Angiotensin-(1–7), an alternative metabolite of the renin–angiotensin system, is up-regulated in human liver disease and has antifibrotic activity in the bile-duct-ligated rat

Lubel, John S; Herath, Chandana B; Tchongue, Jorge; Grace, Josephine A; Jia, Zhiyuan; Spencer, Karen R.; Casley, David; Crowley, Peter; Sievert, William; Burrell, Louise M.; Angus, Peter W

doi:10.1042/cs20080647

Cited by 90 publications

(141 citation statements)

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“…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] .…”

Section: Discussionsupporting

confidence: 83%

“…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.…”

Section: Discussionsupporting

confidence: 83%

“…We observed that the expression of ACE2 and MAS levels were upregulated by telmisartan. Moreover, the inhibition of ACE activity could encumber degradation of Ang (1-7) to Ang (1-5), as has been suggested [7] . Ang (1-7) expression would be enhanced by ARB-mediated inhibition, which in turn could promote MAS expression.…”

Section: Discussionmentioning

confidence: 90%

“…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.…”

Section: Discussionmentioning

confidence: 99%

“…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] .…”

Section: Introductionmentioning

confidence: 99%

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Telmisartan attenuates hepatic fibrosis in bile duct-ligated rats

Liu

Wen

et al. 2012

Acta Pharmacol Sin

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Aim: To evaluate the antifibrotic effect of telmisartan, an angiotensin II receptor blocker, in bile duct-ligated rats. Methods: Adult Sprague-Dawley rats were allocated to 3 groups: sham-operated rats, model rats underwent common bile duct ligation (BDL), and BDL rats treated with telmisartan (8 mg/kg, po, for 4 weeks). The animals were sacrificed on d 29, and liver histology was examined, the Knodell and Ishak scores were assigned, and the expression of angiotensin-converting enzyme (ACE) and ACE2 was evaluated with immunohistochemical staining. The mRNAs and proteins associated with liver fibrosis were evaluated using RTQ-PCR and Western blot, respectively. Results: The mean fibrosis score of BDL rats treated with telmisartan was significantly lower than that of the model rats (1.66±0.87 vs 2.13±0.35, P=0.015). However, there was no significant difference in inflammation between the two groups, both of which showed moderate inflammation. Histologically, treatment with telmisartan significantly ameliorated BDL-caused the hepatic fibrosis. Treatment with telmisartan significantly upregulated the mRNA levels of ACE2 and MAS, and decreased the mRNA levels of ACE, angiotensin II type 1 receptor (AT1-R), collagen type III, and transforming growth factor β1 (TGF-β1). Moreover, treatment with telmisartan significantly increased the expression levels of ACE2 and MAS proteins, and inhibited the expression levels of ACE and AT1-R protein. Conclusion:Telmisartan attenuates liver fibrosis in bile duct-ligated rats via increasing ACE2 expression level.

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Section: Discussionsupporting

confidence: 83%

Section: Discussionsupporting

confidence: 83%

Section: Discussionmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Telmisartan attenuates hepatic fibrosis in bile duct-ligated rats

Liu

Wen

et al. 2012

Acta Pharmacol Sin

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Liver‐Targeted Angiotensin Converting Enzyme 2 Therapy Inhibits Chronic Biliary Fibrosis in Multiple Drug‐Resistant Gene 2‐Knockout Mice

Rajapaksha¹,

Gunarathne²,

Asadi

et al. 2019

Hepatol Commun

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There is a large unmet need for effective therapies for cholestatic disorders, including primary sclerosing cholangitis (PSC), a disease that commonly results in liver failure. Angiotensin (Ang) II of the renin Ang system (RAS) is a potent profibrotic peptide, and Ang converting enzyme 2 (ACE2) of the alternate RAS breaks down Ang II to antifibrotic peptide Ang‐(1‐7). In the present study, we investigated long‐term effects of ACE2 delivered by an adeno‐associated viral vector and short‐term effects of Ang‐(1‐7) peptide in multiple drug‐resistant gene 2‐knockout (Mdr2‐KO) mice. These mice develop progressive biliary fibrosis with pathologic features closely resembling those observed in PSC. A single intraperitoneal injection of ACE2 therapy markedly reduced liver injury (P < 0.05) and biliary fibrosis (P < 0.01) at both established (3‐6 months of age) and advanced (7‐9 months of age) disease compared to control vector‐injected Mdr2‐KO mice. This was accompanied by increased hepatic Ang‐(1‐7) levels (P < 0.05) with concomitant reduction in hepatic Ang II levels (P < 0.05) compared to controls. Moreover, Ang‐(1‐7) peptide infusion improved liver injury (P < 0.05) and biliary fibrosis (P < 0.0001) compared to saline‐infused disease controls. The therapeutic effects of both ACE2 therapy and Ang‐(1‐7) infusion were associated with significant (P < 0.01) reduction in hepatic stellate cell (HSC) activation and collagen expression. While ACE2 therapy prevented the loss of epithelial characteristics of hepatocytes and/or cholangiocytes in vivo, Ang‐(1‐7) prevented transdifferentiation of human cholangiocytes (H69 cells) into the collagen‐secreting myofibroblastic phenotype in vitro. We showed that an increased ratio of hepatic Ang‐(1‐7) to Ang II levels by ACE2 therapy results in the inhibition of HSC activation and biliary fibrosis. Conclusion: ACE2 therapy has the potential to treat patients with biliary diseases, such as PSC.

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Angiotensin Converting Enzyme‐2 Therapy Improves Liver Fibrosis and Glycemic Control in Diabetic Mice With Fatty Liver

et al. 2021

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Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease and is frequently associated with type 2 diabetes. However, there is no specific medical therapy to treat this condition. Angiotensin‐converting enzyme 2 (ACE2) of the protective renin angiotensin system generates the antifibrotic peptide angiotensin‐(1‐7) from profibrotic angiotensin II peptide. In this study, we investigated the therapeutic potential of ACE2 in diabetic NAFLD mice fed a high‐fat (20%), high‐cholesterol (2%) diet for 40 weeks. Mice were given a single intraperitoneal injection of ACE2 using an adeno‐associated viral vector at 30 weeks of high‐fat, high‐cholesterol diet (15 weeks after induction of diabetes) and sacrificed 10 weeks later. ACE2 significantly reduced liver injury and fibrosis in diabetic NAFLD mice compared with the control vector injected mice. This was accompanied by reductions in proinflammatory cytokine expressions, hepatic stellate cell activation, and collagen 1 expression. Moreover, ACE2 therapy significantly increased islet numbers, leading to an increased insulin protein content in β‐cells and plasma insulin levels with subsequent reduction in plasma glucose levels compared with controls. Conclusion: We conclude that ACE2 gene therapy reduces liver fibrosis and hyperglycemia in diabetic NAFLD mice and has potential as a therapy for patients with NAFLD with diabetes.

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Angiotensin-(1–7), an alternative metabolite of the renin–angiotensin system, is up-regulated in human liver disease and has antifibrotic activity in the bile-duct-ligated rat

Cited by 90 publications

References 50 publications

Telmisartan attenuates hepatic fibrosis in bile duct-ligated rats

Telmisartan attenuates hepatic fibrosis in bile duct-ligated rats

Liver‐Targeted Angiotensin Converting Enzyme 2 Therapy Inhibits Chronic Biliary Fibrosis in Multiple Drug‐Resistant Gene 2‐Knockout Mice

Angiotensin Converting Enzyme‐2 Therapy Improves Liver Fibrosis and Glycemic Control in Diabetic Mice With Fatty Liver

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