Identification of urinary miRNA biomarkers for detecting cisplatin-induced proximal tubular injury in rats

Kanki, Masayuki; Moriguchi, Akira; Sasaki, Daisuke; Mitori, Hikaru; Yamada, Atsushi; Unami, Akira; Miyamae, Yoichi

doi:10.1016/j.tox.2014.05.004

Cited by 81 publications

(63 citation statements)

References 36 publications

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“…More recently, Vaidya and colleagues (17) reported that cisplatin induced more severe AKI in miR-155-deficient mice, suggesting an important role of miR-155 in renoprotection. In addition, multiple microRNAs have been identified to correlate with the development of cisplatin nephrotoxicity and thus have the potential to be diagnostic biomarkers (18,19). Our current study initially examined the effect of overall depletion of microRNA by using the PTDicer KO mouse model (Fig.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-375 Is Induced in Cisplatin Nephrotoxicity to Repress Hepatocyte Nuclear Factor 1-β

Hao

Lou

Wei

et al. 2017

Journal of Biological Chemistry

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Edited by Joel GottesfeldNephrotoxicity is a major adverse effect of cisplatin-mediated chemotherapy in cancer patients. The pathogenesis of cisplatininduced nephrotoxicity remains largely unclear, making it difficult to design effective renoprotective approaches. Here, we have examined the role of microRNAs (miRNAs) in cisplatininduced nephrotoxicity. We show that cisplatin nephrotoxicity was not affected by overall depletion of both beneficial and detrimental miRNAs from kidney proximal tubular cells in mice in which the miRNA-generating enzyme Dicer had been conditionally knocked out. To identify miRNAs involved in cisplatin nephrotoxicity, we used microarray analysis to profile miRNA expression and identified 47 up-regulated microRNAs and 20 down-regulated microRNAs in kidney cortical tissues. One upregulated miRNA was miR-375, whose expression was also induced in cisplatin-treated renal tubular cells. Interestingly, inhibition of miR-375 decreased cisplatin-induced apoptosis, suggesting that miR-375 is a cell-damaging or pro-apoptotic agent. Blockade of P53 or NF-B attenuated cisplatin-induced miR-375 expression, supporting a role of P53 and NF-B in miR-375 induction. We also identified hepatocyte nuclear factor 1 homeobox B (HNF-1␤) as a key downstream target of miR-375. Of note, we further demonstrated that HNF-1␤ protected renal cells against cisplatin-induced apoptosis. Together, these results suggest that upon cisplatin exposure, P53 and NF-B collaboratively induce miR-375 expression, which, in turn, represses HNF-1␤ activity, resulting in renal tubular cell apoptosis and nephrotoxicity.

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Section: Discussionmentioning

confidence: 99%

MicroRNA-375 Is Induced in Cisplatin Nephrotoxicity to Repress Hepatocyte Nuclear Factor 1-β

Hao

Lou

Wei

et al. 2017

Journal of Biological Chemistry

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“…While urine is beginning to be more widely used (Yang et al, 2012; Kanki et al, 2014; Yang et al, 2015), field-collected samples are still rarely measured. In this study, we were able to successfully isolate and quantify miRNA expression in field collected urine samples that had be archived in our biorepository.…”

