Renal prothrombin mRNA is significantly decreased in a hyperoxaluric rat model of nephrolithiasis

Grover, Phulwinder K.; Miyazawa, Katsuhito; Coleman, Mark; Stahl, J; Ryall, Rosemary L.

doi:10.1002/path.2061

Cited by 12 publications

(9 citation statements)

References 51 publications

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“…92 The exposure of renal epithelial cells to oxalate causes oxidative damage, mitochondrial damage, activation of second messenger path ways (such as those mediated by p38 MAP kinase and phospholipase A), inflammatory response signaling, changes in the expression of putative modulators of crystallization (such as osteopontin, bikunin and Tamm-Horsfall protein), and changes in the glycocalyx. [93][94][95][96][97][98][99][100][101][102][103][104] The effects of oxalate on renal epithelial cells have been extensively discussed by Jonassen et al 105 Although some of these effects are directly due to oxalate, others are secondary to oxalate induced oxidative damage or inflammatory responses. 96,106 The changes effected by oxalate could promote nephrolithiasis by providing debris for crystal nucleation, making the apical plasma membrane more adhesive to crystals, or altering the availability of crystallizationinhibiting proteins.…”

Section: Potential Roles Of Oxalate In Nephrolithiasismentioning

confidence: 99%

Oxalate in renal stone disease: the terminal metabolite that just won't go away

Marengo

Romani

2008

Nat Rev Nephrol

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The incidence of calcium oxalate nephrolithiasis in the US has been increasing throughout the past three decades. Biopsy studies show that both calcium oxalate nephrolithiasis and nephrocalcinosis probably occur by different mechanisms in different subsets of patients. Before more-effective medical therapies can be developed for these conditions, we must understand the mechanisms governing the transport and excretion of oxalate and the interactions of the ion in general and renal physiology. Blood oxalate derives from diet, degradation of ascorbate, and production by the liver and erythrocytes. In mammals, oxalate is a terminal metabolite that must be excreted or sequestered. The kidneys are the primary route of excretion and the site of oxalate's only known function. Oxalate stimulates the uptake of chloride, water, and sodium by the proximal tubule through the exchange of oxalate for sulfate or chloride via the solute carrier SLC26A6. Fecal excretion of oxalate is stimulated by hyperoxalemia in rodents, but no similar phenomenon has been observed in humans. Studies in which rats were treated with (14)C-oxalate have shown that less than 2% of a chronic oxalate load accumulates in the internal organs, plasma, and skeleton. These studies have also demonstrated that there is interindividual variability in the accumulation of oxalate, especially by the kidney. This Review summarizes the transport and function of oxalate in mammalian physiology and the ion's potential roles in nephrolithiasis and nephrocalcinosis.

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Section: Potential Roles Of Oxalate In Nephrolithiasismentioning

confidence: 99%

Oxalate in renal stone disease: the terminal metabolite that just won't go away

Marengo

Romani

2008

Nat Rev Nephrol

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“…In addition, production of crystallization modulators, such as osteopontin (Opn) (41,76,78), Tamm-Horsfall protein (Umod, uromodulin) (13,58), urinary prothrombin fragment-1 (Uptf-1) (17,18), bikunin (Bk) (32), and inter-␣-trypsin inhibitors (Itih) (61), is altered when cells are exposed to CaOx crystals. In support of this, we have shown that inhibition of NADPH oxidase reduces the production of Opn by renal epithelial cells exposed to CaOx crystals, while CaOx monohydrate crystal exposure of renal epithelial NRK52E cells, pretreated with the NADPH oxidase inhibitor diphenyleneiodium (DPI), reduced the production of ROS compared with cells not treated with DPI (78).…”

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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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“…We propose that the minor (C) allele of SNP rs5896 (encoding threonine) – a protective allele for KSD, which is significantly more frequent in the control group than in the patient group, conserves the glycan site of UPTF1 and influences the UPTF1 inhibitory activity function in protection against CaOx crystallization. F2 mRNA was found to significantly reduce in kidney of a hyperoxaluric rat model of nephrolithiasis [23] and many features of UPTF1 function have been studied [21], [22], [24], [25]. However, the precise mechanism of KSD with respect to UPTF1 remains unclear.…”

Section: Discussionmentioning

confidence: 99%

Association between Human Prothrombin Variant (T165M) and Kidney Stone Disease

et al. 2012

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We previously reported the association between prothrombin (F2), encoding a stone inhibitor protein - urinary prothrombin fragment 1 (UPTF1), and the risk of kidney stone disease in Northeastern Thai patients. To identify specific F2 variation responsible for the kidney stone risk, we conducted sequencing analysis of this gene in a group of the patients with kidney stone disease. Five intronic SNPs (rs2070850, rs2070852, rs1799867, rs2282687, and rs3136516) and one exonic non-synonymous single nucleotide polymorphism (nsSNP; rs5896) were found. The five intronic SNPs have no functional change as predicted by computer programs while the nsSNP rs5896 (c.494 C>T) located in exon 6 results in a substitution of threonine (T) by methionine (M) at the position 165 (T165M). The nsSNP rs5896 was subsequently genotyped in 209 patients and 216 control subjects. Genotypic and allelic frequencies of this nsSNP were analyzed for their association with kidney stone disease. The frequency of CC genotype of rs5896 was significantly lower in the patient group (13.4%) than that in the control group (22.2%) (P = 0.017, OR 0.54, 95% CI 0.32–0.90), and the frequency of C allele was significantly lower in the patient group (36.1%) than that in the control group (45.6%) (P = 0.005, OR 0.68, 95% CI 0.51–0.89). The significant differences of genotype and allele frequencies were maintained only in the female group (P = 0.033 and 0.003, respectively). The effect of amino-acid change on UPTF1 structure was also examined by homologous modeling and in silico mutagenesis. T165 is conserved and T165M substitution will affect hydrogen bond formation with E180. In conclusion, our results indicate that prothrombin variant (T165M) is associated with kidney stone risk in the Northeastern Thai female patients.

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Renal prothrombin mRNA is significantly decreased in a hyperoxaluric rat model of nephrolithiasis

Cited by 12 publications

References 51 publications

Oxalate in renal stone disease: the terminal metabolite that just won't go away

Oxalate in renal stone disease: the terminal metabolite that just won't go away

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

Association between Human Prothrombin Variant (T165M) and Kidney Stone Disease

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