The Urinary F1 Activation Peptide of Human Prothrombin is a Potent Inhibitor of Calcium Oxalate Crystallization in Undiluted Human Urine <i>in Vitro</i>

Ryall, Rosemary L.; Grover, Phulwinder K.; Stapleton, Andrew J.; Barrell, Dianne K.; Tang, Yunhua; Moritz, Robert L.; Simpson, Richard J.

doi:10.1042/cs0890533

Cited by 74 publications

(78 citation statements)

References 24 publications

(52 reference statements)

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“…PF1 and BK are potent inhibitors of CaOx crystal growth (3,4,38), and can be produced in the kidney (30,42). While the entire ITI molecule has been shown to inhibit CaOx crystallization (9), the heavy chain components do not have inhibitory activity, and BK is thought to be responsible for the ability of ITI to inhibit CaOx crystallization (21).…”

Section: Discussionmentioning

confidence: 99%

“…Such proteins include TammHorsfall protein (THP) (20), osteopontin (uropontin) (2), prothrombin fragment 1 (PF1) (38), inter-␣-trypsin inhibitor (ITI) (9), and bikunin (BK), a portion of ITI (3), calgranulin (34), CD59 (7), and albumin (10). Although some reports suggest defects, deficiencies, or variations of these molecules among SF vs. normal subjects (13,14,26,27,43), it remains unclear whether any of these is a cause or a consequence of stones; no research thus far has translated molecular knowledge into clinical practice.…”

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confidence: 99%

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Urine protein markers distinguish stone-forming from non-stone-forming relatives of calcium stone formers

Bergsland

Kelly²,

Coe³

et al. 2006

American Journal of Physiology-Renal Physiology

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We have investigated urine protein inhibitors of calcium oxalate crystallization to determine whether variations in these proteins are associated with kidney stone disease and whether protein measurements improve the identification of stone formers compared with conventional risk factors (RF). Using Western blotting, we studied variations in the electrophoretic mobility patterns and relative abundances of crystallization-inhibitory proteins in urine from 50 stone-forming (SF) and 50 non-stone-forming (NS) first-degree relatives of calcium SF patients, matched by gender and age. Standard urine chemistry stone risk measurements were also made. Multivariate discriminant analysis was used to test the association of these proteins with nephrolithiasis. Differences in form and abundance of several urine proteins including inter-␣-trypsin inhibitor (ITI), prothrombin fragment 1 (PF1), CD59, and calgranulin B (calB) were found to be associated with stone formation. By multivariate discriminant analysis, measurements of forms of PF1, ITI, and calB in men and ITI and CD59 in women, classified 84% of men and 76% of women correctly by stone status. In contrast, standard urine chemistry RF identified only 70% of men correctly and failed to distinguish female SF from NS. Thus a small subset of protein measurements distinguished SF from NS far better than conventional RF in a population of relatives of calcium SF,

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Urine protein markers distinguish stone-forming from non-stone-forming relatives of calcium stone formers

Bergsland

Kelly²,

Coe³

et al. 2006

American Journal of Physiology-Renal Physiology

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“…2,13 There are many reports about the proteins extracted from human urine and the matrices of urinary stones which exhibit inhibitory activity on calcium oxalate crystal nucleation, growth, and aggregation. 4,5,14,15 Nephrocalcin is a known glycoprotein which exhibits a strong inhibitory effect on nucleation, growth, and aggregation of COM crystals. 16 Recently, it has been reported that these substances also have some effect on crystal-cell interaction.…”

