Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2023 Jan 18;13(1):953.
doi: 10.1038/s41598-023-28239-2.

The systemic and hepatic alternative renin-angiotensin system is activated in liver cirrhosis, linked to endothelial dysfunction and inflammation

Lukas Hartl #  1   2 , Benedikt Rumpf #  1   3 , Oliver Domenig  4 , Benedikt Simbrunner  1   2   5 , Rafael Paternostro  1   2 , Mathias Jachs  1   2 , Marko Poglitsch  4 , Rodrig Marculescu  6 , Michael Trauner  1 , Roman Reindl-Schwaighofer  7 , Manfred Hecking  7 , Mattias Mandorfer  1   2 , Thomas Reiberger  8   9   10
Affiliations

The systemic and hepatic alternative renin-angiotensin system is activated in liver cirrhosis, linked to endothelial dysfunction and inflammation

Lukas Hartl et al. Sci Rep. .

Abstract

We aimed to assess the systemic and hepatic renin-angiotensin-system (RAS) fingerprint in advanced chronic liver disease (ACLD). This prospective study included 13 compensated (cACLD) and 12 decompensated ACLD (dACLD) patients undergoing hepatic venous pressure gradient (HVPG) measurement. Plasma components (all patients) and liver-local enzymes (n = 5) of the RAS were analyzed using liquid chromatography-tandem mass spectrometry. Patients with dACLD had significantly higher angiotensin (Ang) I, Ang II and aldosterone plasma levels. Ang 1-7, a major mediator of the alternative RAS, was almost exclusively detectable in dACLD (n = 12/13; vs. n = 1/13 in cACLD). Also, dACLD patients had higher Ang 1-5 (33.5 pmol/L versus cACLD: 6.6 pmol/L, p < 0.001) and numerically higher Ang III and Ang IV levels. Ang 1-7 correlated with HVPG (ρ = 0.655; p < 0.001), von Willebrand Factor (ρ = 0.681; p < 0.001), MELD (ρ = 0.593; p = 0.002) and interleukin-6 (ρ = 0.418; p = 0.047). Considerable activity of ACE, chymase, ACE2, and neprilysin was detectable in all liver biopsies, with highest chymase and ACE2 activity in cACLD patients. While liver-local classical and alternative RAS activity was already observed in cACLD, systemic activation of alternative RAS components occurred only in dACLD. Increased Ang 1-7 was linked to severe liver disease, portal hypertension, endothelial dysfunction and inflammation.

PubMed Disclaimer

Conflict of interest statement

The authors have nothing to disclose regarding the work under consideration for publication. Conflicts of interests outside the submitted work: L.H., B.R. M.J., R.P. have nothing to disclose. O.D. and M.P: are employed at Attoquant Diagnostics. B.Sim. received travel support from AbbVie and Gilead. D.B. received speaker fees from AbbVie and Siemens, as well as grant support form Gilead and Siemens, as well as travel support from AbbVie and Gilead. M.T. served as a speaker and/or consultant and/or advisory board member for Albireo, BiomX, Falk, Boehringer Ingelheim, Bristol-Myers Squibb, Falk, Genfit, Gilead, Intercept, Janssen, MSD, Novartis, Phenex, Pliant, Regulus, and Shire, and received travel support from AbbVie, Falk, Gilead, and Intercept, as well as grants/research support from Albireo, Alnylam, Cymabay, Falk, Gilead, Intercept, MSD, Takeda, and UltraGenyx. He is also co-inventor of patents on the medical use of 24-norursodeoxycholic acid. M.M. served as a speaker and/or consultant and/or advisory board member for AbbVie, Gilead, and W. L. Gore & Associates and received travel support from AbbVie and Gilead. M.H. served as a speaker and/or consultant for Astellas Pharma, AstraZeneca, Eli Lilly, Fresenius Medical Care, Janssen-Cilag, Siemens Healthcare and Vifor and received academic study support from Astellas Pharma, Boehringer Ingelheim, Eli Lilly, Nikkiso and Siemens Healthcare. T.R. served as a speaker and/or consultant and/or advisory board member for AbbVie, Bayer, Boehringer Ingelheim, Gilead, Intercept, MSD, Siemens, and W. L. Gore & Associates and received grants/research support from AbbVie, Boehringer Ingelheim, Gilead, Intercept, MSD, Myr Pharmaceuticals, Pliant, Philips, Siemens, and W. L. Gore & Associates as well as travel support from Abbvie, Boehringer Ingelheim, Gilead and Roche.

