Salt stress in the renal tubules is Linked to TAL specific expression of uromodulin and an upregulation of heat shock genes

Lesley A. Graham (Lead / Corresponding author), Alisha Aman, Desmond D. Campbell, Julian Augley, Delyth Graham, Martin W. McBride, Niall J. Fraser, Nicholas R. Ferreri, Anna F. Dominiczak, Sandosh Padmanabhan

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    Abstract

    Previously, our comprehensive cardiovascular characterisation study validated Uromodulin as a blood pressure gene. Uromodulin is a glycoprotein exclusively synthesised at the thick ascending limb of the loop of Henle and is encoded by the Umod gene. Umod-/- mice have significantly lower blood pressure than Umod+/+ mice, are resistant to salt-induced changes in blood pressure, and show a leftward shift in pressure-natriuresis curves reflecting changes of sodium reabsorption. Salt stress triggers transcription factors and genes that alter renal sodium reabsorption. To date there are no studies on renal transcriptome responses to salt stress. Here we aimed to delineate salt stress pathways in tubules isolated from Umod+/+ mice (a model of sodium retention) and Umod-/- mice (a model of sodium depletion) ±300mOsmol sodium chloride (n=3 per group) performing RNA-Seq. In response to salt stress, the tubules of Umod+/+ mice displayed an up regulation of heat shock transcripts. The greatest changes occurred in the expression of: Hspa1a (Log2 fold change 4.35, p=2.48e-12) and Hspa1b (Log2 fold change 4.05, p=2.48e-12). This response was absent in tubules of Umod-/- mice. Interestingly, 7 of the genes discordantly expressed in the Umod-/- tubules were electrolyte transporters. Our results are the first to show that salt stress in renal tubules alters the transcriptome, increasing the expression of heat shock genes. This direction of effect in Umod+/+ tubules suggest the difference is due to the presence of Umod facilitating greater sodium entry into the tubule cell reflecting a specific response to salt stress.

    Original languageEnglish
    Pages (from-to)964-972
    Number of pages9
    JournalPhysiological Genomics
    Volume50
    Issue number11
    Early online date14 Sep 2018
    DOIs
    Publication statusPublished - 1 Nov 2018

    Fingerprint

    Uromodulin
    Shock
    Up-Regulation
    Salts
    Hot Temperature
    Kidney
    Sodium
    Genes
    Blood Pressure
    Transcriptome
    Loop of Henle
    Natriuresis
    Sodium Chloride
    Electrolytes
    Glycoproteins
    Transcription Factors
    RNA
    Pressure

    Keywords

    • heat shock
    • RNA-Seq
    • salt stress
    • sodium
    • uromodulin
    • thick ascending limb of the loop of Henle

    Cite this

    Graham, L. A., Aman, A., Campbell, D. D., Augley, J., Graham, D., McBride, M. W., ... Padmanabhan, S. (2018). Salt stress in the renal tubules is Linked to TAL specific expression of uromodulin and an upregulation of heat shock genes. Physiological Genomics, 50(11), 964-972. https://doi.org/10.1152/physiolgenomics.00057.2018
    Graham, Lesley A. ; Aman, Alisha ; Campbell, Desmond D. ; Augley, Julian ; Graham, Delyth ; McBride, Martin W. ; Fraser, Niall J. ; Ferreri, Nicholas R. ; Dominiczak, Anna F. ; Padmanabhan, Sandosh. / Salt stress in the renal tubules is Linked to TAL specific expression of uromodulin and an upregulation of heat shock genes. In: Physiological Genomics. 2018 ; Vol. 50, No. 11. pp. 964-972.
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    abstract = "Previously, our comprehensive cardiovascular characterisation study validated Uromodulin as a blood pressure gene. Uromodulin is a glycoprotein exclusively synthesised at the thick ascending limb of the loop of Henle and is encoded by the Umod gene. Umod-/- mice have significantly lower blood pressure than Umod+/+ mice, are resistant to salt-induced changes in blood pressure, and show a leftward shift in pressure-natriuresis curves reflecting changes of sodium reabsorption. Salt stress triggers transcription factors and genes that alter renal sodium reabsorption. To date there are no studies on renal transcriptome responses to salt stress. Here we aimed to delineate salt stress pathways in tubules isolated from Umod+/+ mice (a model of sodium retention) and Umod-/- mice (a model of sodium depletion) ±300mOsmol sodium chloride (n=3 per group) performing RNA-Seq. In response to salt stress, the tubules of Umod+/+ mice displayed an up regulation of heat shock transcripts. The greatest changes occurred in the expression of: Hspa1a (Log2 fold change 4.35, p=2.48e-12) and Hspa1b (Log2 fold change 4.05, p=2.48e-12). This response was absent in tubules of Umod-/- mice. Interestingly, 7 of the genes discordantly expressed in the Umod-/- tubules were electrolyte transporters. Our results are the first to show that salt stress in renal tubules alters the transcriptome, increasing the expression of heat shock genes. This direction of effect in Umod+/+ tubules suggest the difference is due to the presence of Umod facilitating greater sodium entry into the tubule cell reflecting a specific response to salt stress.",
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    Graham, LA, Aman, A, Campbell, DD, Augley, J, Graham, D, McBride, MW, Fraser, NJ, Ferreri, NR, Dominiczak, AF & Padmanabhan, S 2018, 'Salt stress in the renal tubules is Linked to TAL specific expression of uromodulin and an upregulation of heat shock genes', Physiological Genomics, vol. 50, no. 11, pp. 964-972. https://doi.org/10.1152/physiolgenomics.00057.2018

    Salt stress in the renal tubules is Linked to TAL specific expression of uromodulin and an upregulation of heat shock genes. / Graham, Lesley A. (Lead / Corresponding author); Aman, Alisha; Campbell, Desmond D.; Augley, Julian; Graham, Delyth; McBride, Martin W.; Fraser, Niall J.; Ferreri, Nicholas R.; Dominiczak, Anna F.; Padmanabhan, Sandosh.

    In: Physiological Genomics, Vol. 50, No. 11, 01.11.2018, p. 964-972.

    Research output: Contribution to journalArticle

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    AU - Graham, Lesley A.

    AU - Aman, Alisha

    AU - Campbell, Desmond D.

    AU - Augley, Julian

    AU - Graham, Delyth

    AU - McBride, Martin W.

    AU - Fraser, Niall J.

    AU - Ferreri, Nicholas R.

    AU - Dominiczak, Anna F.

    AU - Padmanabhan, Sandosh

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    KW - sodium

    KW - uromodulin

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