Endothelin‐1 antagonism in glomerulonephritis
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Owen2016.docx (239.1Mb)
Date
29/11/2016Author
Owen, Elizabeth Louise
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Abstract
A common feature of glomerular disease is a protein leak into the urine.
Proteinuria occurs in kidney disease and is an important risk factor for
cardiovascular disease (CVD). ET‐1 is a potent vasoconstrictor/pressor peptide
that is up‐regulated in CVD and many forms of inflammatory renal diseases. The
actions of ET‐1 are mediated via two G‐protein coupled receptors, the ETAR
which serves primarily in the pro‐hypertensive actions of ET‐1 and is often
considered as the main pathological receptor subtype, with the ETBR serving to
clear circulating ET‐1. Antagonism of one or both of receptors has been shown
to be of clinical benefit in the treatment of hypertension. This research
demonstrated a beneficial effect of selective ETAR antagonism using Sitaxsentan
in a rat model of GN. ETAR blockade reduced blood pressure and importantly
reduced glomerular inflammation as assessed by glomerular macrophage (Mϕ)
infiltration. Further, we aimed to demonstrate that Mϕ, key mediators of
inflammation are activated by ET‐1 to adopt a pro‐inflammatoy phenotype.
However, early studies demonstrated that ET‐1 does not activate Mϕ as
hypothesised. Mϕ were more phagocytic, and ET‐1 was chemokinetic for
macrophages, an ETBR medicated event. ET‐1 was also removed by Mϕ,
suggesting a potential regulatory role of Mϕ in the ET system. This phenomenon
led to inclusion of additional in vivo studies to investigate the role of Mϕ in the
regulation of ET‐1 and its pressor effects. These effects were investigated in a
murine model of Mϕ ablation using CD11b‐DTR mice. These experiments
determined in vivo that Mϕ ablation augments pressor responses to ET‐1,
suggesting that Mϕ are required to regulate ET‐1. In vitro, Mϕ remove ET‐1 by
several mechanisms involving proteolytic degradation of the peptide and ETBR
mediated clearance, demonstrating a potential mechanism for the in vivo
observation. Furthermore, proteinuria is believed to be due to damage or
effacement of specialized visceral glomerular epithelial cells or podocytes. We
identified in vitro that the ETAR mediates ET‐1 induced human podocyte cell
effacement by actin cytoskeleton aberrations and slit‐diaphragm protein down-regulation,
ET‐1 and pro‐inflammatory cytokine production. This thesis
provides evidence to support our initial hypotheses that selective ETAR antagonism ameliorates proteinuric renal disease via its effects on podocytes
and macrophages. Continued studies both in vitro and in vivo will strengthen
the body of evidence to promote the therapeutic use of ETR antagonists in
inflammatory renal disease.
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