title: Intestinal renin-angiotensin system is stimulated after deletion of Lkb1.
abstract: OBJECTIVE
  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.
authors.affiliation: Cardiff School of Biosciences, Cardiff University, Cardiff, UK. shorningb@cardiff.ac.uk
authors.forename: Boris Y
authors.initials: BY
authors.lastname: Shorning
authors.forename: Thierry
authors.initials: T
authors.lastname: Jardé
authors.forename: Afshan
authors.initials: A
authors.lastname: McCarthy
authors.forename: Alan
authors.initials: A
authors.lastname: Ashworth
authors.forename: Wendy W J
authors.initials: WW
authors.lastname: de Leng
authors.forename: George Johan A
authors.initials: GJ
authors.lastname: Offerhaus
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Resta
authors.forename: Trevor
authors.initials: T
authors.lastname: Dale
authors.forename: Alan R
authors.initials: AR
authors.lastname: Clarke
mesh_terms: D055372:AMP-Activated Protein Kinases; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000804:Angiotensin II / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D017353:Gene Deletion; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism*; D051379:Mice; D055262:Mucin-2 / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism*; D010580:Peutz-Jeghers Syndrome / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D012083:Renin / Q000235:genetics / Q000378:metabolism*; D012084:Renin-Angiotensin System / Q000235:genetics / Q000502:physiology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C119712:Agtrap protein, mouse; C524626:Muc2 protein, mouse; D055262:Mucin-2; D000804:Angiotensin II; D017346:Protein Serine-Threonine Kinases; C491654:Stk11 protein, mouse; D055372:AMP-Activated Protein Kinases; D007703:Peptidyl-Dipeptidase A; D012083:Renin