Genome-Wide Gene Expression Profiling of Randall’s Plaques in Calcium Oxalate Stone Formers

Taguchi, Kazumi; Hamamoto, Shuzo; Okada, Atsushi; Unno, Rei; Kamisawa, Hideyuki; Naiki, Taku; Ando, Ryosuke; Mizuno, Kentaro; Kawai, Noriyasu; Tozawa, Keiichi; Kohri, Kenjiro; Yasui, Takahiro

doi:10.1681/asn.2015111271

Cited by 88 publications

(95 citation statements)

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“…(4,44,45) For example, high-resolution Fourier transform infrared microspectroscopy and electron diffraction studies have revealed that calcium phosphate crystals are the major component of Randall's plaque, which are the areas of the renal papillae that contain interstitial calcium phosphate deposits that provide a nidus of urothelial surface for calcium oxalate deposition. (4,6,16,46,47) Moreover, immunohistological examinations of renal biopsies from patients with kidney stones have shown the presence of the urinary macromolecules osteopontin and THP in association with Randall's plaques, (44,45,48) and to explore the similarities between the RCALC1 and human NC histological phenotypes, we therefore investigated serial sections of kidneys from the RCALC1 mice and WT littermates for such abnormalities using immunofluorescence to detect osteopontin and THP and von Kossa staining to detect calcification. This revealed the presence of osteopontin in the areas of interstitial calcification within the renal papillae of RCALC1 mice (Fig.…”

Section: Identification and Characterization Of Mice With Autosomal Dmentioning

confidence: 99%

“…These results are consistent with those from other studies that have reported an increased apoptosis and differential expression of genes involved in proliferation in Randall's plaques from stone formers when compared with a control group of patients. (48) Furthermore, stone formation in rats is reported to be associated with an increase in apoptosis, and studies in renal cells have also shown that calcium phosphate stones are associated with apoptosis and changes in cell proliferation. (48,66,67) Thus, renal injury and cell death may be common mechanisms in the etiology of renal calcification and the resulting NC and NL by generating sites that promote calcium crystal aggregation and growth.…”

Section: Journal Of Bone and Mineral Researchmentioning

confidence: 99%

“…(48) Furthermore, stone formation in rats is reported to be associated with an increase in apoptosis, and studies in renal cells have also shown that calcium phosphate stones are associated with apoptosis and changes in cell proliferation. (48,66,67) Thus, renal injury and cell death may be common mechanisms in the etiology of renal calcification and the resulting NC and NL by generating sites that promote calcium crystal aggregation and growth. (59,68) On the basis of these findings, we propose the following possible model for the interstitial renal papillary calcification and likely NC in RCALC1 mice.…”

Section: Journal Of Bone and Mineral Researchmentioning

confidence: 99%

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Mice with a Brd4 Mutation Represent a New Model of Nephrocalcinosis

Gorvin

Loh

Stechman

et al. 2019

Journal of Bone and Mineral Research

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Nephrolithiasis (NL) and nephrocalcinosis (NC), which comprise renal calcification of the collecting system and parenchyma, respectively, have a multifactorial etiology with environmental and genetic determinants and affect ∼10% of adults by age 70 years. Studies of families with hereditary NL and NC have identified >30 causative genes that have increased our understanding of extracellular calcium homeostasis and renal tubular transport of calcium. However, these account for <20% of the likely genes that are involved, and to identify novel genes for renal calcification disorders, we investigated 1745 12‐month‐old progeny from a male mouse that had been treated with the chemical mutagen N‐ethyl‐N‐nitrosourea (ENU) for radiological renal opacities. This identified a male mouse with renal calcification that was inherited as an autosomal dominant trait with >80% penetrance in 152 progeny. The calcification consisted of calcium phosphate deposits in the renal papillae and was associated with the presence of the urinary macromolecules osteopontin and Tamm‐Horsfall protein, which are features found in Randall's plaques of patients with NC. Genome‐wide mapping located the disease locus to a ∼30 Mbp region on chromosome 17A3.3‐B3 and whole‐exome sequence analysis identified a heterozygous mutation, resulting in a missense substitution (Met149Thr, M149T), in the bromodomain‐containing protein 4 (BRD4). The mutant heterozygous (Brd4+/M149T) mice, when compared with wild‐type (Brd4+/+) mice, were normocalcemic and normophosphatemic, with normal urinary excretions of calcium and phosphate, and had normal bone turnover markers. BRD4 plays a critical role in histone modification and gene transcription, and cDNA expression profiling, using kidneys from Brd4+/M149T and Brd4+/+ mice, revealed differential expression of genes involved in vitamin D metabolism, cell differentiation, and apoptosis. Kidneys from Brd4+/M149T mice also had increased apoptosis at sites of calcification within the renal papillae. Thus, our studies have established a mouse model, due to a Brd4 Met149Thr mutation, for inherited NC. © 2019 American Society for Bone and Mineral Research.

