Expression of proteins that inhibit calcium oxalate crystallization in vitro in the urine of normal and stone-forming individuals

Hedgepeth, Ryan C.; Lei, Yang; Resnick, Martin I.; Marengo, Susan Ruth

doi:10.1053/ajkd.2001.20594

Cited by 24 publications

(17 citation statements)

References 29 publications

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“…By contrast, Suzuki et al (43) found higher urinary concentrations of BK in male SF compared with healthy male controls and that a greater proportion of SF than normal patients had an aberrant BK 25-kDa species, which is identified to be deglycosylated BK, a form with reduced effectiveness in inhibiting CaOx crystal growth. Marengo et al (14,26) found increased HMM forms (P␣I and ITI), but not BK, in SF (14,26), and these differences were constant over several months (26).…”

Section: Discussionmentioning

confidence: 92%

“…Immunohistochemical analysis of human kidneys has shown that PF1 is synthesized in the proximity of renal stones and is more abundant in the kidneys of SF than in healthy individuals (41). However, to date no differences have been found in the relative amounts of any prothrombin forms in the urine of CaOx SF vs. normal controls (14).…”

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: 92%

Section: Discussionmentioning

confidence: 99%

mentioning

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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“…Individual heavy chains have not shown crystallization inhibitory properties in vitro (45), but urinary excretion of Itih proteins has been linked to stone formation (5,22,55). Urinary GAGs, such as chondroitin sulfate, heparin sulfate, and hyaluronic acid, are considered to play a significant role in stone formation (43).…”

Section: Discussionmentioning

confidence: 99%

Regulation of macromolecular modulators of urinary stone formation by reactive oxygen species: transcriptional study in an animal model of hyperoxaluria

Khan

Joshi

Wang

et al. 2014

American Journal of Physiology-Renal Physiology

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We used an unbiased approach of gene expression profiling to determine differential gene expression of all the macromolecular modulators (MMs) considered to be involved in stone formation, in hyperoxaluric rats, with and without treatment with the NADPH oxidase inhibitor apocynin. Male rats were fed rat chow or chow supplemented with 5% wt/wt hydroxy-l-proline (HLP) with or without apocynin-supplemented water. After 28 days, rats were euthanized and their kidneys explanted. Total RNA was isolated and microarray analysis was conducted using the Illumina bead array reader. Gene ontology analysis and the pathway analyses of the genes were done using Database for Annotation, Visualization of Integrated Discovery enrichment analysis tool. Quantitative RT-PCR of selected genes was carried out to verify the microarray results. Expression of selected gene products was confirmed using immunohistochemistry. Administration of HLP led to crystal deposition. Genes encoding for fibronectin, CD 44, fetuin B, osteopontin, and matrix-gla protein were upregulated while those encoding for heavy chains of inter-alpha-inhibitor 1, 3, and 4, calgranulin B, prothrombin, and Tamm-Horsfall protein were downregulated. HLP-fed rats receiving apocynin had a significant reversal in gene expression profiles: those that were upregulated came down while those that were downregulated stepped up. Apocynin treatment resulted in near complete absence of crystals. Clearly, there are two types of MMs; one is downregulated while the other is upregulated during hyperoxaluria and crystal deposition. Apparently gene and protein expressions of known macromolecular modulators of CaOx crystallization are likely regulated by ROS produced in part through the activation of NADPH oxidase.

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“…Normal urine inhibits all aspects of CaOx crystal formation in vitro, and several studies support the hypothesis that defective inhibition of urinary crystallization may be of critical importance in determining individual susceptibility to stone formation (1)(2)(3)(4). However, other studies have failed to demonstrate differences in urinary macromolecules between stone formers and controls (5)(6)(7). Several candidate inhibitory macromolecules have been isolated and identified in both urine and kidney stones, including osteopontin (OPN), nephrocalcin, crystal matrix protein, bikunin, and Tamm-Horsfall protein (8 -12).…”

mentioning

confidence: 91%

Osteopontin Is a Critical Inhibitor of Calcium Oxalate Crystal Formation and Retention in Renal Tubules

Wesson¹,

Johnson

Mazzali

et al. 2003

Journal of the American Society of Nephrology

253

177

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Abstract. Calcium nephrolithiasis is the most common form of renal stone disease, with calcium oxalate (CaOx) being the predominant constituent of renal stones. Current in vitro evidence implicates osteopontin (OPN) as one of several macromolecular inhibitors of urinary crystallization with potentially important actions at several stages of CaOx crystal formation and retention. To determine the importance of OPN in vivo, hyperoxaluria was induced in mice targeted for the deletion of the OPN gene together with wild-type control mice. Both groups were given 1% ethylene glycol, an oxalate precursor, in their drinking water for up to 4 wk. At 4 wk, OPN-deficient mice demonstrated significant intratubular deposits of CaOx crystals, whereas wild-type mice were completely unaffected. Retained crystals in tissue sections were positively identified as CaOx monohydrate by both polarized optical microscopy and x-ray powder diffraction analysis. Furthermore, hyperoxaluria in the OPN wild-type mice was associated with a significant 2-to 4-fold upregulation of renal OPN expression by immunocytochemistry, lending further support to a renoprotective role for OPN. These data indicate that OPN plays a critical renoprotective role in vivo as an inhibitor of CaOx crystal formation and retention in renal tubules. jeremy. hughes@ed.ac.uk

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Expression of proteins that inhibit calcium oxalate crystallization in vitro in the urine of normal and stone-forming individuals

Cited by 24 publications

References 29 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

Regulation of macromolecular modulators of urinary stone formation by reactive oxygen species: transcriptional study in an animal model of hyperoxaluria

Osteopontin Is a Critical Inhibitor of Calcium Oxalate Crystal Formation and Retention in Renal Tubules

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