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Tonicity-responsive microRNAs contribute to the maximal induction of osmoregulatory transcription factor OREBP in response to high-NaCl hypertonicity.

ABSTRACT: Osmotic response element binding protein (OREBP) is a Rel-like transcription factor critical for cellular osmoresponses. Previous studies suggest that hypertonicity-induced accumulation of OREBP protein might be mediated by transcription activation as well as posttranscriptional mRNA stabilization or increased translation. However, the underlying mechanisms remain incompletely elucidated. Here, we report that microRNAs (miRNAs) play critical regulatory roles in hypertonicity-induced induction of OREBP. In renal medullary epithelial mIMCD3 cells, hypertonicity greatly stimulates the activity of the 3'-untranslated region of OREBP (OREBP-3'UTR). Furthermore, overexpression of OREBP-3'UTR or depletion of miRNAs by knocking-down Dicer greatly increases OREBP protein expression. On the other hand, significant alterations in miRNA expression occur rapidly in response to high NaCl exposure, with miR-200b and miR-717 being most significantly down-regulated. Moreover, increased miR-200b or miR-717 causes significant down-regulation of mRNA, protein and transcription activity of OREBP, whereas inhibition of miRNAs or disruption of the miRNA-3'UTR interactions abrogates the silencing effects. In vivo in mouse renal medulla, miR-200b and miR-717 are found to function to tune OREBP in response to renal tonicity alterations. Together, our results support the notion that miRNAs contribute to the maximal induction of OREBP to participate in cellular responses to osmotic stress in mammalian renal cells.

SUBMITTER: Huang W

PROVIDER: S-EPMC3025551 | biostudies-literature | 2011 Jan

REPOSITORIES: biostudies-literature

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Tonicity-responsive microRNAs contribute to the maximal induction of osmoregulatory transcription factor OREBP in response to high-NaCl hypertonicity.

Huang Weifeng W Liu Huili H Wang Tao T Zhang Tiantian T Kuang Juntao J Luo Yu Y Chung Stephen S M SS Yuan Li L Yang James Y JY

Nucleic acids research 20100917 2

Osmotic response element binding protein (OREBP) is a Rel-like transcription factor critical for cellular osmoresponses. Previous studies suggest that hypertonicity-induced accumulation of OREBP protein might be mediated by transcription activation as well as posttranscriptional mRNA stabilization or increased translation. However, the underlying mechanisms remain incompletely elucidated. Here, we report that microRNAs (miRNAs) play critical regulatory roles in hypertonicity-induced induction of ...[more]

PMID: 20852262

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Project description:The air-breathing singhi catfish (Heteropneustes fossilis) is frequently being challenged by different environmental insults such as hyper-ammonia, dehydration and osmotic stresses in their natural habitats throughout the year. The present study investigated the effect of hyperosmotic stress, due to exposure to hypertonic environment (300 mM mannitol) for 14 days, on gluconeogenesis in this catfish. In situ exposure to hypertonic environment led to significant stimulation of gluconeogenic fluxes from the perfused liver after 7 days of exposure, followed by further increase after 14 days in presence of three different potential gluconeogenic substrates (lactate, pyruvate and glutamate). Environmental hypertonicity also caused a significant increase of activities of key gluconeogenic enzymes, namely phosphoenolpyruvate carboxykinase, fructose 1, 6-bisphosphatase and glucose 6-phosphatase by about 2-6 fold in liver, and 3-6 fold in kidney tissues. This was accompanied by more abundance of enzyme proteins by about 1.8-3.7 fold and mRNAs by about 2.2-5.2 fold in both the tissues with a maximum increase after 14 days of exposure. Hence, the increase in activities of key gluconeogenic enzymes under hypertonic stress appeared to be as a result of transcriptional regulation of genes. Immunocytochemical analysis further confirmed the tissue specific localized expression of these enzymes in both the tissues with the possibility of expressing more in the same localized places. The induction of gluconeogenesis during exposure to environmental hypertonicity possibly occurs as a consequence of changes in hydration status/cell volume of different cell types. Thus, these adaptational strategies related to gluconeogenesis that are observed in this catfish under hypertonic stress probably help in maintaining glucose homeostasis and also for a proper energy supply to support metabolic demands mainly for ion transport and other altered metabolic processes under various environmental hypertonic stress-related insults.

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Tonicity-responsive microRNAs contribute to the maximal induction of osmoregulatory transcription factor OREBP in response to high-NaCl hypertonicity.

Publications

Tonicity-responsive microRNAs contribute to the maximal induction of osmoregulatory transcription factor OREBP in response to high-NaCl hypertonicity.

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