Significance of chymase‐dependent angiotensin II formation in the progression of human liver fibrosis

Koyama, Koji; Jin, Denan; Takai, Shinji; Hayashi, Michihiro; Takeshita, Atsushi; Shibayama, Yuro; Tanigawa, Nobuhiko; Miyazaki, Mizuo

doi:10.1111/j.1872-034x.2007.00271.x

Cited by 27 publications

(52 citation statements)

References 35 publications

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“…Fun et al (72) demonstrated the significance of chymase-dependent angiotensin II formation to the progression of tubulointerstitial fibrosis in obstructed kidneys in hamsters. In human liver fibrosis, both chymase and angiotensin II levels were significantly augmented, and significant correlations between chymase and angiotensin II levels, between chymase level and fibrotic degree, and between angiotensin II level and fibrotic degree were observed (73). Furthermore, chymase inhibition significantly attenuated the liver fibrosis in experimental animal models (74,75).…”

Section: Target Diseases Other Than Cardiovascular Diseasesmentioning

confidence: 74%

New Approaches to Blockade of the Renin–Angiotensin–Aldosterone System: Chymase as an Important Target to Prevent Organ Damage

2010

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Abstract. Chymase plays a crucial role in angiotensin II formation in various tissues. Angiotensin II induces gene expression of transforming growth factor (TGF)-β and matrix metalloproteinase (MMP)-9 precursors, and chymase can convert precursors of TGF-β and MMP-9 to their active forms. In cultured fibroblasts, significant increases in cell growth and TGF-β levels were observed after chymase injection; these increases were inhibited by a chymase inhibitor, but not by an angiotensin II-receptor blocker. In apolipoprotein E-deficient mice, abdominal aortic aneurysm (AAA) development depends on an increase in MMP-9 activities induced by angiotensin II infusion, but the inhibition of MMP-9 activation by a chymase inhibitor resulted in attenuation of the angiotensin II-induced AAA development. The upregulation of MMP-9 and TGF-β levels is involved in damage to various organs, but these gene expressions are not completely induced by angiotensin II alone. Therefore, chymase inhibition may be useful for attenuating MMP-9 and TGF-β levels, in addition to reducing angiotensin II formation, and this function may provide powerful organ protection. In this review, we propose the possible use of chymase inhibitors as agents to prevent organ damage.

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Section: Target Diseases Other Than Cardiovascular Diseasesmentioning

confidence: 74%

New Approaches to Blockade of the Renin–Angiotensin–Aldosterone System: Chymase as an Important Target to Prevent Organ Damage

2010

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“…Other molecules mediate the interaction of Kupffer cells and Ito cells, as well as other cells involved in the liver fibrosis, to develop deposition of extracellular matrix. Vasodilator and vasoconstrictor substances such as nitric oxide, norepinephrine, angiotensin II, and endothelin are also involved in the mechanism of liver fibrosis (Hirose et al 2007;Kitamura and Hayashi 2008;Komeda et al 2008;Koshy et al 2005;Miller et al 2007;Moreno and Muriel 2006). IL-10 has been involved in the control of hepatic fibrosis due to Kupffer cell deactivation (Thompson et al 1998), and it was elevated in serum from patients with VL, decaying exponentially after therapy (de Medeiros et al 1998).…”

Section: Discussionmentioning

confidence: 96%

TGF-beta and mesenchymal hepatic involvement after visceral leishmaniasis

et al. 2008

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The liver involvement in the human visceral leishmaniasis (VL) has been related to parasitism and activated Kupffer cells with further occasional fibrotic alterations, especially after long-term disease without treatment. However, fibrotic alterations have been reported after therapy, whose clinical finding is the persistence of hepatomegaly. Fibrotic involvement of the liver after therapy was never well understood, and the aim of this study was to evaluate this finding through ultrastructural and morphometric analysis. A case-control study was performed with 20 patients (15 cases and five controls). Cases included patients with persistent hepatomegaly (residual) after treatment of VL submitted to liver biopsy to exclude other causes of liver enlargement, including serum tests of viral hepatitis. The material was evaluated by electron microscopy allowing ultrastructural with morphometric analysis of medium portion of hepatic lobule. Narrow sinusoidal lumen and prominent Kupffer cells were found with insignificant alterations of hepatocytes, pit, and endothelial cells. On ultrastructural analysis, the enlargement of the space of Disse was due to fibrous collagen, increase of number of Ito cells, and nonfibrous extracellular matrix that were associated with Kupffer cells enlargement. Immunohistochemistry showed an intense expression of TGF-beta in patients with VL. These findings suggest a production of TGF-beta by Kupffer cells that resulted in the characteristic fibrotic involvement of the liver. Residual hepatomegaly in visceral leishmaniasis could result from sustained Kupffer cell activation with perihepatocytic fibrosis.

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“…In human autopsy and biopsy cirrhotic livers, the expression of chymase is increased compared to that in normal livers, and it is suggested that the chymase contributes to the liver fibrosis [31] . Recently, it has been shown that, in human chronic cirrhosis, chymase-positive cells and activity are increased and Ang II formation is increased (but ACE activity is unaltered) compared to non-cirrhosis or early cirrhosis [32] . This suggests that chymase-dependent Ang II formation has a role in the fibrosis associated with liver cirrhosis [32] .…”

Section: Fibrosismentioning

confidence: 99%

“…Recently, it has been shown that, in human chronic cirrhosis, chymase-positive cells and activity are increased and Ang II formation is increased (but ACE activity is unaltered) compared to non-cirrhosis or early cirrhosis [32] . This suggests that chymase-dependent Ang II formation has a role in the fibrosis associated with liver cirrhosis [32] .…”

Section: Fibrosismentioning

confidence: 99%

Therapeutic potential of non-peptide chymase inhibitors

Doggrell¹

2008

Expert Opinion on Therapeutic Patents

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Significance of chymase‐dependent angiotensin II formation in the progression of human liver fibrosis

Abstract: These results suggest that chymase-dependent angiotensin II formation may play an important role in hepatic fibrosis of patients with cirrhosis.

Cited by 27 publications

References 35 publications

New Approaches to Blockade of the Renin–Angiotensin–Aldosterone System: Chymase as an Important Target to Prevent Organ Damage

New Approaches to Blockade of the Renin–Angiotensin–Aldosterone System: Chymase as an Important Target to Prevent Organ Damage

TGF-beta and mesenchymal hepatic involvement after visceral leishmaniasis

Therapeutic potential of non-peptide chymase inhibitors

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