Phenotypic dissection of the mouse Ren1d knockout by complementation with human renin

Charlotte Buckley, 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

Research output: Contribution to journalArticlepeer-review

Abstract

Normal renin synthesis and secretion is important for the maintenance of juxtaglomerular apparatus architecture. Mice lacking a functional Ren1d 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 Ren1d-null background, restoring granulation in juxtaglomerular cells. Correct processing of human renin in dense core granules was confirmed by immunogold labeling. 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 Ren1d−/− 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 Ren1d−/− non-granulated defect and suggests that granulopoiesis requires a structural motif that is conserved between the mouse Ren1d 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
DOIs
Publication statusPublished - 26 Jan 2018

Keywords

  • granulation
  • human renin
  • juxtaglomerular
  • macula densa
  • renin
  • renin angiotensin system
  • electron microscopy (EM)
  • confocal microscopy
  • immunochemistry
  • mouse
  • secretion
  • animal model
  • transgenic mice

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