Evaluation of the Proteolytic Activity of Factor D Accumulated as an Active Serine Protease in Patients with Chronic Renal Failure

Inagi, Reiko; Miyata, Toshio; Oda, Osamu; Maeda, Kenji; Inoue, Kôzô

doi:10.1159/000187824

Cited by 10 publications

(4 citation statements)

References 17 publications

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“…Our results show that expression levels of CFD in rat urine, kidney tissue, and clinical samples were increased by progression of diabetic nephropathy. It is known that plasma concentrations of CFD increase up to 10-fold in the end stage of renal failure, suggesting that its metabolism is related to renal functions [ 42 , 43 , 44 ]. CFD metabolism in patients showed that the proportion of CFD elimination in the urine was increased in patients with tubular dysfunctions, it demonstrated that under normal circumstances CFD is filtered through the glomeruli and reabsorbed by tubular cells [ 45 ].…”

Section: Discussionmentioning

confidence: 99%

Identification of Novel Biomarker for Early Detection of Diabetic Nephropathy

et al. 2021

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Diabetic nephropathy (DN) is one of the most common complications of diabetes mellitus. After development of DN, patients will progress to end-stage renal disease, which is associated with high morbidity and mortality. Here, we developed early-stage diagnostic biomarkers to detect DN as a strategy for DN intervention. For the DN model, Zucker diabetic fatty rats were used for DN phenotyping. The results revealed that DN rats showed significantly increased blood glucose, blood urea nitrogen (BUN), and serum creatinine levels, accompanied by severe kidney injury, fibrosis and microstructural changes. In addition, DN rats showed significantly increased urinary excretion of kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL). Transcriptome analysis revealed that new DN biomarkers, such as complementary component 4b (C4b), complementary factor D (CFD), C-X-C motif chemokine receptor 6 (CXCR6), and leukemia inhibitory factor (LIF) were identified. Furthermore, they were found in the urine of patients with DN. Since these biomarkers were detected in the urine and kidney of DN rats and urine of diabetic patients, the selected markers could be used as early diagnosis biomarkers for chronic diabetic nephropathy.

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Section: Discussionmentioning

confidence: 99%

Identification of Novel Biomarker for Early Detection of Diabetic Nephropathy

et al. 2021

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“…It is known that adipsin plasma levels increase ≈10-fold in end-stage renal failure, suggesting that its metabolism is closely linked to the renal functions. [18][19][20] Pascual et al 21 studied adipsin metabolism in humans by injecting purified radiolabeled adipsin into 5 healthy individuals and 12 patients with various renal diseases or renal failure. The proportion of adipsin elimination in the urine was increased in patients with tubular dysfunction, indicating that under normal circumstances adipsin is filtered through the glomeruli and reabsorbed by tubular cells.…”

