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Endothelial Dysfunction and Cardiovascular Risk in Lupus Nephritis New Roles For Old Players
Endothelial Dysfunction and Cardiovascular Risk in Lupus Nephritis New Roles For Old Players
Endothelial dysfunction and cardiovascular risk in lupus nephritis: new roles for old
players?
Daniele Mancardi1, ElisaArrigo1, Martina Cozzi2,3, Irene Cecchi2, Massimo Radin2, Roberta
Fenoglio2, Dario Roccatello2, and Savino Sciascia2.
Corresponding Author:
Savino Sciascia, MD, PhD
Center of Research of Immunopathology and Rare Diseases- Coordinating Center of Piemonte and
Valle d’Aosta Network for Rare Diseases, and SCDU Nephrology and Dialysis, Department of
Clinical and Biological Sciences, S. Giovanni Bosco Hospital and University of Turin, Italy.
Piazza del Donatore di Sangue 3, 10154, Torino, Italy.
Email savino.sciascia@unito.it, Tel +390112402056 Fax +390112402052
Funding: MR is funded by a grant from the Italian Ministry of Health SG-2018-12368028
This article has been accepted for publication and undergone full peer review but has not been
through the copyediting, typesetting, pagination and proofreading process, which may lead to
differences between this version and the Version of Record. Please cite this article as doi:
10.1111/eci.13441
This article is protected by copyright. All rights reserved
Abstract.
Accepted Article
In Systemic Lupus Erythematosus (SLE) patients, most of the clinical manifestation share a
vascular component triggered by endothelial dysfunction. Endothelial cells (ECs) activation
occurs both on the arterial and venous side, and the high vascular density of kidneys accounts for
the detrimental outcomes of SLE through lupus nephritis (LN). Kidney damage, in turn, exerts a
negative feedback on the cardiovascular (CV) system aggravating risk factors for CV diseases
such as hypertension, stroke and coronary syndrome among others. Despite the intensive
investigation on SLE and LN, the role of endothelial dysfunction, as well as the underlying
mechanisms, remains to be fully understood, with no specifically targeted pharmacological
treatment. It is not known, in fact, if the activation pathway(s) in venous ECs are similar to the one
in arterial ECs and doubts persist on the shared manifestation of microcirculation compared to
macro-circulation. In this work, we aim to review the recent literature about the role of endothelial
activation and dysfunction in the development of CV complications in SLE and LN patients. We,
therefore, focus on arterio-venous similarities and differences and on specific pathways of great
vessels compared to capillaries. Critically summarising the available data is of pivotal importance
for both basic researchers and clinicians in order to develop and test new pharmacological
approaches in the treatment of basic components of SLE and LN.
Acknowledgement.
The authors have no conflict of interest to disclose. The study has been supported by “Fondo
Ex60%” and “Fondo Finanziamento delle Attivita Base di Ricerca”.
.
of maintenance SMG-SNU
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Improvement of Severance
months] Republic of
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Nephropathies Nephropathy
(RENAL AID)
National Institutes of
Immune System Lupus Health Clinical Center,
Observational
Related Nephritis Not reported 9000 Rockville Pike, NCT00001979
(registry)
Kidney Disease Other GN Bethesda, Maryland,
United States
National Institutes of
Study of Systemic Natural History of
Observational Health Clinical Center,
Lupus SLE SLE [ Time Frame: NCT00001372
(registry) 9000 Rockville Pike,
Erythematosus 12/31/2050]
Bethesda, Maryland,
Figure 1. Description of the main surface markers of arterial and venous endothelial cells
and their principal role in ECs biology.
Notch1: promotes expression of EPH-B2 upon ERK activity and VEGF signalling cascade. It can
be inhibited by CUP-TFII and suppress differentiation to arterial EC;
NRP1(Neuropilin 1), NRP2 (Neuropilin 2): membrane glycoproteins regulated by VEGF,
involved in neoangiogenic processes and cell fate determination;
Eph-B2 (Ephrin type-B receptor 2), Eph-B4 (Ephrin type-B receptor 4): Eph-B2 is produced in
arteries while Eph-B4 is mainly present in veins. Overexpression of Eph-B4 is associated with
autoimmune response and glomerulopathies.
COUP-TFII (COUP Transcription Factor II): majorly activated in arterial ECs, is a pivotal
determinant of ECs fate;
Dll-4 (Delta like-4): gene related to expression of Notch ligands;