Identification of a novel lncRNA induced by the nephrotoxin ochratoxin A and expressed in human renal tumor tissue

Polović, Mirjana; Dittmar, Sandro; Hennemeier, Isabell; Humpf, Hans‐Ulrich; Seliger, Barbara; Fornara, Paolo; Theil, Gerit; Azinovic, Patrick; Nolze, Alexander; Köhn, Marcel; Schwerdt, Gerald; Gekle, Michael

doi:10.1007/s00018-017-2731-6

Cited by 24 publications

(12 citation statements)

References 35 publications

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“…Total RNA was isolated as described [34,35]. Sequencing of aortic samples was performed with an Illumina HiSeq2000 at the Core Unit DNA Technologies of the Medical Faculty, University of Leipzig (Leipzig, Germany).…”

Section: Next Generation Sequencing and Gene Enrichment Analysismentioning

confidence: 99%

“…Glucose consumption and lactate production were assessed using commercially available kits (Glucose [HK] assay kit, Sigma, Darmstadt, Germany and Lactate Reagent, Trinity Biotech, via Menarini Diagnostics, Berlin, Germany) according to the manufacturer's instructions [34]. Albumin was determined by ELISA (Bethyl Laboratories, Montgomery, TX, USA).…”

Section: Determination Of Albumin Creatinine Glucose and Lactatementioning

confidence: 99%

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Knockout of vascular smooth muscle EGF receptor in a mouse model prevents obesity-induced vascular dysfunction and renal damage in vivo

et al. 2020

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Aims/hypothesis Obesity causes type 2 diabetes leading to vascular dysfunction and finally renal end-organ damage. Vascular smooth muscle (VSM) EGF receptor (EGFR) modulates vascular wall homeostasis in part via serum response factor (SRF), a major regulator of VSM differentiation and a sensor for glucose. We investigated the role of VSM-EGFR during obesity-induced renovascular dysfunction, as well as EGFR–hyperglycaemia crosstalk. Methods The role of VSM-EGFR during high-fat diet (HFD)-induced type 2 diabetes was investigated in a mouse model with inducible, VSM-specific EGFR-knockout (KO). Various structural and functional variables as well as transcriptome changes, in vivo and ex vivo, were assessed. The impact of hyperglycaemia on EGFR-induced signalling and SRF transcriptional activity and the underlying mechanisms were investigated at the cellular level. Results We show that VSM-EGFR mediates obesity/type 2 diabetes-induced vascular dysfunction, remodelling and transcriptome dysregulation preceding renal damage and identify an EGFR–glucose synergism in terms of SRF activation, matrix dysregulation and mitochondrial function. EGFR deletion protects the animals from HFD-induced endothelial dysfunction, creatininaemia and albuminuria. Furthermore, we show that HFD leads to marked changes of the aortic transcriptome in wild-type but not in KO animals, indicative of EGFR-dependent SRF activation, matrix dysregulation and mitochondrial dysfunction, the latter confirmed at the cellular level. Studies at the cellular level revealed that high glucose potentiated EGFR/EGF receptor 2 (ErbB2)-induced stimulation of SRF activity, enhancing the graded signalling responses to EGF, via the EGFR/ErbB2–ROCK–actin–MRTF pathway and promoted mitochondrial dysfunction. Conclusions/interpretation VSM-EGFR contributes to HFD-induced vascular and subsequent renal alterations. We propose that a potentiated EGFR/ErbB2–ROCK–MRTF–SRF signalling axis and mitochondrial dysfunction underlie the role of EGFR. This advanced working hypothesis will be investigated in mechanistic depth in future studies. VSM-EGFR may be a therapeutic target in cases of type 2 diabetes-induced renovascular disease. Data availability The datasets generated during and/or analysed during the current study are available in: (1) share_it, the data repository of the academic libraries of Saxony-Anhalt (10.25673/32049.2); and (2) in the gene expression omnibus database with the study identity GSE144838 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE144838).

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Section: Next Generation Sequencing and Gene Enrichment Analysismentioning

confidence: 99%

Section: Determination Of Albumin Creatinine Glucose and Lactatementioning

confidence: 99%

Knockout of vascular smooth muscle EGF receptor in a mouse model prevents obesity-induced vascular dysfunction and renal damage in vivo

et al. 2020

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“…The latter play a role in gene expression regulation (as reviewed by Fernandes et al, 2019; Li et al, 2019 [50,51]) and are susceptible to environmental factors [52,53]. For instance, the transcript WISP1-AS1 was previously described as OTA-specifically induced and as involved in OTA-induced gene regulation and apoptosis [12]. In addition to providing a robust way of selecting relevant biological candidates, a network such as the one built in the present study also has the advantage of considering non-coding transcripts.…”