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Section: Identification and Characterization Of Mice With Autosomal Dmentioning

confidence: 99%

Section: Journal Of Bone and Mineral Researchmentioning

confidence: 99%

Section: Journal Of Bone and Mineral Researchmentioning

confidence: 99%

See 1 more Smart Citation

Mice with a Brd4 Mutation Represent a New Model of Nephrocalcinosis

Gorvin

Loh

Stechman

et al. 2019

Journal of Bone and Mineral Research

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Section: Introductionmentioning

confidence: 99%

“…We recently reported the gene expression profile of RP in CaOx stone patients, showing that renal cell injury, oxidative stress and sodium/potassium transporters contribute to RP development. 10 As previous studies showed a difference in the lithogenesis of CaOx and CaP stones, a detailed investigation of RPs with CaP stones is required to better understand CaP stone formation. Therefore, we compared the gene expression profiles in renal papillary tissue with RPs of CaP and CaOx stone patients by a microarray, and analyzed the pathway to elucidate the role of RP in CaP lithogenesis.…”

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confidence: 99%

Helper T‐cell signaling and inflammatory pathway lead to formation of calcium phosphate but not calcium oxalate stones on Randall's plaques

et al. 2019

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Objectives To elucidate the difference in the lithogenesis of calcium oxalate and calcium phosphate stones. Methods Renal papillary tissues were obtained from 23 idiopathic calcium oxalate and seven calcium phosphate stone patients who had undergone endoscopic lithotripsy. Samples were individually collected from two different regions in each patient: the papillary mucosa containing Randall's plaque and mucosa not containing Randall's plaque. A microarray analysis was carried out on those tissues to compare their gene expression patterns. Furthermore, a causal pathway analysis comparing their differences was carried out. Results Cluster analysis showed that gene expression profiles of calcium phosphate stone patients markedly differed from those of calcium oxalate stone patients. Disease and function analysis showed that Randall's plaque‐containing tissues of calcium phosphate stone‐forming patients had significantly higher movement and migration of mononuclear leukocytes, and lower tendency toward infection and lymph node formation than Randall's plaque‐containing tissues of calcium oxalate stone formers. Additional pathway analysis showed increased immune cell signaling in calcium phosphate formers, such as the helper T cell 1 and 2 pathways, which was confirmed by their messenger ribonucleic acid expression. Conclusions The present results show the upregulation of helper T‐cell signaling pathways in Randall's plaque‐containing papillae in calcium phosphate, but not in calcium oxalate stone formers. Thus, helper T‐cell immune responses and the related inflammatory processes seem to lead to the formation of calcium phosphate stones on Randall's plaques.

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Collagen fibrils and cell nuclei are entrapped within Randall's plaques but not in CaOx matrix overgrowth: A microscopic inquiry into Randall's plaque stone pathogenesis

Canela

Bledsoe

Worcester

et al. 2021

The Anatomical Record

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Calcium oxalate (CaOx) stones can grow attached to the renal papillary calcification known as Randall's plaque. Although stone growth on Randall's plaque is a common phenomenon, this mechanism of stone formation is still poorly understood. The objective of this study was to investigate the microenvironment of mature Randall's plaque, explore its molecular composition and differentiate plaque from CaOx overgrowth using multimodal imaging on demineralized stone sections. Fluorescence imaging showed consistent differences in autofluorescence patterns between Randall's plaque and calcium oxalate overgrowth regions. Second harmonic generation imaging established the presence of collagen only in regions of decalcified Randall's plaque but not in regions of CaOx overgrowth matrix. Surprisingly, in these stone sections we observed cell nuclei with preserved morphology within regions of mature Randall's plaque. These conserved cells had variable expression of vimentin and CD45. The presence of nuclei in mature plaque indicates that mineralization is not necessarily associated with cell death. The markers identified suggest that some of the entrapped cells may be undergoing dedifferentiation or could emanate from a mesenchymal or immune origin. We propose that entrapped cells may play an important role in the growth and maintenance of Randall's plaque. Further characterization of these cells and thorough analyses of the mineralized stone forming renal papilla will be fundamental in understanding the pathogenesis of Randall's plaque and CaOx stone formation.

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Genome-Wide Gene Expression Profiling of Randall’s Plaques in Calcium Oxalate Stone Formers

Cited by 88 publications

References 50 publications

Mice with a Brd4 Mutation Represent a New Model of Nephrocalcinosis

Mice with a Brd4 Mutation Represent a New Model of Nephrocalcinosis

Helper T‐cell signaling and inflammatory pathway lead to formation of calcium phosphate but not calcium oxalate stones on Randall's plaques

Collagen fibrils and cell nuclei are entrapped within Randall's plaques but not in CaOx matrix overgrowth: A microscopic inquiry into Randall's plaque stone pathogenesis

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