SEARCH

SEARCH BY CITATION

Abstract

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 (AT1) and type 2 (AT2) 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, AT1, and AT2 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. AT1 mRNA expression was found in both SSc and normal fibroblasts, whereas AT2 mRNA was found only in SSc fibroblasts. Exogenous Ang II augmented the production of type I procollagen and transforming growth factor β1 by cultured fibroblasts via activation of AT1.

Conclusion

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 AT1 receptor antagonists may be a novel strategy for the treatment of tissue fibrosis in SSc patients.