Concentration of Leukocyte Elastase in Plasma and Polymorphonuclear Neutrophil Extracts in Type 2 Diabetes

Piwowar, Agnieszka; Knapik-Kordecka, Maria; Warwas, Maria

doi:10.1515/cclm.2000.198

Cited by 35 publications

(30 citation statements)

References 26 publications

(25 reference statements)

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“…From a pathological perspective however, because megalin is a multiligand scavenger, the lysosomal supply of cathepsin B and other acid hydrolases via this pathway might be compromised by competition upon severe glomerular proteinuria, which could play a role in tubular epithelial cell damage and progressive interstitial disease secondary to glomerular injury (19). Such competition would readily explain the increased cathepsin B activity observed in the urine upon proteinuric conditions such as type 2 diabetes mellitus (20), which so far has been attributed to increased PCT excretion of the enzyme. Our results show instead, in two models of tubular proteinuria, that a high urinary level of cathepsin B is caused by impaired reabsorption, not by elevated secretion.…”

Section: Discussionmentioning

confidence: 99%

Endocytosis provides a major alternative pathway for lysosomal biogenesis in kidney proximal tubular cells

Nielsen

Courtoy

Jacobsen

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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Recruitment of acid hydrolases to lysosomes generally occurs by intracellular sorting based on recognition of a common mannose 6-phosphate signal in the transGolgi network and selective transport to late endosomes/lysosomes. Here we provide evidence for an alternative, efficient secretion-recapture pathway mediated by megalin and exemplified by cathepsin B in kidney proximal convoluted tubules (PCT). We found that in mouse kidneys with defective megalin expression [megalin knockout (KO)] or apical PCT trafficking (ClC-5 KO), the (pro)cathepsin B mRNA level was essentially preserved, but the protein content was greatly decreased and the enzyme was excreted in the urine as mannose 6-phosphate-devoid species. In polarized PCT-derived cells, purified cathepsin B was avidly and selectively taken up at the apical membrane, and uptake was abolished by the megalin competitor, receptor-associated protein. Direct interaction of cathepsin B with megalin was demonstrated by surface plasmon resonance. Procathepsin B was detected in normal mouse serum. Purified cathepsin B injected into mice was efficiently taken up by kidneys (Ϸ10% of injection) and targeted to lysosomes where it remained active, as shown by autoradiography and subcellular fractionation. A single cathepsin B injection into cathepsin B KO mice could reconstitute full lysosomal enzyme activity in the kidneys. These findings demonstrate a pathway whereby circulating lysosomal enzymes are continuously filtered in glomeruli, reabsorbed by megalinmediated endocytosis, and transferred into lysosomes to exert their function, providing a major source of enzymes to PCT. These results also extend the significance of megalin in PCT and have several physiopathological and clinical implications.lysosomes ͉ mannose 6-phosphate ͉ megalin ͉ cathepsin B

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Section: Discussionmentioning

confidence: 99%

Endocytosis provides a major alternative pathway for lysosomal biogenesis in kidney proximal tubular cells

Nielsen

Courtoy

Jacobsen

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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“…Both spontaneous neutrophil adherence and fMLP-induced aggregation of neutrophils are associated with the presence of diabetic complications and in particular overt proteinuria [16,18]. Recently, an association has been identified between neutrophil elastase content, the concentration of glycaemia and angiopathy in diabetes [19,20].…”

mentioning

confidence: 99%

Impaired neutrophil actin assembly causes persistent CD11b expression and reduced primary granule exocytosis in Type II diabetes

2002

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Aims/hypothesis. Neutrophil dysfunction has a role in the pathogenesis of complications in Type II (non-insulin-dependent) diabetes mellitus. Neutrophils adhere through expression of the β 2 integrin CD11b/CD18 which closely associates with the actin cytoskeleton. The aim of this study was to investigate the effect of actin polymerisation on CD11b expression and exocytosis of the primary granule marker CD69 in neutrophils from patients with Type II diabetes. Methods. Neutrophils were activated with fMLP or PMA, actin polymerisation was inhibited with cytochalasin D. Cells were stained for CD11b and CD69 expression and intracellular F-actin was measured with phalloidin-FITC. Cellular fluorescence was measured by flow cytometry. Actin content of Triton X-100 fractions of cells was measured by SDS-PAGE and Coomassie blue staining. Results. PMA caused an increase in neutrophil F-actin that was greater in control subjects than in patients with Type II diabetes (50.8% vs 33.4%, p<0.001) and correlated with actin integrated optical density (IOD) by p=0.01). Loss of CD11b from cell surfaces only occurred in neutrophils with high Factin. The proportion of cells losing CD11b was lower in patients than in control subjects (23.1% vs 37.5%, p<0.001) and lowest in patients with additional cardiovascular risk markers (20.1% vs 27.7%; p<0.05). Cytochalasin D prevented loss of CD11b (p<0.001). CD69 expression was reduced in patients with Type II diabetes (22.6% vs 36.4%, p<0.001) and correlated with F-actin content (r=0.78, p<0.0001). Conclusion/interpretation. In Type II diabetes impaired neutrophil actin polymerisation leads to persistent expression of CD11b and reduced exocytosis of primary granules and could contribute to the pathogenesis of diabetic complications. [Diabetologia (2002) 45:719-727]