Section: Discussionmentioning

confidence: 99%

Elevation of Urinary Adipsin in Preeclampsia

et al. 2014

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846P reeclampsia, a devastating pregnancy-specific syndrome complicating 2% to 8% of pregnancies, is responsible for ≈60 000 maternal deaths worldwide every year. It is characterized by new-onset hypertension, proteinuria, and edema and usually develops after 20 weeks of gestation.1,2 Early diagnosis and treatment of preeclampsia is essential for prevention of seizure development and maintaining the fetus in the uterus to mature. Many attempts have been made to meet these purposes. It has been found that altered concentration of soluble fms-like tyrosine kinase 1 (sFlt-1) and placental growth factor (PIGF) can predict the occurrence of preeclampsia weeks before the appearance of the clinical symptoms. [3][4][5][6] Uterine artery Doppler studies that assess the pulsability index reveal increased uterine vascular resistance well before the preeclampsia clinical signs arise.7 These predictive tests are valuable for identifying highrisk pregnant women but are incapable of conveniently monitoring the exact occurrence of the disease. In this study, we assumed that in preeclampsia a urinary protein that closely correlated with the 24-hour urine protein could be identified with advanced proteomics technologies and could be developed as a simple rapid assay for point-of-care use and for home monitoring as well.In 1843, John Lever of Guy's Hospital in London discovered the presence of albumin by boiling the urine from pregnant women with puerperal convulsions. 8 Proteinuria in preeclampsia since then has been studied extensively. The glomerular injury that results in proteinuria is characterized as endotheliosis, manifested as glomerular endothelial swelling with loss of endothelia fenestrae and occlusion of the capillary lumens.9,10 Proteinuria is measured currently by a 24-hour urine protein determination or a dipstick examination on a random urine sample. The 24-hour urine protein quantification is no doubt the most accurate and reliable approach but is time consuming and inconvenient. Dipstick is semiquantitative, easy to use, quick, and inexpensive. However, many studies have reported a poor correlation between the dipstick examination and the 24-hour urine assay with high false-positive or false-negative rates. 11,12 We aimed to find a urine protein in preeclampsia that closely correlated with the 24-hour urine protein and was at a Abstract-Early diagnosis and treatment of preeclampsia are essential for prevention of seizure development and fetus maturation. Although various methods have been developed for predicting or monitoring the onset of preeclampsia, a simple assay that can be used as a home or point of care test remains unavailable. We attempted to find a urinary protein that could be used as a biomarker for developing such a test. Urinary samples were collected from 124 preeclampsia and 135 healthy pregnant women for screening using a protein array technology and quantification by ELISA. A urinary protein, adipsin, was found significantly increased, and the adipsin creatinine ratio was closely correlated wi...

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“…Substrates. It has previously been shown that Factor D possesses extremely low activity toward activated peptide substrates such as peptide p-nitroanilides (20) and thioesters (8). We have explored the activity of Factor D toward a group of synthetic substrates, including a direct comparison of the reactivities of Factor D and of trypsin toward some of the same substrates, to better quantify this aspect of the reactivity of the enzyme.…”

Section: Activity Of Factor D Toward Thioester and P-nitroanilidementioning

confidence: 99%

Induced Fit Activation Mechanism of the Exceptionally Specific Serine Protease, Complement Factor D^†

et al. 1999

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We have investigated the mechanism by which the complement protease, Factor D, achieves its high specificity for the cleavage of Factor B in complex with C3(H2O). Kinetic experiments showed that Factor B and C3(H2O) associate with a KD of >/=2.5 microM and that Factor D acts on this complex with a second-order rate constant of kcat/KM >/= 2 x 10(6) M-1 s-1, close to the rate of a diffusion-controlled reaction for proteins of this size. In contrast, Factor D, which is a member of the trypsin family of serine proteases, was 10(3)-10(4)-fold less active than trypsin toward both thioester and p-nitroanilide substrates containing an arginine at P1. Furthermore, peptides spanning the Factor B cleavage site were not detectably cleaved by Factor D (kcat/KM /=9 kcal/mol of binding energy to stabilize the transition state for reaction. In support of this, we demonstrate that chemical modification of Factor D at a single lysine residue that is distant from the active site abolishes the activity of the enzyme toward Factor B while not affecting activity toward small synthetic substrates. We propose that Factor D may exemplify a special case of the induced fit mechanism in which the requirement for conformational activation of the enzyme results in a substantial increase in substrate specificity.

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Evaluation of the Proteolytic Activity of Factor D Accumulated as an Active Serine Protease in Patients with Chronic Renal Failure

Cited by 10 publications

References 17 publications

Identification of Novel Biomarker for Early Detection of Diabetic Nephropathy

Identification of Novel Biomarker for Early Detection of Diabetic Nephropathy

Elevation of Urinary Adipsin in Preeclampsia

Induced Fit Activation Mechanism of the Exceptionally Specific Serine Protease, Complement Factor D^†

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Evaluation of the Proteolytic Activity of Factor D Accumulated as an Active Serine Protease in Patients with Chronic Renal Failure

Cited by 10 publications

References 17 publications

Identification of Novel Biomarker for Early Detection of Diabetic Nephropathy

Identification of Novel Biomarker for Early Detection of Diabetic Nephropathy

Elevation of Urinary Adipsin in Preeclampsia

Induced Fit Activation Mechanism of the Exceptionally Specific Serine Protease, Complement Factor D†

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Induced Fit Activation Mechanism of the Exceptionally Specific Serine Protease, Complement Factor D^†