Toxicogenomic biomarkers for renal papillary injury in rats

Uehara, Takeki; Kondo, Chiaki; Morikawa, Yuji; Hanafusa, Hiroyuki; Ueda, Seiko; Minowa, Yohsuke; Nakatsu, Noriyuki; Ono, Atsushi; Maruyama, Toshiyuki; Kato, Ikuo; Yamate, Jyoji; Yamada, Hiroshi; Ohno, Yasuo; Urushidani, Tetsuro

doi:10.1016/j.tox.2012.09.012

Cited by 11 publications

(5 citation statements)

References 18 publications

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“…This nuclear localization was observed in various cell lines transfected with an RanBP3L‐GFP vector and in NRK‐52, mIMCD3, and primary cultured IMCD cells that were cultivated in hyperosmotic conditions. It has been shown that RanBP3L induces SMAD1/5/8 nuclear export in mesenchymal stem cells (29). Using immunofluorescence analysis in primary cultured IMCD cells (cultivated at 300 or 600 mosmol/kg), we did not observe this effect.…”

Section: Discussionmentioning

confidence: 99%

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The kidney‐specific expression of genes can be modulated by the extracellular osmolality

et al. 2016

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With this study, we wanted to prove the hypothesis that the unique extracellular osmolality within the renal medulla modulates a specific gene expression pattern. The physiologic functions of the kidneys are mediated by the segment-specific expression of key proteins. So far, we have limited knowledge about the mechanisms that control this gene expression pattern. The hyperosmolality in the renal medullary interstitium is of major importance as a driving force for urine concentration. We made use of primarily cultured rat renal inner medullary collecting-duct cells and microarray analysis to identify genes affected by the environmental osmolality of the culture medium. We identified hundreds of genes that were either induced or repressed in expression by hyperosmolality in a time- and osmolality-dependent fashion. Further analysis demonstrated that many of them, physiologically, showed a kidney- and even collecting-duct-specific expression, including secreted proteins, kinases, and transcription factors. On the other hand, we identified factors, down-regulated in expression, that have a diuretic effect. In conclusion, the kidney is the only organ that has such a hyperosmotic environment, and study provides an excellent method for controlling tissue-specific gene expression.-Schulze Blasum, B., Schröter, R., Neugebauer, U., Hofschröer, V., Pavenstädt, H., Ciarimboli, G., Schlatter E., Edemir, B. The kidney-specific expression of genes can be modulated by the extracellular osmolality.

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Section: Discussionmentioning

confidence: 99%

“…The expression of all these factors was highly up‐regulated by hyperosmolality. Wnt4, Ccl7, andLamc2 forexample have been described to be involved in renal development or are induced by kidney injury (27–29). So far, no function has been described for Tbx3 in the kidney, but Elf5 has been described to activate the Aqp2 promotor (30).…”

Section: Discussionmentioning

confidence: 99%

The kidney‐specific expression of genes can be modulated by the extracellular osmolality

et al. 2016

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“…Bojic et al (2015) reported that Timp1 was a good diagnostic biomarker of sepsis-associated AKI and may involve in the pathogenesis of sepsis and septic shock. Uehara et al (2013) successfully identified Timp1 as a candidate genomic biomarker for the early detection of acute papillary injuries in rats.…”

Section: Discussionmentioning

confidence: 99%

Identification and Validation of Potential Biomarkers and Their Functions in Acute Kidney Injury

Chen

Chen²,

Olivero

et al. 2020

Front. Genet.

