Interstitial calcinosis in renal papillae of genetically engineered mouse models: relation to Randall’s plaques

Wu, Xue-Ru

doi:10.1007/s00240-014-0699-3

Cited by 17 publications

(6 citation statements)

References 113 publications

(138 reference statements)

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“…Intratubular crystal aggregates were seen in the collecting ducts at the inner medulla and renal papillae in these mice, while wild type littermates had no crystal deposition in the kidney. This papillary interstitial calcinosis of the THP -/- mice is very similar to Randall's plaques seen in calcium oxalate stone formers, but ureteral stones have been found in this model[ 26 ].…”

Section: Macromolecules and Crystallizationsupporting

confidence: 54%

Kidney stone matrix proteins: Role in stone formation

Negri¹,

Spivacow²

2023

World J Nephrol

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Stone formation is induced by an increased level of urine crystallization promoters and reduced levels of its inhibitors. Crystallization inhibitors include citrate, magnesium, zinc, and organic compounds such as glycosaminoglycans. In the urine, there are various proteins, such as uromodulin (Tamm-Horsfall protein), calgranulin, osteopontin, bikunin, and nephrocalcin, that are present in the stone matrix. The presence of several carboxyl groups in these macromolecules reduces calcium oxalate monohydrate crystal adhesion to the urinary epithelium and could potentially protect against lithiasis. Proteins are the most abundant component of kidney stone matrix, and their presence may reflect the process of stone formation. Many recent studies have explored the proteomics of urinary stones. Among the stone matrix proteins, the most frequently identified were uromodulin, S100 proteins (calgranulins A and B), osteopontin, and several other proteins typically engaged in inflammation and immune response. The normal level and structure of these macromolecules may constitute protection against calcium salt formation. Paradoxically, most of them may act as both promoters and inhibitors depending on circumstances. Many of these proteins have other functions in modulating oxidative stress, immune function, and inflammation that could also influence stone formation. Yet, the role of these kidney stone matrix proteins needs to be established through more studies comparing urinary stone proteomics between stone formers and non-stone formers.

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Section: Macromolecules and Crystallizationsupporting

confidence: 54%

Kidney stone matrix proteins: Role in stone formation

Negri¹,

Spivacow²

2023

World J Nephrol

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“…[10, 12] There is the possibility of other instigators and situations, such as reduction in crystallization inhibitory capacity as shown in THP null mice. [66] Lack of overt inflammation around the plaques would also indicate malfunctioning crystal clearance system. Experimental studies have shown that crystals, CaOx as well as CaP, provoke inflammatory responses, attract monocytes and macrophages which surround the crystals and eventually dispose of them.…”

Section: Discussionmentioning

confidence: 99%

Osteogenic changes in kidneys of hyperoxaluric rats

Joshi

Clapp

Wang

et al. 2015

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Many calcium oxalate (CaOx) kidney stones develop attached to renal papillary subepithelial deposits of calcium phosphate (CaP), called Randall’s plaque (RP). Pathogenesis of the plaques is not fully understood. We hypothesize that abnormal urinary environment in stone forming kidneys leads to epithelial cells losing their identity and becoming osteogenic. To test our hypothesis male rats were made hyperoxaluric by administration of hydroxy-l-proline (HLP). After 28 days, rat kidneys were extracted. We performed genome wide analyses of differentially expressed genes and determined changes consistent with dedifferentiation of epithelial cells into osteogenic phenotype. Selected molecules were further analyzed using quantitative-PCR and immunohistochemistry. Genes for runt related transcription factors (RUNX1 and 2), zinc finger protein Osterix, bone morphogenetic proteins (BMP2 and 7), bone morphogenetic protein receptor(BMPR2), collagen, osteocalcin, osteonectin, osteopontin (OPN), matrix-gla-protein (MGP), osteoprotegrin (OPG), cadherins, fibronectin (FN) and vimentin (VIM) were up regulated while those for alkaline phosphatase (ALP) and cytokeratins 10 and 18 were down regulated. In conclusion, epithelial cells of hyperoxaluric kidneys acquire a number of osteoblastic features but without CaP deposition, perhaps a result of down regulation of ALP and up regulation of OPN and MGP. Plaque formation may additionally require localized increases in calcium and phosphate and decrease in mineralization inhibitory potential.

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“…88 A recent review highlights models of interstitial calcinosis such as mice deficient for Umod, Opn, Npt2a, and Nherf1. 89 The Sat1 2/2 mice provide a novel model of calcium oxalate stone formation, where calcium oxalate crystals were observed in the lumen of kidney cortical tubules as well as the bladder, which could be used to screen novel therapies. 34 Given that human mutations have now been identified in the Sat1 homolog SLC26A1, therapies targeting this channel in order to prevent hyperoxaluria need to be explored further and this murine model would facilitate this.…”

Section: Progress In Animal Models Of Nephrolithiasismentioning

confidence: 99%

Progress in Understanding the Genetics of Calcium-Containing Nephrolithiasis

Sayer

2016

JASN

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Renal stone disease is a frequent condition, causing a huge burden on health care systems globally. Calcium-based calculi account for around 75% of renal stone disease and the incidence of these calculi is increasing, suggesting environmental and dietary factors are acting upon a preexisting genetic background. The familial nature and significant heritability of stone disease is known, and recent genetic studies have successfully identified genes that may be involved in renal stone formation. The detection of monogenic causes of renal stone disease has been made more feasible by the use of high-throughput sequencing technologies and has also facilitated the discovery of novel monogenic causes of stone disease. However, the majority of calcium stone formers remain of undetermined genotype. Genome-wide association studies and candidate gene studies implicate a series of genes involved in renal tubular handling of lithogenic substrates, such as calcium, oxalate, and phosphate, and of inhibitors of crystallization, such as citrate and magnesium. Additionally, expression profiling of renal tissues from stone formers provides a novel way to explore disease pathways. New animal models to explore these recently-identified mechanisms and therapeutic interventions are being tested, which hopefully will provide translational insights to stop the growing incidence of nephrolithiasis.

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Interstitial calcinosis in renal papillae of genetically engineered mouse models: relation to Randall’s plaques

Cited by 17 publications

References 113 publications

Kidney stone matrix proteins: Role in stone formation

Kidney stone matrix proteins: Role in stone formation

Osteogenic changes in kidneys of hyperoxaluric rats

Progress in Understanding the Genetics of Calcium-Containing Nephrolithiasis

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