Figures

Figure 1
Figure 1
Components of the classical and alternative renin–angiotensin system (RAS) in patients with compensated (cACLD, n = 13) and decompensated cirrhosis (dACLD, n = 12). (a) Depiction of the RAS fingerprint in patients with cACLD and dACLD. Comparison of quantitative levels of (b) classical RAS components (Ang I and Ang II) and (c) alternative RAS components (Ang 1–7, Ang 1–5) between patients with cACLD and dACLD. For RAS fingerprint analysis, the size of the spheres and numbers beside them represent the median absolute concentrations of angiotensins (pmol/L) analyzed by mass spectrometry. Ang angiotensin, ACE angiotensin converting enzyme, AP aminopeptidase, cACLD compensated advanced chronic liver disease, dACLD decompensated advanced chronic liver disease, DAP dipeptidyl aminopeptidase, NEP neprilysin, RAS renin–angiotensin system.
Figure 2
Figure 2
Correlations between components of the classical and alternative RAS (PRA-S, Ang I, Ang II and Ang 1–7) and parameters of liver disease severity (MELD), severity of portal hypertension (HVPG), liver stiffness (LSM), endothelial dysfunction (vWF) and inflammation (IL-6). Correlations were assessed using Spearman’s Rho. ∗ denotes p values < 0.05, whereas ∗∗ indicates p values < 0.001. Ang angiotensin, HVPG hepatic venous pressure gradient, IL-6 interleukin-6, LSM liver stiffness measurement, MELD model for end-stage liver disease, RAS renin–angiotensin system, PRA-S plasma renin activity surrogate, vWF von Willebrand factor antigen.
Figure 3
Figure 3
Tissue activity of components of the (a,b) classical (ACE, chymase) and (c,d) alternative RAS (neprilysin [NEP], ACE2) in 5 patients with compensated (cACLD; n = 3) and decompensated advanced chronic liver disease (dACLD; n = 2). ACE angiotensin converting enzyme, cACLD compensated advanced chronic liver disease, dACLD decompensated advanced chronic liver disease, NEP neprilysin, RAS renin–angiotensin system.
See this image and copyright information in PMC

References

    1. Costa D, et al. Systemic inflammation increases across distinct stages of advanced chronic liver disease and correlates with decompensation and mortality. J. Hepatol. 2021;74:819–828. doi: 10.1016/j.jhep.2020.10.004. - DOI - PubMed
    1. Königshofer P, et al. Distinct structural and dynamic components of portal hypertension in different animal models and human liver disease etiologies. Hepatology. 2022;75:610–622. doi: 10.1002/hep.32220. - DOI - PMC - PubMed
    1. Reiberger T, Mandorfer M. Beta adrenergic blockade and decompensated cirrhosis. J. Hepatol. 2017;66:849–859. doi: 10.1016/j.jhep.2016.11.001. - DOI - PubMed
    1. Kalambokis GN, Baltayannis G, Christodoulou D, Christou L. Beta adrenergic blockade and advanced cirrhosis: Does it really improve survival in patients with acute-on-chronic liver failure? J. Hepatol. 2017;67:878–880. doi: 10.1016/j.jhep.2017.02.038. - DOI - PubMed
    1. Fidelman N, et al. The transjugular intrahepatic portosystemic shunt: An update. Am. J. Roentgenol. 2012;199:746–755. doi: 10.2214/AJR.12.9101. - DOI - PubMed

Publication types