Section: Discussionmentioning

confidence: 99%

“…Despite this evidence, many published studies were based on experiments with higher OTA concentrations (micromolar range and even higher) and may, therefore, report unspecific toxicological reactions. We previously observed that nanomolar OTA triggers apoptosis [10], leads to gene expression dysregulation [11,12], influences signaling pathways [11,13], and can induce characteristic traits of interstitial nephritis in vitro [14]. However, the understanding of OTA nephrotoxicity following exposure to nanomolar concentrations is still limited.…”

Section: Introductionmentioning

confidence: 99%

Weighted Correlation Network Analysis Reveals CDK2 as a Regulator of a Ubiquitous Environmental Toxin-Induced Cell-Cycle Arrest

Dubourg

Nolze

Kopf

et al. 2020

Cells

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Environmental food contaminants constitute a threat to human health. For instance, the globally spread mycotoxin Ochratoxin A (OTA) contributes to chronic kidney damage by affecting proximal tubule cells via unknown mechanisms. We applied a top-down approach to identify relevant toxicological mechanisms of OTA using RNA-sequencing followed by in-depth bioinformatics analysis and experimental validation. Differential expression analyses revealed that OTA led to the regulation of gene expression in kidney human cell lines, including for genes enriched in cell cycle-related pathways, and OTA-induced gap 1 and 2 (G1 and G2) cell-cycle arrests were observed. Weighted correlation network analysis highlighted cyclin dependent kinase 2 (CDK2) as a putative key regulator of this effect. CDK2 was downregulated by OTA exposure, and its overexpression partially blocked the OTA-induced G1 but not G2 cell-cycle arrest. We, therefore, propose CDK2 as one of the key regulators of the G1 cell-cycle arrest induced by low nanomolar concentrations of OTA.

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“…Long noncoding RNAs (lncRNAs) belong to a class of regulatory noncoding RNAs with transcript lengths greater than 200 nucleotides and serve vital roles in transcriptional and posttranscriptional gene expression regulation [3,4]. Recently, dysregulation of lncRNAs has been found to be important in various human diseases, such as cancer, diabetes and cardiovascular diseases [5][6][7].…”

Section: Introductionmentioning

confidence: 99%

Integrated analysis of differentially expressed long noncoding RNAs and mRNAs associated with high-fat diet-induced hepatic insulin resistance in mice

et al. 2020

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Background: Hepatic insulin resistance (IR) is an early pathological characteristic of many metabolic diseases, such as type 2 diabetes. Long noncoding RNAs (lncRNAs) have been identified as mediators of IR and related diseases. However, the roles of lncRNAs in hepatic IR remain largely unknown. Method: High-throughput sequencing was performed on ten liver tissue samples from five normal diet (ND)-fed mice and five high-fat diet (HFD)-induced hepatic IR mice, respectively. lncRNAs and mRNAs that were differentially expressed (DE) between the two groups were identified by bioinformatic analyses. Seven DE lncRNAs were validated by quantitative real-time PCR (q-PCR). The potential functions of the DE lncRNAs were predicted by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses of target genes. In addition, integrated analysis was performed for the DE lncRNAs and mRNAs to predict their interaction relationships. Results: A total of 232 DE lncRNAs were identified in the HFD-induced hepatic IR mice compared with the ND-fed mice. These DE lncRNAs included 108 upregulated and 124 downregulated lncRNAs, and 7 of the DE lncRNAs were validated by q-PCR. In addition, 291 DE mRNAs including 166 upregulated and 125 downregulated mRNAs were identified in the HFD group. Furthermore, target genes of the DE lncRNAs were predicted, and functional enrichment results showed that the enriched genes were involved in IR-and glycolipid metabolism-related processes. Additionally, the coexpression network was also constructed to further reflect the potential functions of the DE lncRNAs. Conclusion: The study describes the expression profiles of lncRNAs and mRNAs and the functional networks involved in HFD-induced hepatic IR. These findings may provide a new perspective for the study of lncRNAs in hepatic IR-and glycolipid metabolism-related diseases.

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Identification of a novel lncRNA induced by the nephrotoxin ochratoxin A and expressed in human renal tumor tissue

Cited by 24 publications

References 35 publications

Knockout of vascular smooth muscle EGF receptor in a mouse model prevents obesity-induced vascular dysfunction and renal damage in vivo

Knockout of vascular smooth muscle EGF receptor in a mouse model prevents obesity-induced vascular dysfunction and renal damage in vivo

Weighted Correlation Network Analysis Reveals CDK2 as a Regulator of a Ubiquitous Environmental Toxin-Induced Cell-Cycle Arrest

Integrated analysis of differentially expressed long noncoding RNAs and mRNAs associated with high-fat diet-induced hepatic insulin resistance in mice

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