Endothelin in human autoimmune diseases with renal involvement
Department of Physiology and Medical Clinic Innenstadt, University of Munich, Munich and 1Institute for Clinical Pharmacology, Technical University of Dresden, Dresden, Germany.
Correspondence to: PD Dr Wolfgang Neuhofer, Department of Physiology, University of Munich, Pettenkoferstrasse 12, D-80336 Munich, Germany. E-mail: Wolfgang.Neuhofer{at}med.uni-muenchen.de
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Abstract |
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 Top Abstract IntroductionEndothelin in the normal...Endothelin and autoimmune...DiscussionReferences |
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Endothelin (ET)-1 is a potent renal vasoconstrictor with pro-inflammatory, profibrotic and mitogenic potential. Animal studies support a pathogenetic contribution of ET-1 and its cognate receptors in several renal manifestations of autoimmune disorders. However, data in humans are limited. The present minireview thus summarizes the observations available in humans. Similar to animal models, ET-1 is overexpressed in glomerular and tubulointerstitial lesions, which is reflected by an increased urinary excretion of ET-1. Since antagonizing the ET system has beneficial effects in experimental models, this approach may be translated to the human kidney, thus counteracting vasoconstriction, inflammation and extracellular matrix deposition during the course of human autoimmune disease.
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Introduction |
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TopAbstractIntroductionEndothelin in the normal...Endothelin and autoimmune...DiscussionReferences |
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The kidney can be affected during the course of several systemic autoimmune diseases, including systemic lupus erythematosus, systemic sclerosis (SSc), various forms of vasculitis and others. The spectrum of renal manifestations includes glomerulonephritis (GN), glomerulosclerosis, tubulointerstitial inflammation and fibrosis, and vascular alterations leading to ischaemic lesions, all of which may compromise renal function. The clinical course may be benign and silent, but may also lead to a progressive deterioration of renal function or even to life-threatening complications in SSc. The latter is known as scleroderma renal crisis, with an estimated incidence of 15–19.5% in diffuse cutaneous SSc, whereas functional abnormalities or proteinuria occur in 26% of patients with SSc [1–3]. Following the discovery of endothelin (ET)-1 by Yanagisawa in 1988, numerous animal and cell culture studies have implicated ET-1 and ET receptors in several conditions associated with fibrotic remodelling of the kidney or renal vasoconstriction. These include GN due to different etiologies, vascular abnormalities, glomerulosclerosis and tubulointerstitial inflammation and fibrosis. Much less data are, however, available for the human kidney and interspecies differences have been reported in animals. The present minireview thus summarizes the role of the ET system in progressive renal pathologies in the human kidney in autoimmune diseases and compares these findings with the results obtained in experimental models.
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Endothelin in the normal human kidney |
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Herman et al. [4] assessed the expression and localization of ET and ET receptors in the normal human kidney. The authors demonstrated that endothelial cells from glomeruli, arteries, capillaries and veins expressed ET-1, whereas mesangial cells and smooth muscle cells showed only minor immunoreactivity in the non-diseased kidney [4]. In primary human mesangial cells, ET-1 potently stimulates mitogenesis via both ETA and ETB receptors [4]. This finding is important, since mesangial expansion is an integral part in progressive glomerular injury.
Pupilli et al. [5] demonstrated expression of prepro-ET-1 mRNA in cortex, and, more abundantly in the medulla of the normal human kidney. In cortex, endothelial cells from several vascular structures expressed ET-1, whereas a specific ET-1 signal was absent in tubules and in glomeruli, except for the juxtaglomerular region. In the renal medulla, vasa recta, peritubular capillaries and medullary collecting ducts showed intense ET-1 hybridization signals [5].
Collectively, the data available for the normal human kidney are compatible with findings in animals, suggesting that ET-1 is primarily produced by endothelial cells and collecting ducts, contributing to adjustment of glomerular filtration rate and medullary sodium and water reabsorption in an autocrine/paracrine manner. Accordingly, ET-1 is detectable in minor amounts in urine even in healthy subjects [6, 7].
