Contact-system activation in children with vasculitis

Kahn, Robin; Herwald, Heiko; Müller‐Esterl, Werner; Schmitt, Roland; Sjögren, Anders; Truedsson, Lennart; Karpman, Diana

doi:10.1016/s0140-6736(02)09743-x

Cited by 35 publications

(62 citation statements)

References 33 publications

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“…The latter is consistent with a previous study showing the presence of the B1R agonist by using specific antipeptide antibodies, mainly in glomeruli but also in proximal and distal tubuli from patients with vasculitis. 26 B1R staining in the interstitial inflammatory and fibrotic space is consistent with previous reports describing B1R expression in macrophages and fibroblasts in vitro. 3,9,27 Although additional experiments are needed to define better the interstitial cells that express the B1R, the most important conclusion to be drawn from our data is that the B1R is not detectable in control kidney biopsies but clearly is expressed in pathologic biopsies from patients with glomerulonephritis.…”

Section: Discussionsupporting

confidence: 92%

Blockade of the Kinin B1 Receptor Ameloriates Glomerulonephritis

Klein¹,

Gonzalez²,

Decramer³

et al. 2010

Journal of the American Society of Nephrology

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Severe inflammation characterizes rapidly progressive glomerulonephritides, and expression of the kinin B1 receptor (B1R) associates with inflammation. Delayed B1R blockade reduces renal inflammation in a model of unilateral ureteral obstruction, but whether B1R modulates the pathophysiology of glomerulonephritides is unknown. Here, we observed an association of B1R protein expression and inflammation, in both glomeruli and the renal interstitium, in biopsies of patients with glomerulonephritides, HenochSchö nlein purpura nephropathy, and ANCA-associated vasculitis. In the nephrotoxic serum-induced glomerulonephritis model, we observed upregulation of the B1R receptor; treatment with a B1R antagonist beginning 2 weeks after the onset of disease reduced both glomerular and tubular lesions and improved renal function. B1R blockade reduced renal chemokine expression and macrophage accumulation. Collectively, our data demonstrate that blockade of the kinin B1R has significant potential for the treatment of glomerulonephritis. Rapidly progressive glomerulonephritides constitute a group of kidney diseases sharing common pathologic features. These nephropathies are characterized by severe glomerular inflammation, mainly composed of infiltrating macrophages and T cells. This leads to the formation of glomerular crescents composed of immune and proliferating epithelial cells from the Bowman's capsule. After the primary glomerular insult, inflammation and lesions extend to the tubulointerstitial compartment and induce tubular damage and progressive interstitial fibrosis, leading to the loss of renal function; therefore, renal inflammation is a key player in the initiation and the progression of these pathologies. It has been suggested that any strategy or agent able to limit or attenuate renal inflammation should significantly slow the progression of glomerulonephritides to ESRD. 1 Endogenous kinins (bradykinin-related peptides)are produced through cleavage of kininogens by kallikreins. These peptides mediate their biologic effects by activation of two G protein-coupled receptors: a constitutively expressed B2 receptor (B2R) and an inducible B1 receptor (B1R). 2 Bradykinin and kallidin are the natural agonists of the B2R, whereas their metabolites, generated by the enzyme kininase I, desArg9-BK and Lys-des-Arg9-BK, respectively, are spe-

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Section: Discussionsupporting

confidence: 92%

Blockade of the Kinin B1 Receptor Ameloriates Glomerulonephritis

Klein¹,

Gonzalez²,

Decramer³

et al. 2010

Journal of the American Society of Nephrology

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“…I n vivo activation of the kinin pathway occurs when the circulating plasma prekallikrein-high-molecular weight kininogen (HK) 4 complex binds to receptors present on endothelial cells and neutrophils. Proteolytic cleavage of plasma prekallikrein results in the generation of active plasma kallikrein that in turn cleaves HK and liberates bradykinin (1).…”

mentioning

confidence: 99%

“…Bradykinin also stimulates intimal hypertrophy and proliferation of smooth muscle cells during endothelial damage (1). The kinin system is activated during several conditions associated with systemic inflammation such as vasculitis (4), sepsis (1), and colitis (5).…”

mentioning

confidence: 99%

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Neutrophil-Derived Proteinase 3 Induces Kallikrein-Independent Release of a Novel Vasoactive Kinin

