Cardiff University | Prifysgol Caerdydd ORCA
Online Research @ Cardiff 
WelshClear Cookie - decide language by browser settings

Intestinal renin-angiotensin system is stimulated after deletion of Lkb1

Shorning, Boris, Jarde, Thierry, McCarthy, Afshan, Ashworth, Alan, de Leng, Wendy W. J., Offerhaus, George Johan A., Resta, Nicoletta, Dale, Trevor Clive and Clarke, Alan Richard 2012. Intestinal renin-angiotensin system is stimulated after deletion of Lkb1. Gut 61 (2) , pp. 202-213. 10.1136/gutjnl-2011-300046

Full text not available from this repository.

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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
European Cancer Stem Cell Research Institute (ECSCRI)
Subjects: Q Science > Q Science (General)
Q Science > QH Natural history > QH301 Biology
Q Science > QH Natural history > QH426 Genetics
Publisher: BMJ Publishing Group
ISSN: 0017-5749
Related URLs:
Last Modified: 08 Jan 2018 21:32
URI: http://orca-mwe.cf.ac.uk/id/eprint/26015

Citation Data

Cited 5 times in Google Scholar. View in Google Scholar

Cited 10 times in Scopus. View in Scopus. Powered By Scopus® Data

Actions (repository staff only)

Edit Item Edit Item