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Acute kidney injury (AKI) is a global public health concern associated with high morbidity, mortality, and health-care costs, and the therapeutic measures are still limited. This study aims to investigate crucial genes correlated with AKI, and their potential functions, which might contribute to a better understanding of AKI pathogenesis. The highthroughput data GSE52004 and GSE98622 were downloaded from Gene Expression Omnibus; four group sets were extracted and integrated. Differentially expressed genes (DEGs) in the four group sets were identified by limma package in R software. The overlapping DEGs among four group sets were further analyzed by the VennDiagram package, and their potential functions were analyzed by the GO and KEGG pathway enrichment analyses using the DAVID database. Furthermore, the protein-protein interaction (PPI) network was constructed by STRING, and the functional modules of the PPI network were filtered by MCODE and ClusterOne in Cytoscape. Hub genes of overlapping DEGs were identified by Cyto-Hubba and cytoNCA. The expression of 35 key genes was validated by quantitative real-time PCR (qRT-PCR). Western blot and immunofluorescence were performed to validate an important gene Egr1. A total of 722 overlapping DEGs were differentially expressed in at least three group sets. These genes mainly enriched in cell proliferation and fibroblast proliferation. Additionally, 5 significant modules and 21 hub genes, such as Havcr1, Krt20, Sox9, Egr1, Timp1, Serpine1, Edn1, and Apln were screened by analyzing the PPI networks. The 5 significant modules were mainly enriched in complement and coagulation cascades and Metabolic pathways, and the top 21 hub genes were mainly enriched in positive regulation of cell proliferation. Through validation, Krt20 were identified as the top 1 upregulated genes with a log2 (fold change) larger than 10 in all these 35 genes, and 21 genes were validated as significantly upregulated; Egr1 was validated as an upregulated gene in AKI in both RNA and protein level. In conclusion, by integrated analysis of different high-throughput data and validation by experiment, several crucial genes were identified in AKI, such as Havcr1, Krt20, Sox9, Egr1, Timp1, Serpine1, Edn1, and Apln. These genes were very important in the process of AKI, which could be further utilized to explore novel diagnostic and therapeutic strategies.

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“…It is used as a kidney injury biomarker because elevated urinary and serum levels of TIMP‐1 have been found in nephropathies of diverse etiologies (Hörstrup et al , ). This increase in its urinary levels has been associated with damage in the proximal tubule (Minowa et al , ) as well as collecting ducts (renal papilla) (Uehara et al , ). TIMP‐1 has also been detected in amniotic and extra‐embryonic fluids from human and rabbit origin.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of kidney injury biomarkers in rat amniotic fluid after gestational exposure to cadmium

Jacobo-Estrada

Cárdenas-González

Santoyo-Sánchez

et al. 2016

J of Applied Toxicology

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Cadmium is a well-characterized nephrotoxic agent that is also capable of accumulating and diffusing across the placenta; however, only a few studies have addressed its effects over fetal kidneys and none of them has used a panel of sensitive and specific biomarkers for the detection of kidney injury. The goal of this study was to determine cadmium renal effects in rat fetuses by the quantification of early kidney injury biomarkers. Pregnant Wistar rats were exposed by inhalation to an isotonic saline solution or to CdCl2 solution (DDel =1.48 mg Cd kg(-1) day(-1) ) during gestational days (GD) 8-20. On GD 21, dams were euthanized and samples obtained. Kidney injury biomarkers were quantified in amniotic fluid samples and fetal kidneys were microscopically evaluated to search for histological alterations. Our results showed that cadmium exposure significantly raised albumin, osteopontin, vascular endothelial growth factor and tissue inhibitor of metalloproteinases-1 levels in amniotic fluid, whereas it decreased creatinine. Clusterin, calbindin and IFN-inducible protein 10 did not show any change. Accordingly, histological findings showed tubular damage and precipitations in the renal pelvis. In conclusion, gestational exposure to cadmium induces structural alterations in fetal renal tissue that can be detected by some kidney injury biomarkers in amniotic fluid samples. Copyright © 2016 John Wiley & Sons, Ltd.

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Toxicogenomic biomarkers for renal papillary injury in rats

Cited by 11 publications

References 18 publications

The kidney‐specific expression of genes can be modulated by the extracellular osmolality

The kidney‐specific expression of genes can be modulated by the extracellular osmolality

Identification and Validation of Potential Biomarkers and Their Functions in Acute Kidney Injury

Evaluation of kidney injury biomarkers in rat amniotic fluid after gestational exposure to cadmium

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