Intestinal renin-angiotensin system is stimulated after deletion of Lkb1

Boris Y. Shorning, Thierry Jardé, Afshan McCarthy, Alan Ashworth, Wendy W J De Leng, George Johan A Offerhaus, Nicoletta Resta, Trevor Dale, Alan R. Clarke

Research output: Contribution to journalArticle

Abstract

Background and aims: LKB1 is a serine-threonine kinase, mutation of which can lead to the development of multiple benign intestinal hamartomas (PeutzeJeghers 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 cryptevillus 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 PeutzeJeghers 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.

Original languageEnglish (US)
Pages (from-to)202-213
Number of pages12
JournalGut
Volume61
Issue number2
DOIs
StatePublished - Feb 2012
Externally publishedYes

Fingerprint

Organoids
Intestinal Mucosa
Renin-Angiotensin System
Renin
Angiotensin II
Angiotensin Type 1 Receptor
Up-Regulation
Food
Angiotensinogen
Hamartoma
MAP Kinase Signaling System
Protein-Serine-Threonine Kinases
Captopril
Microarray Analysis
Angiotensin-Converting Enzyme Inhibitors
Intestines
Cues
Neoplasms
Peptide Hydrolases
Apoptosis

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Shorning, B. Y., Jardé, T., McCarthy, A., Ashworth, A., De Leng, W. W. J., Offerhaus, G. J. A., ... Clarke, A. R. (2012). Intestinal renin-angiotensin system is stimulated after deletion of Lkb1. Gut, 61(2), 202-213. https://doi.org/10.1136/gutjnl-2011-300046

Intestinal renin-angiotensin system is stimulated after deletion of Lkb1. / Shorning, Boris Y.; Jardé, Thierry; McCarthy, Afshan; Ashworth, Alan; De Leng, Wendy W J; Offerhaus, George Johan A; Resta, Nicoletta; Dale, Trevor; Clarke, Alan R.

In: Gut, Vol. 61, No. 2, 02.2012, p. 202-213.

Research output: Contribution to journalArticle

Shorning, BY, Jardé, T, McCarthy, A, Ashworth, A, De Leng, WWJ, Offerhaus, GJA, Resta, N, Dale, T & Clarke, AR 2012, 'Intestinal renin-angiotensin system is stimulated after deletion of Lkb1', Gut, vol. 61, no. 2, pp. 202-213. https://doi.org/10.1136/gutjnl-2011-300046
Shorning BY, Jardé T, McCarthy A, Ashworth A, De Leng WWJ, Offerhaus GJA et al. Intestinal renin-angiotensin system is stimulated after deletion of Lkb1. Gut. 2012 Feb;61(2):202-213. https://doi.org/10.1136/gutjnl-2011-300046
Shorning, Boris Y. ; Jardé, Thierry ; McCarthy, Afshan ; Ashworth, Alan ; De Leng, Wendy W J ; Offerhaus, George Johan A ; Resta, Nicoletta ; Dale, Trevor ; Clarke, Alan R. / Intestinal renin-angiotensin system is stimulated after deletion of Lkb1. In: Gut. 2012 ; Vol. 61, No. 2. pp. 202-213.
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