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Osteogenic changes in kidneys of hyperoxaluric rats.

ABSTRACT: Many calcium oxalate (CaOx) kidney stones develop attached to renal papillary sub-epithelial 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 28days, 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 upregulated while those for alkaline phosphatase (ALP) and cytokeratins 10 and 18 were downregulated. In conclusion, epithelial cells of hyperoxaluric kidneys acquire a number of osteoblastic features but without CaP deposition, perhaps a result of downregulation of ALP and upregulation of OPN and MGP. Plaque formation may additionally require localized increases in calcium and phosphate and decrease in mineralization inhibitory potential.

SUBMITTER: Joshi S

PROVIDER: S-EPMC4523408 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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Osteogenic changes in kidneys of hyperoxaluric rats.

Joshi Sunil S Clapp William L WL Wang Wei W Khan Saeed R SR

Biochimica et biophysica acta 20150627 9

Many calcium oxalate (CaOx) kidney stones develop attached to renal papillary sub-epithelial 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 28days, rat kidneys were extrac ...[more]

PMID: 26122267

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Project description:Calcium oxalate stones account for >80% of urinary stones, however the mechanisms underlying their formation remains to be elucidated. Hyperoxaluria serves an important role in the pathophysiological process of stone formation. In the present study, differences in the miRNA expression profiles between experimental hyperoxaluric rats and normal rats were analyzed, in order to identify target genes and signaling pathways involved in the pathogenesis of hyperoxaluria. Ethylene glycol and ammonium chloride was fed to male hyperoxaluric rats (EXP) and normal age‑matched male rats (CON). The oxalate concentration in the urine of each experimental rat was collected every 24 h and measured on day 14. Three rats exhibiting the highest concentrations were selected for microarray analysis. Microarray analysis was performed to evaluate differences in the expression of microRNA (miRNA) in the kidney tissues from EXP and CON groups, and miRNAs that exhibited a >2‑fold or a <0.5‑fold alteration in expression between these groups were screened for differential expression patterns according to the threshold P‑values. Reverse transcription‑quantitative polymerase chain reaction analysis was employed to confirm the microarray results. In order to predict the potential role of miRNAs in pathophysiological processes, gene ontology (GO), pathway and target prediction analyses were conducted. A total of 28 miRNAs were observed to be differentially expressed (>2‑fold change) between EXP and CON groups. Among these miRNAs, 20 were upregulated and 8 were downregulated. GO and pathway analyses revealed that the insulin resistance and phosphatidylinositol‑bisphosphonate 3‑kinase/AKT serine threonine kinase signaling pathways were potentially associated with miRNA regulation in this setting. In conclusion, the results of the present study identified differentially expressed miRNAs in hyperoxaluric rats, and provided a novel perspective for the role of miRNAs in the formation of calcium oxalate stones.

Dataset Information

Osteogenic changes in kidneys of hyperoxaluric rats.

Publications

Osteogenic changes in kidneys of hyperoxaluric rats.

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