Phenotypic dissection of the mouse Ren-1(d) knockout by complementation with human renin

Charlotte Buckley (Lead / Corresponding author), Robert J. Nelson, Linda J. Mullins, Matthew G. F. Sharp, Stewart Fleming, Christopher J. Kenyon, Sabrina Semprini, Dominik Steppan, Janos Peti-Peterdi, Armin Kurtz, Helen Christian, John J. Mullins (Lead / Corresponding author)

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    Abstract

    Normal renin synthesis and secretion is important for the maintenance of juxtaglomerular apparatus architecture. Mice lacking a functional Ren-1(d) gene are devoid of renal juxtaglomerular cell granules and exhibit an altered macula densa morphology. Due to the species-specificity of renin activity, transgenic mice are ideal models for experimentally investigating and manipulating expression patterns of the human renin gene in a native cellular environment without confounding Renin-angiotensin-system interactions. A 55 kb transgene encompassing the human renin locus was crossed onto the mouse Ren-1(d)-null background, restoring granulation in juxtaglomerular cells. Correct processing of human renin in dense core granules was confirmed by immunogold labelling. After stimulation of the renin-angiotensin system, juxtaglomerular cells contained rhomboid protogranules with paracrystalline contents, dilated rough endoplasmic reticulum and electron-lucent granular structures. However, complementation of Ren-1(d-/-) mice with human renin was unable to rescue the abnormality seen in macula densa structure. The juxtaglomerular apparatus was still able to respond to tubuloglomerular feedback in isolated perfused juxtaglomerular apparatus preparations, although minor differences in glomerular tuft contractility and macula densa cell calcium handling were observed. This study reveals that the human renin protein is able to complement the mouse Ren-1(d-/-) non-granulated defect and suggests that granulopoiesis requires a structural motif that is conserved between the mouse Ren-1(d) and human renin proteins. It also suggests that the altered macula densa phenotype is related to the activity of the renin-1d enzyme in a local juxtaglomerular renin-angiotensin system.

    Original languageEnglish
    Pages (from-to)1151-1162
    Number of pages12
    JournalJournal of Biological Chemistry
    Volume293
    Issue number4
    Early online date9 Nov 2017
    DOIs
    Publication statusPublished - 26 Jan 2018

    Keywords

    • Journal article
    • Renin
    • Granulation
    • Human Renin
    • Juxtaglomerular
    • Macula Densa
    • Humans
    • Genetic Complementation Test
    • Mice, Knockout
    • Animals
    • Mice
    • Renin/biosynthesis
    • Juxtaglomerular Apparatus/enzymology
    • Transgenes

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  • Cite this

    Buckley, C., Nelson, R. J., Mullins, L. J., Sharp, M. G. F., Fleming, S., Kenyon, C. J., Semprini, S., Steppan, D., Peti-Peterdi, J., Kurtz, A., Christian, H., & Mullins, J. J. (2018). Phenotypic dissection of the mouse Ren-1(d) knockout by complementation with human renin. Journal of Biological Chemistry, 293(4), 1151-1162. https://doi.org/10.1074/jbc.RA117.000160