Angiotensin II in the lesional skin of systemic sclerosis patients contributes to tissue fibrosis via angiotensin II type 1 receptors.
OBJECTIVE
Tissue fibrosis in systemic sclerosis (SSc) is attributed to excessive deposition of extracellular matrix components produced by fibroblasts in skin lesions. Angiotensin II (Ang II), a vasoconstrictive peptide, is reported to have profibrotic activity as a result of induction of the extracellular matrix. The aim of the present study was to examine the expression of Ang II and its type 1 (AT(1)) and type 2 (AT(2)) receptors in affected skin and dermal fibroblasts from patients with SSc and to study the role of Ang II in collagen production by SSc dermal fibroblasts.


METHODS
Levels of Ang II in sera from SSc patients and normal subjects were measured by a solid-phase immobilized-epitope immunoassay. Expression of angiotensinogen (Angt) in the skin was evaluated by immunohistochemistry. Expression of Angt, AT(1), and AT(2) in cultured dermal fibroblasts was analyzed by reverse transcription-polymerase chain reaction and immunohistochemistry. Levels of type I procollagen produced by cultured dermal fibroblasts were measured by enzyme-linked immunosorbent assay.


RESULTS
Serum Ang II levels in patients with diffuse cutaneous SSc were significantly higher than those in patients with limited cutaneous SSc and in healthy donors. Immunohistochemical and immunoblotting analyses showed that Angt was present in skin from SSc patients, but not in normal skin. Angt messenger RNA (mRNA) was expressed in fibroblasts from patients with diffuse cutaneous SSc who had high levels of serum Ang II, but not in normal fibroblasts. AT(1) mRNA expression was found in both SSc and normal fibroblasts, whereas AT(2) mRNA was found only in SSc fibroblasts. Exogenous Ang II augmented the production of type I procollagen and transforming growth factor beta1 by cultured fibroblasts via activation of AT(1).


CONCLUSIONS
Aberrant Ang II production may be involved in tissue fibrosis through excessive production of the extracellular matrix components in SSc dermal fibroblasts. This suggests that the use of AT(1) receptor antagonists may be a novel strategy for the treatment of tissue fibrosis in SSc patients.
Kawaguchi
Yasushi
Y
Tokyo Women's Medical University School of Medicine, Tokyo, Japan. y-kawa@ior.twmu.ac.jp
Takagi
Kae
K
Hara
Masako
M
Fukasawa
Chikako
C
Sugiura
Tomoko
T
Nishimagi
Emi
E
Harigai
Masayoshi
M
Kamatani
Naoyuki
N
D000328:Adult; D000368:Aged; D000804:Angiotensin II / Q000097:blood*; D000808:Angiotensinogen / Q000235:genetics; D019898:Autocrine Communication; D015153:Blotting, Western; D002402:Cathepsin D / Q000235:genetics; D002478:Cells, Cultured; D005109:Extracellular Matrix / Q000378:metabolism / Q000473:pathology; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D005355:Fibrosis; D015870:Gene Expression; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D011347:Procollagen / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism*; D012595:Scleroderma, Systemic / Q000378:metabolism* / Q000473:pathology*; D012867:Skin / Q000378:metabolism / Q000473:pathology*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D053773:Transforming Growth Factor beta1
D011347:Procollagen; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; C508960:TGFB1 protein, human; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D000808:Angiotensinogen; D000804:Angiotensin II; D002402:Cathepsin D