblasts. 31,32 Here, our results demonstrated TGF-β activation induced by Ang II, which was in line with other studies that demonstrated Ang II regulated synthesis of TGF-β. 11,17 However, the effect of Ang II on MMPs and TIMPs in different studies remains controversial.…”

Section: Discussionsupporting

confidence: 92%

Angiotensin II regulates collagen metabolism through modulating tissue inhibitor of metalloproteinase-1 in diabetic skin tissues

Ren

Hao

Yang

et al. 2013

Diabetes and Vascular Disease Research

View full text Add to dashboard Cite

We investigated the effect of angiotensin II (Ang II) on matrix metalloproteinase-1 (MMP-1)/tissue inhibitor of metalloproteinase-1 (TIMP-1) balance in regulating collagen metabolism of diabetic skin. Skin tissues from diabetic model were collected, and the primary cultured fibroblasts were treated with Ang II receptor inhibitors before Ang II treatment. The collagen type I (Coll I) and collagen type III (Coll III) were measured by histochemistry. The expressions of transforming growth factor-β (TGF-β), MMP-1, TIMP-1 and propeptides of types I and III procollagens in skin tissues and fibroblasts were quantified using polymerase chain reaction (PCR), Western blot or enzyme-linked immunosorbent assay (ELISA). Collagen dysfunction was documented by changed collagen I/III ratio in streptozotocin (STZ)-injected mice compared with controls. This was accompanied by increased expression of TGF-β, TIMP-1 and propeptides of types I and III procollagens in diabetic skin tissues. In primary cultured fibroblasts, Ang II prompted collagen synthesis accompanied by increases in the expressions of TGF-β, TIMP-1 and types I and III procollagens, and these increases were inhibited by losartan, an Ang II type 1 (AT1) receptor blocker, but not affected by PD123319, an Ang II type 2 (AT2) receptor antagonist. These findings present evidence that Ang-II-mediated changes in the productions of MMP-1 and TIMP-1 occur via AT1 receptors and a TGF-β-dependent mechanism.

show abstract

Section: Discussionsupporting

confidence: 92%

Angiotensin II regulates collagen metabolism through modulating tissue inhibitor of metalloproteinase-1 in diabetic skin tissues

Ren

Hao

Yang

et al. 2013

Diabetes and Vascular Disease Research

View full text Add to dashboard Cite

show abstract

“…Such contaminants are difficult to trace because they are highly variable in terms of chemical structure and are active at low concentrations. Of note, levels of PDGF and angiotensin II have been found to be elevated in patients with SSc (29)(30)(31).…”

Section: Discussionmentioning

confidence: 99%

Lack of evidence of stimulatory autoantibodies to platelet‐derived growth factor receptor in patients with systemic sclerosis

Classen¹,

Henrohn²,

Rorsman³

et al. 2009

Arthritis & Rheumatism

View full text Add to dashboard Cite

Objective. Systemic sclerosis (SSc) is a severe connective tissue disease of unknown etiology, characterized by fibrosis of the skin and multiple internal organs. Recent findings suggested that the disease is driven by stimulatory autoantibodies to platelet-derived growth factor receptor (PDGFR), which stimulate the production of reactive oxygen species (ROS) and collagen by fibroblasts. These results opened novel avenues of research into the diagnosis and treatment of SSc. The present study was undertaken to confirm the presence of anti-PDGFR antibodies in patients with SSc.Methods. Immunoglobulins from 37 patients with SSc were purified by protein A/G chromatography. PDGFR activation was tested using 4 different sensitive bioassays, i.e., cell proliferation, ROS production, signal transduction, and receptor phosphorylation; the latter was also tested in a separate population of 7 patients with SSc from a different research center.Results. Purified IgG samples from patients with SSc were positive when tested for antinuclear autoantibodies, but did not specifically activate PDGFR␣ or PDGFR␤ in any of the tests. Cell stimulation with PDGF itself consistently produced a strong signal.Conclusion. The present results raise questions regarding the existence of agonistic autoantibodies to PDGFR in SSc.

show abstract

“…Ang II is implicated as a critical mediator of cutaneous wound healing and pathologic scarring (14). Ang II stimulates proliferation, migration and matrix production of human dermal fibroblasts (19)(20)(21)(22). Immunohistochemical staining of normal skin, wounded skin and hypertrophic scars has revealed that AT 1 and AT 2 expression are increased in scar epithelium and endothelium and that angiotensin-converting enzymes (ACE) activity is also increased, but reports of these findings do not describe immunostaining of the deep dermis (15,16).…”

Section: Introductionmentioning

confidence: 99%

Angiotensin-II Mediates Nonmuscle Myosin II Activation and Expression and Contributes to Human Keloid Disease Progression

Bond

Bergeron

Thurlow

et al. 2011

Mol Med

View full text Add to dashboard Cite

Aberrant fibroblast migration in response to fibrogenic peptides plays a significant role in keloid pathogenesis. Angiotensin II (Ang II) is an octapeptide hormone recently implicated as a mediator of organ fibrosis and cutaneous repair. Ang II promotes cell migration but its role in keloid fibroblast phenotypic behavior has not been studied. We investigated Ang II signaling in keloid fibroblast behavior as a potential mechanism of disease. Primary human keloid fibroblasts were stimulated to migrate in the presence of Ang II and Ang II receptor 1 (AT 1 ), Ang II receptor 2 (AT 2 ) or nonmuscle myosin II (NMM II) antagonists. Keloid and the surrounding normal dermis were immunostained for NMM IIA, NMM IIB, AT 2 and AT 1 expression. Primary human keloid fibroblasts were stimulated to migrate with Ang II and the increased migration was inhibited by the AT 1 antagonist EMD66684, but not the AT 2 antagonist PD123319. Inhibition of the promigratory motor protein NMM II by addition of the specific NMM II antagonist blebbistatin inhibited Ang II-stimulated migration. Ang II stimulation of NMM II protein expression was prevented by AT 1 blockade but not by AT 2 antagonists. Immunostaining demonstrated increased NMM IIA, NMM IIB and AT 1 expression in keloid fibroblasts compared with scant staining in normal surrounding dermis. AT 2 immunostaining was absent in keloid and normal human dermal fibroblasts. These results indicate that Ang II mediates keloid fibroblast migration and possibly pathogenesis through AT 1 activation and upregulation of NMM II.

show abstract

Angiotensin II in the lesional skin of systemic sclerosis patients contributes to tissue fibrosis via angiotensin II type 1 receptors

Cited by 105 publications

References 55 publications

Angiotensin II regulates collagen metabolism through modulating tissue inhibitor of metalloproteinase-1 in diabetic skin tissues

Angiotensin II regulates collagen metabolism through modulating tissue inhibitor of metalloproteinase-1 in diabetic skin tissues

Lack of evidence of stimulatory autoantibodies to platelet‐derived growth factor receptor in patients with systemic sclerosis

Angiotensin-II Mediates Nonmuscle Myosin II Activation and Expression and Contributes to Human Keloid Disease Progression

Contact Info

Product

Resources

About