Kahn¹,

Hellmark²,

Leeb-Lundberg

et al. 2009

The Journal of Immunology

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The kinin-forming pathway is activated on endothelial cells and neutrophils when high-molecular weight kininogen (HK) is cleaved by plasma kallikrein liberating bradykinin, a potent mediator of inflammation. Kinins are released during inflammatory conditions such as vasculitis, associated with neutrophil influx around blood vessels. Some patients with vasculitis have elevated plasma levels of neutrophil-derived proteinase 3 (PR3) and anti-PR3 Abs. This study investigated if neutrophil-derived PR3 could induce activation of the kinin pathway. PR3 incubated with HK, or a synthetic peptide derived from HK, induced breakdown and release of a novel tridecapeptide termed PR3-kinin, NH2-MKRPPGFSPFRSS-COOH, consisting of bradykinin with two additional amino acids on each terminus. The reaction was specific and inhibited by anti-PR3 and α1-antitrypsin. Recombinant wild-type PR3 incubated with HK induced HK breakdown, whereas mutated PR3, lacking enzymatic activity, did not. PR3-kinin bound to and activated human kinin B1 receptors, but did not bind to B2 receptors, expressed by transfected HEK293 cells in vitro. In human plasma PR3-kinin was further processed to the B2 receptor agonist bradykinin. PR3-kinin exerted a hypotensive effect in vivo through both B1 and B2 receptors as demonstrated using wild-type and B1 overexpressing rats as well as wild-type and B2 receptor knockout mice. Neutrophil extracts from vasculitis patients and healthy controls contained comparable amounts of PR3 and induced HK proteolysis, an effect that was abolished when PR3 was immunoadsorbed. Neutrophil-derived PR3 can proteolyze HK and liberate PR3-kinin, thereby initiating kallikrein-independent activation of the kinin pathway.

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“…Excessive bradykinin generation is symptomatic of hereditary or acquired angioedema in patients (15,16), and blockage of kinin action in mouse models of angioedema rescues this phenotype (13). Bradykinin-induced vascular leakage and edema formation are also critically involved in sepsis, vasculitis, allergic asthma, rhinitis, diabetes, and cancer (11,14,(17)(18)(19). Importantly, bradykinin generation on bacterial surfaces is crucial for the massive infiltration and extravasion of plasma compounds into lung tissues seen in Salmonella infections (20).…”

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confidence: 99%

Local Bradykinin Formation Is Controlled by Glycosaminoglycans

Renné

Schuh²,

Müller‐Esterl

2005

The Journal of Immunology

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Bradykinin is a potent inflammatory mediator that induces vasodilation, vascular leakage, and pain sensations. This short-lived peptide hormone is liberated from its large precursor protein high molecular weight kininogen (HK) through the contact system cascade involving coagulation factor XII and plasma kallikrein. Although bradykinin release is well established in vitro, the factors and mechanisms controlling bradykinin generation in vivo are still incompletely understood. In this study we demonstrate that binding of HK to glycosaminoglycans (GAGs) of the heparan and chondroitin sulfate type efficiently interferes with bradykinin release in plasma and on endothelial surfaces. Proteolytic bradykinin production on endothelial cells is restored following degradation of cell surface GAG through heparinase. Alternatively, application of HK fragments D3 or light chain, which compete with uncleaved HK for cell binding, promote kininogen proteolysis and bradykinin release. Intravital microscopy revealed that HK fragments increase bradykinin-mediated mesentery microvascular leakage. Topical application of D3 or light chain enhanced bradykinin generation and edema formation in the mouse skin. Our results demonstrate that bradykinin formation is controlled by HK binding to and detachment from GAGs. Separation of the precursor from cell surfaces is a prerequisite for its efficient proteolytic processing. By this means, fragments arising from HK processing propagate bradykinin generation, revealing a novel regulatory level for the kallikrein-kinin system.

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Contact-system activation in children with vasculitis

Cited by 35 publications

References 33 publications

Blockade of the Kinin B1 Receptor Ameloriates Glomerulonephritis

Blockade of the Kinin B1 Receptor Ameloriates Glomerulonephritis

Neutrophil-Derived Proteinase 3 Induces Kallikrein-Independent Release of a Novel Vasoactive Kinin

Local Bradykinin Formation Is Controlled by Glycosaminoglycans

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