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Endothelin and autoimmune disease in the human kidney |
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TopAbstractIntroductionEndothelin in the normal...Endothelin and autoimmune...DiscussionReferences |
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Several rodent models have implicated the ET system in various forms of GN; however, data in humans are limited. Lehrke et al. [8] assessed the expression of ET-1 and ET receptor subtypes in renal biopsies from 26 patients with proteinuric glomerular diseases (including IgA nephropathy, lupus nephritis, membranous GN, nephrosclerosis, amyloidosis, mesangiocapillary GN, post-infectious GN, focal segmental GN, interstitial nephritis and diabetic nephropathy). Prepro-ET-1 mRNA was significantly increased in patients with high-grade proteinuria (
2 g/day) and a creatinine clearance 
80 ml/min. ETA receptor expression was not associated with proteinuria and creatinine clearance; however, ETB receptor levels were significantly increased in patients with high-grade proteinuria. Immunohistological analysis of renal tissue from a subgroup of patients with IgA nephropathy (n = 16) demonstrated robust expression of ET-1 in proximal tubules and slightly increased presence in glomeruli and vessels, whereas patients with high-grade proteinuria exhibited pronounced glomerular staining [8]. Interestingly, the extent of proteinuria correlated significantly with proximal tubular ET-1 expression and ETB receptor immunoreactivity in glomeruli and proximal tubules [8]. Glomerular neutrophil infiltration is a common observation in GN, whereas several neutrophil products including reactive oxygen species (ROS) in turn stimulate ET-1 production in human mesangial cells [9]. Similarly, activated neutrophils isolated from patients with IgA nephropathy stimulated ET-1 production by mesangial cells significantly more than neutrophils derived from control subjects, and this effect apparently depends on the release of ROS [10]. Herman et al. [4] found mesangial staining for ET-1 in patients with lupus nephritis and modest to moderate mesangial proliferation, whereas vascular expression was not altered. In Henoch–Schönlein purpura, a vasculitic disorder in children with renal involvement, and in post-streptococcal GN with hypertension in children, elevated systemic ET-1 concentrations have also been reported [11, 12].
Renal crisis represents the most severe form of kidney involvement in SSc, characterized by renal vasoconstriction, sodium and water retention, and hypertension, followed by pulmonary oedema and cardiopulmonary failure. A pathogenetic role of ET-1 and ETB receptors has been suggested by Kobayashi et al. [13]. In autopsy samples from two patients who died from respiratory failure due to renal crisis, expression of ET-1 and ETB receptors was evident in the media of small renal arteries, whereas no staining was observed in controls [13]. These arteries showed fibrinoid necrosis, thrombosis and intimal thickening, thus causing multiple ischaemic infarctions [13]. These pathological findings show some analogy to vascular alterations found in pulmonary arterial hypertension, where ET-1 is an established causative factor. A role of ET-1 is further supported by the finding that infusion of ET-1 at plasma concentrations as observed during pathological conditions results in renal vasoconstriction and sodium retention in humans [14].
In rodents, ET-1 is increased in urine and correlates with disease severity. Consistent with a glomerular and/or tubular production of ET-1, urinary ET-1 excretion is 2.5–6-fold increased in patients with GN, particularly in those with mesangial proliferative and membranous proliferative GN [7]. In agreement, Ohta et al. [6] reported 5 to 10-fold elevated urinary ET-1 excretion in patients with lupus nephritis and end-stage renal disease. Comparable with the results obtained in animal studies, urinary ET-1 levels in humans apparently correlate with the severity of proteinuria, since patients with nephrotic syndrome excrete significantly more ET-1 than patients with nephritic syndrome [7]. Thus, urinary ET-1 may be suitable for non-invasive monitoring of disease activity.
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Discussion |
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TopAbstractIntroductionEndothelin in the normal...Endothelin and autoimmune...DiscussionReferences |
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Data addressing the role of the ET system in renal manifestations of autoimmune diseases in humans are limited; nevertheless they are in agreement with results obtained in experimental models, supporting a role of ET-1 and ET receptors in renal involvement. Of particular interest is the finding that ET-1 and ETB receptors are upregulated at those sites that are affected during the disease process, whereas ETA receptor expression is not altered.
Treatment of autoimmune-associated with severe renal complications is based on immunosuppressive and cytotoxic approaches (i.e. steroids, cyclophosphamide and azathioprine), particularly in those patients presenting with rapid progression. In SSc-associated renal crisis, antagonizing angiotensin II formation or action is pivotal to ameliorate renal vasoconstriction and subsequent renal failure due to exaggerated activation of the renin–angiotensin system. Most clinicians treating patients with SSc no longer use D-penicillamine, particularly due to limited efficacy and the inherent potential to precipitate renal failure [15].
Based on the observation that antagonizing the ET system delays or even leads to regression of glomerular and tubulointerstitial lesions in animal models, and in view of the apparent pathophysiological similarities in the human kidney, ET receptor antagonism might offer an additional therapeutic tool. Nevertheless, the issue weather activation of the ET-system is causally involved in the pathogenesis of renal complications in human autoimmune diseases needs to be addressed in greater detail. Future observations at the case level and controlled clinical trials will be required to illuminate this exciting new approach.
The authors have declared that the work was supported by an unrestricted educational grant from Actelion Pharmaceuticals.
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References |
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