Section: Discussionmentioning

confidence: 99%

Calcium oxalate monohydrate crystal binding substance produced from Madin‐Darby canine kidney cells

et al. 2002

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Background : The interaction between kidney urothelium and crystals is a critical event in the growth of renal calculi. When studying calcium oxalate monohydrate (COM) crystal binding to MadinDarby canine kidney (MDCK) cells in culture, we observed that crystals also attached to areas on the coverslips devoid of cells. This phenomenon could be the result of substances produced by the cells that adhere to the glass and subsequently bind COM crystals. We investigated the characteristics of this COM binding substance. Methods : Media was collected from cultures of MDCK cells (conditioned media) and proteins were separated by high performance liquid chromatography. The molecular weights and purity of isolated proteins were determined by polyacrylamide gel electrophoresis. The conditioned media and each separated fraction were applied to glass and to MDCK cells and COM-binding ability determined using 14 C-labeled crystals. The binding of radio-labelled calcium oxalate dihydrate, brushite, uric acid, and apatite to coverslips were also studied. Results : Fourteen times more COM bound to coverslips incubated with conditioned media than those with control media. The molecular weight of the protein bound to the glass was determined to be 200 kDa. The COM crystals binding to this protein was 1.5 µ g/ng. Other crystals bound to a lesser extent. The incubation of cells with this protein inhibited COM binding by 39%. Conclusion : The MDCK cells produce a 200-kDa protein that has a high binding affinity for COM crystals. This protein binds to glass and is responsible for crystal binding to areas devoid of cells. This protein also has an inhibitory effect on COM binding to MDCK cells in culture.

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“…In this study, we have focused our attention on purification, identification and functional analysis of a novel CaOx crystal growth inhibitor and on its potential role in the pathogenic mechanisms of nephrolithiasis. Currently known stone inhibitory proteins are nephrocalcin (22), TammHorsfall protein (23), uropontin (24), inter-α-trypsin inhibitor (bikunin) (25), and urinary prothrombin fragment 1 (crystal matrix protein) (26). Interestingly, these stone inhibitors have similar physical and chemical properties; they are small anionic proteins that bind to calcium and inhibit either growth or aggregation of CaOx crystals.…”

Section: Introductionmentioning

confidence: 99%

Identification of human urinary trefoil factor 1 as a novel calcium oxalate crystal growth inhibitor

Chutipongtanate

Nakagawa²,

Sritippayawan³

et al. 2005

Journal of Clinical Investigation

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Previous research on proteins that inhibit kidney stone formation has identified a relatively small number of well-characterized inhibitors. Identification of additional stone inhibitors would increase understanding of the pathogenesis and pathophysiology of nephrolithiasis. We have combined conventional biochemical methods with recent advances in mass spectrometry (MS) to identify a novel calcium oxalate (CaOx) crystal growth inhibitor in normal human urine. Anionic proteins were isolated by DEAE adsorption and separated by HiLoad 16/60 Superdex 75 gel filtration. A fraction with potent inhibitory activity against CaOx crystal growth was isolated and purified by anion exchange chromatography. The protein in 2 subfractions that retained inhibitory activity was identified by matrix-assisted laser desorption/ionization-time-of-flight MS and electrospray ionization-quadrupole-time-of-flight tandem MS as human trefoil factor 1 (TFF1). Western blot analysis confirmed the mass spectrometric protein identification. Functional studies of urinary TFF1 demonstrated that its inhibitory potency was similar to that of nephrocalcin. The inhibitory activity of urinary TFF1 was dose dependent and was inhibited by TFF1 antisera. Anti-C-terminal antibody was particularly effective, consistent with our proposed model in which the 4 C-terminal glutamic residues of TFF1 interact with calcium ions to prevent CaOx crystal growth. Concentrations and relative amounts of TFF1 in the urine of patients with idiopathic CaOx kidney stone were significantly less (2.5-fold for the concentrations and 5-to 22-fold for the relative amounts) than those found in controls. These data indicate that TFF1 is a novel potent CaOx crystal growth inhibitor with a potential pathophysiological role in nephrolithiasis.

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The Urinary F1 Activation Peptide of Human Prothrombin is a Potent Inhibitor of Calcium Oxalate Crystallization in Undiluted Human Urine in Vitro

Cited by 74 publications

References 24 publications

Urine protein markers distinguish stone-forming from non-stone-forming relatives of calcium stone formers

Urine protein markers distinguish stone-forming from non-stone-forming relatives of calcium stone formers

Calcium oxalate monohydrate crystal binding substance produced from Madin‐Darby canine kidney cells

Identification of human urinary trefoil factor 1 as a novel calcium oxalate crystal growth inhibitor

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