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@PHDTHESIS{Bagarolo:1020590,
author = {Bagarolo, Giulia Ilaria},
othercontributors = {Jankowski, Joachim and Blank, Lars M. and Schurgers, Leon},
title = {{I}dentification of novel peptidic mediators involved in
gut-liver and heart-kidney crosstalk},
school = {RWTH Aachen University},
type = {Dissertation},
address = {Aachen},
publisher = {RWTH Aachen University},
reportid = {RWTH-2025-09110},
pages = {1 Online-Ressource : Illustrationen},
year = {2025},
note = {Veröffentlicht auf dem Publikationsserver der RWTH Aachen
University; Dissertation, RWTH Aachen University, 2025},
abstract = {Organ crosstalk is crucial as it enhances distant organs'
regulation, communication, and homeostasis. Literature
frequently reports how the dysfunction of one organ
influences others, leading to various syndromes and
disorders. Some of the most studied organ connections focus
on the gut, liver, kidney, heart, and lungs. This thesis
aimed to investigate biomolecules involved in two main
crosstalks: the gut-liver and the heart-kidney, specifically
in relation to chronic liver cirrhosis (CLC)-induced portal
hypertension and cardiorenal syndrome (CRS). The
relationships between organs are often regulated by
circulating peptides and metabolites, which are generally
considered disease markers. However, many of these markers
are still unknown. The common thread of this research was
the employment of liquid chromatography-mass spectrometry
(LC-MS) to isolate and investigate plasma-derived mediators
involved in portal hypertension and cardiorenal syndrome. In
the first part of the thesis, plasma from patients suffering
from portal hypertension and undergoing the transjugular
intrahepatic portosystemic shunt (TIPS) was collected and
investigated to identify mediator changes after TIPS
intervention and to discover potential gut-released
biomolecules. By coupling the LC-MS non-targeted approach
with statistical analysis, 12 differentially abundant
biomolecules were identified. Of these, ten were drastically
decreased after TIPS intervention, and the gut potentially
released two peptides. Regarding the heart-kidney crosstalk
in the context of CRS, we investigated the function of a
novel renal marker derived from modified tryptophan,
C-mannosyltryptophan (CMW), as a potential uremic toxin
candidate. CMW was first identified via LC-MS in a cohort of
CKD patients, and its average concentration was estimated.
The modified amino acid correlated with higher
cardiovascular events and hypertension. To establish CMW as
a potential novel uremic toxin, in vitro experiments with
human aortic endothelial cells (HAoECs) were stimulated with
CMW. The results showed that CMW initiated a signalling
cascade involving p38, VCAM1, and VE-cadherin, leading to
probable endothelial cell barrier disruption and possible
leukocyte extravasation. Endothelial barrier disruption and
leukocyte migration are processes related to inflammation
and the development of cardiovascular diseases. In
conclusion, this research identified ten biomarker
candidates for portal hypertension in patients with CLD,
whose involvement in regulating pathological gut-liver
crosstalk needs confirmation. Additionally, two potential
gut-released peptides were identified, which can provide
further insight into the intestine-liver relationship. In
the context of cardiorenal syndrome, the novel modified
amino acid CMW, already associated with renal function in
literature, was shown to correlate with cardiovascular
events and potentially trigger an inflammation cascade,
leading to the genesis and progression of cardiovascular
diseases. These findings further support the close
connection between the kidney and heart, indicating the need
for further research to confirm the involvement of CMW in
the heart-kidney crosstalk.},
cin = {531010-3 ; 932310 / 161710 / 160000},
ddc = {570},
cid = {$I:(DE-82)531010-3_20140620$ / $I:(DE-82)161710_20140620$ /
$I:(DE-82)160000_20140620$},
pnm = {CaReSyAn - Combatting the CardioRenal Syndrome: towards an
integrative Analysis to reduce cardiovascular burden in
chronic kidney disease (764474)},
pid = {G:(EU-Grant)764474},
typ = {PUB:(DE-HGF)11},
doi = {10.18154/RWTH-2025-09110},
url = {https://publications.rwth-aachen.de/record/1020590},
}
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