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

Abstract

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.

Liver Dysfunction and Its Association with the Risk of Death in COVID-19 Patients: A Prospective Cohort Study

“…Several studies demonstrated that ACE2, as a receptor for SARS-CoV-2, was expressed in cholangiocytes and hepatocytes. 32,33 Moreover, ACE2 was found to be highly expressed in cholangiocytes, which may be the reason for higher levels of serum ALP being observed among COVID-19 patients. Therefore, this study does not exclude that SARS-CoV-2 evokes LD partially through infecting liver directly.…”

Myocardial Injury at Early Stage and Its Association with Death Risk of Patients with COVID-19: A Hospital-Based Prospective Case-Cohort Study

“…In the present study, we found that oxygenation index was negatively associated with AST and LDH among COVID-19 patients, suggesting that respiratory function failure may contribute, at least partially, to SARS-CoV-2-evoked myocardial injury. Increasing data demonstrate that angiotension converting enzyme (ACE)2, as a receptor for SARS-CoV-2, exerts a signi cant role in the pathogenesis of COVID-19 patients [22][23][24]. Recently, a report found that ACE2 was also expressed in cardiocytes [25].…”

COVID-19 is a risk factor for severe liver damage for patients with intrahepatic cholestasis of pregnancy: a case report

“…Based on the literature and clinical experience, the pathophysiological mechanisms of the patient reported in the case were speculated as follows. First, in addition to alveolar type 2 cells, cholangiocytes also expressed angiotensin converting enzyme2 (ACE2) [8], and could be targeted by SARS-CoV-2 to cause damage to cholangiocytes and hepatocytes. Second, SARS-CoV-2 activated lymphocytes to proliferate and secrete large amounts of pro-inflammatory cytokines, called "cytokine storm", which could attack the tissue cells to cause liver damage, myocardial injury and kidney failure [9].…”