Upregulation of angiotensin‐converting enzyme (ACE) 2 in hepatic fibrosis by ACE inhibitors

Abstract

1. The role of angiotensin-converting enzyme (ACE) 2 is likely to balance the status of the renin-angiotensin system (RAS) by degrading angiotensin (Ang) II and generating Ang-(1-7). Earlier demonstrations that ACE2 is insensitive to ACE inhibitors prompted us to evaluate the effect of ACE inhibitors on ACE2 expression. 2. Liver fibrosis was induced in rats with 40% CCl(4) (2.5 mL/kg, s.c., twice per week). Half the rats were further treated with perindopril (2 mg/kg, p.o., daily). After 2 and 4 weeks treatment, ACE2 immunoreactivity was assessed by immunohistochemical staining, ACE2 protein expression was determined by western blot and mRNA expression of ACE2 and the Ang-(1-7) receptor Mas was determined by reverse transcription-polymerase chain reaction (RT-PCR). 3. As an in vitro study, hepatic stellate cells (HSC) were treated with AngII (0.1-10 micromol/L) alone or in combination with the synthesized peptide ACEI (Sigma-Aldrich). Western blot and RT-PCR were used to evaluate ACE2 expression and Mas mRNA levels. Furthermore, after treatment of HSC with the Mas antagonist A779 (1 micromol/L), the protein expression of connective tissue growth factor (CTGF) was detected to evaluate the interaction between AngII, ACEI and the ACE2-Mas axis. 4. Expression of both ACE2 mRNA and protein and Mas mRNA was markedly upregulated in both CCl(4)-injured rat liver and AngII-treated HSC. Further significant upregulation was observed following additional administration of ACEI. In addition, ACEI treatment of HSC inhibited AngII-induced overexpression of connective tissue growth factor and this effect was ameliorated by blockade of the Mas receptor with A779. 5. The findings of the present study suggest that ACE inhibitors are able to upregulate ACE2 under conditions of liver injury both in vivo and in vitro, which may indicate potential benefits of ACE inhibitors in the therapeutic treatment of liver fibrosis.

Telmisartan attenuates hepatic fibrosis in bile duct-ligated rats

“…This result suggests that the local RAS is activated in BDL rats and that inhibition of the RAS with telmisartan could inhibit the progression of fibrosis. These findings are consistent with previous reports in which the ACE2/Ang (1-7)-Mas axis plays a key role during liver fibrosis [6,7] .…”

“…This observation is consistent with other studies in which ACE2 upregulation in fibrotic livers has been observed [6,7] . MAS expression levels closely paralleled the elevated ACE2 expression levels in rat liver, suggesting that increased ACE2 expression levels may favor the formation of Ang (1-7) and further amplify MAS expression levels.…”

“…There is considerable animal model data supporting an antifibrotic role for the ACE2/Ang (1-7)-MAS axis of the RAS in hepatic fibrosis [1][2][3][6][7][8] . Therefore, we speculate that the RAS may be shifted away from profibrotic responses towards antifibrotic responses by the upregulation of a novel ACE2/Ang (1-7)-MAS axis in the liver.…”

“…Lane 1, sham-operated rats (G1); Lane 2, the BDL without ARB (G2); Lane 3, the BDL+8 mg/kg telmisartan daily (G3). [6,7] . Sukumaran et al suggested that telmisartan provided beneficial protection against heart failure in rats, at least partly by suppressing inflammation, oxidative stress, and endoplasmic reticulum stress, as well as through modulation of the ACE2/Ang (1-7)-Mas axis [23] .…”

“…It is well known that the RAS influences cell differentiation, nutrition, and fibrosis, and it has been reported to play a role in heart and kidney disease [4,5] . Moreover, recent studies have revealed that the RAS plays an important role in the progression of many chronic liver diseases [6,7] . Furthermore, angiotensin II receptor blocker (ARB) modulation of the RAS to treat liver fibrosis has been reported in both animal and human studies [8,9] .…”