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“…Although classically associated with innate immunity and pathogen destruction, NSPs are also involved in the regulation of inflammation and the pathogenesis of many chronic inflammatory conditions. Proteinase 3 (PR3) is secreted from activated neutrophils and is critically involved in bacterial defense but also regulates non-infectious inflammatory processes by inducing endothelial cell apoptosis and modulating the activities of cytokines including TNF-α, IL-1β, IL-8, IL-18 and IL-32 [42][43][44][45][46][47][48] Recent studies further suggest that PR3, as well as other NSPs, namely neutrophil elastase (NE) and cathepsin G (CG) contribute to neutrophil-dependent inflammation and progression of chronic inflammatory diseases including T2DM, cystic fibrosis and glomerulonephritis [49][50][51][52]. Conversely, NSP inhibitors such as α-1-antitrypsin (AAT) have been proposed as treatments in patients with chronic inflammatory diseases including diabetes, cystic fibrosis and ischemic heart disease [28,[53][54][55][56].…”

Section: Neutrophil Serine Proteases and Inflammationmentioning

confidence: 99%

The Impact of Neutrophil Proteinase 3 on IGFBP-3 Proteolysis in Obesity

Robins¹,

Oh²

2014

Intern Med

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Obesity is a complex disorder and is a major risk factor associated with the incidence of insulin resistance (IR), diabetes, cardiovascular disease (CVD) and other metabolic disorders. The endocrine paradigm suggests that visceral fat in obesity, consisting primarily of adipocytes, secretes various pro-inflammatory adipokines such as tumor necrosis factor (TNF), leptin, visfatin, resistin, and IL-6 creating a state of local inflammation further resulting in chronic systemic inflammation and accelerating the events leading to systemic IR, diabetes and metabolic syndrome.The insulin-like growth factor (IGF) system plays a major role in growth, development and maintenance of homeostasis in normal cells. IGF binding protein-3 (IGFBP-3), the major binding protein in circulation, has been shown to be associated with obesity, IR, type II diabetes mellitus (T2DM) and CVD. Recent studies have demonstrated the IGFBP-3-specific receptor (IGFBP-3R) is a novel protein mediating the anti-inflammatory function of IGFBP-3. IGFBP-3 inhibits adipokine-induced insulin resistance and early manifestations of atherosclerosis via inhibition of NF-κB signaling in adipocytes.Furthermore, decreases in total IGFBP-3 levels and increases in proteolyzed IGFBP-3 in circulation have been documented in obese populations compared to their normal counterparts further establishing a positive correlation between IGFBP-3 proteolysis and adiposity parameters as well as IR. Conversely, our recent studies have identified that neutrophil serine protease (NSP) PR3, an IGFBP-3 specific protease in obesity, is positively correlated with IGFBP-3 proteolysis, IR, body mass index, TNF and IL-8. These findings strongly suggest that obesity-induced activation of PR3 abrogates the anti-inflammatory, insulin-sensitizing IGFBP-3/IGFBP-3R cascade, resulting in IR and its progression to T2DM. The complete characterization of the underlying mechanism and functional significance of the PR3-IGFBP-3/IGFBP-3R cascade in obesity will foster identification of the diagnostic and therapeutic potential of PR3 inhibition in insulin resistance and its sequelae.

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Concentration of Leukocyte Elastase in Plasma and Polymorphonuclear Neutrophil Extracts in Type 2 Diabetes

Cited by 35 publications

References 26 publications

Endocytosis provides a major alternative pathway for lysosomal biogenesis in kidney proximal tubular cells

Endocytosis provides a major alternative pathway for lysosomal biogenesis in kidney proximal tubular cells

Impaired neutrophil actin assembly causes persistent CD11b expression and reduced primary granule exocytosis in Type II diabetes

The Impact of Neutrophil Proteinase 3 on IGFBP-3 Proteolysis in Obesity

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