Section: Discussionmentioning

confidence: 99%

Urinary microRNAs as potential biomarkers of pesticide exposure

Weldon

Shubin

Smith

et al. 2016

Toxicology and Applied Pharmacology

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MicroRNAs (miRNAs) are post-transcriptional regulators that silence messenger RNAs. Because miRNAs are stable at room temperature and long-lived, they have been proposed as molecular biomarkers to monitor disease and exposure status. While urinary miRNAs have been used clinically as potential diagnostic markers for kidney and bladder cancers and other diseases, their utility in non-clinical settings has yet to be fully developed. Our goal was to investigate the potential of urinary miRNAs to act as biomarkers of pesticide exposure and early biological response by identifying the miRNAs present in urine from 27 parent/child, farmworker/non-farmworker pairs (16FW/11NFW) collected during two agricultural seasons (thinning and post-harvest) and characterizing the between- and within-individual variability of these miRNA epigenetic regulators. MiRNAs were isolated from archived urine samples and identified using PCR arrays. Comparisons were made between age, households, season, and occupation. Of 384 miRNAs investigated, 297 (77%) were detectable in at least one sample. Seven miRNAs were detected in at least 50% of the samples, and one miRNA was present in 96% of the samples. Principal components and hierarchical clustering analyses indicate significant differences in miRNA profiles between farmworker and non-farmworker adults as well as between seasons. Six miRNAs were observed to be positively associated with farmworkers status during the post-harvest season. Expression of five of these miRNA trended towards a positive dose response relationship with organophosphate pesticide metabolites in farmworkers. These results suggest that miRNAs may be novel biomarkers of pesticide exposure and early biological response.

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“…In particular, miRNA122 is increased after hepatocellular damage in vivo and in vitro (26,27). With regard to the kidney, some studies indicate that miRNAs may be suitable urinary biomarkers for the detection of drug-induced nephrotoxicity (28,29).…”

Section: Introductionmentioning

confidence: 99%

“…Moderate upregulation of mir-21 decreases cell death but massive overexpression may lead to increased cell death, resulting in severe inflammation and fibrosis (30). mir-29a and mir-192 are highly expressed in the kidney, including PTEC, and their expression is regulated by TGF-β1 (29,31); mir-34a, on the other hand, has been related to apoptosis during disease and nephrotoxicity (32,33).…”

Section: Introductionmentioning

confidence: 99%

Combining Extracellular miRNA Determination with Microfluidic 3D Cell Cultures for the Assessment of Nephrotoxicity: a Proof of Concept Study

Suter‐Dick

Mauch

Ramp

et al. 2018

AAPS J

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Abstract.Drug-induced kidney injury is often observed in the clinics and can lead to longterm organ failure. In this work, we evaluated a novel in vitro system that aims at detecting whether compounds can cause renal proximal tubule damage in man. For this, we implemented organotypic cultures of human conditionally immortalized proximal tubule epithelial cells overexpressing the organic anion transporter 1 (ciPTEC-OAT1) in a threechannel OrganoPlate under microfluidic conditions. Cells were exposed to four known nephrotoxicants (cisplatin, tenofovir, cyclosporine A, and tobramycin). The effect on cell viability and NAG release into the medium was determined. A novel panel of four miRNAs (mir-21, mir-29a, mir-34a, and mir-192) was selected as potential biomarkers of proximal tubule damage. After nephrotoxicant treatment, miRNA levels in culture medium were earlier indicators than cell viability (WST-8 assay) and outperformed NAG for proximal tubule damage. In particular, mir-29a, mir-34a, and mir-192 were highly reproducible between experiments and across compounds, whereas mir-21 showed more variability. Moreover, similar data were obtained in two different laboratories, underlining the reproducibility and technical transferability of the results, a key requirement for the implementation of novel biomarkers. In conclusion, the selected miRNAs behaved like sensitive biomarkers of damage to tubular epithelial cells caused by several nephrotoxicity mechanisms. This biomarker panel, in combination with the 3D cultures of ciPTEC-OAT1 in the OrganoPlate, represents a novel tool for in vitro nephrotoxicity detection. These results pave the way for the application of miRNAs in longitudinal, time-course in vitro toxicity studies.

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Identification of urinary miRNA biomarkers for detecting cisplatin-induced proximal tubular injury in rats

Cited by 81 publications

References 36 publications

MicroRNA-375 Is Induced in Cisplatin Nephrotoxicity to Repress Hepatocyte Nuclear Factor 1-β

MicroRNA-375 Is Induced in Cisplatin Nephrotoxicity to Repress Hepatocyte Nuclear Factor 1-β

Urinary microRNAs as potential biomarkers of pesticide exposure

Combining Extracellular miRNA Determination with Microfluidic 3D Cell Cultures for the Assessment of Nephrotoxicity: a Proof of Concept Study

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