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Intestinal renin–angiotensin system is stimulated after deletion of Lkb1
  1. Boris Y Shorning1,
  2. Thierry Jardé1,
  3. Afshan McCarthy2,
  4. Alan Ashworth2,
  5. Wendy W J de Leng3,
  6. George Johan A Offerhaus3,4,
  7. Nicoletta Resta5,
  8. Trevor Dale1,
  9. Alan R Clarke1
  1. 1Cardiff School of Biosciences, Cardiff University, Cardiff, UK
  2. 2The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, UK
  3. 3Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands
  4. 4Department of Pathology, Academic Medical Center Amsterdam, Amsterdam, The Netherlands
  5. 5Dipartimento di Biomedicina dell'Età Evolutiva, Università degli Studi di Bari, Bari, Italy
  1. Correspondence to Dr Boris Y Shorning, Cardiff School of Biosciences, Cardiff University, Museum Avenue, Cardiff CF10 3AX, UK; shorningb{at}cardiff.ac.uk

Abstract

Background and aims LKB1 is a serine-threonine kinase, mutation of which can lead to the development of multiple benign intestinal hamartomas (Peutz–Jeghers syndrome). In this study, the authors investigate the mechanisms underlying this phenotype by exploring the transcriptional changes associated with Lkb1 deletion in intestinal epithelium.

Methods The authors used mice with Lkb1 deleted in the intestinal epithelium using a Cyp1a1-specific inducible Cre recombinase and used Affymetrix (Santa Clara, California, USA) microarray analysis to examine the transcriptional changes occurring immediately after Lkb1 loss. The authors also generated crypt–villus organoid culture to analyse Lkb1 role in intestinal responses to exogenous stimuli.

Results Affymetrix analysis identified the most significant change to be in Ren1 expression, a gene encoding a protease involved in angiotensinogen processing. Lkb1 deletion also enhanced ACE expression and subsequently angiotensin II (AngII) production in the mouse intestine. Intestinal apoptosis induced by Lkb1 deficiency was suppressed by ACE inhibitor captopril. Lkb1-deficient intestinal epithelium showed dynamic changes in AngII receptor type 1, suggesting a possible compensatory response to elevated AngII levels. A similar reduction in epithelial AngII receptor type 1 was also observed in human Peutz–Jeghers syndrome tumours contrasting with high expression of the receptor in the tumour stroma. Mechanistically, the authors showed two pieces of data that position Lkb1 in renin expression regulation, and they implied the importance of Lkb1 in linking cell responses with nutrient levels. First, the authors showed that Lkb1 deletion in isolated epithelial organoid culture resulted in renin upregulation only when the organoids were challenged with external cues such as AngII; second, that renin upregulation was dependent upon the MEK/ERK pathway in a circadian fashion and corresponded to active feeding time when nutrient levels were high.

Conclusions Taken together, these data reveal a novel role for Lkb1 in regulation of the gastrointestinal renin–angiotensin system.

  • Mouse intestine
  • Lkb1
  • MEK/ERK pathway
  • local renin–angiotensin system
  • apoptosis
  • array
  • cancer genetics
  • intestinal gene regulation
  • colorectal physiology
  • epithelial differentiation
  • epithelial cells
  • cell signalling
  • gastrointestinal neoplasia
  • polyposis
  • molecular carcinogenesis
  • colorectal neoplasia
  • polyposis
  • familial adenomatous polyposis
  • molecular pathology
  • Peutz–Jeghers syndrome
  • cancer genetics

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Footnotes

  • Funding Cancer Research UK, Cardiff CRUK Centre Development Fund, Breast Cancer Campaign, Breakthrough Breast Cancer, Stichting Vanderes, Dutch Digestive Disease Foundation WO 07-05; Fondazione Cassa di Risparmio di Puglia.

  • Competing interests None.

  • Ethics approval The Ethics committees of the University Medical Center Utrecht and Academic Medical Center Amsterdam, Holland as well as University of Bari (Italy) Ethics committee.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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