angiotensinogen and Crohn-Disease

Angiotensin II (AII) is a powerful splanchnic vasoconstrictor with pro-inflammatory and pro-fibrotic properties. Angiotensin converting enzyme (ACE) inhibitors and AII Receptor Antagonists (ARBs) are therapeutic in animal models of colitis. The aim of this case-control study is to determine the expression of angiotensinogen and related genes in human ileal Crohn's disease.. Using quantitative real-time polymerase chain reaction (RT-PCR), we measured mRNA expression levels of angiotensinogen (AGT), hypoxia inducible factor (HIF)1α and melanoma cell adhesion molecule (MCAM; CD146) in 101 human samples (69 biopsy, 12 resection) from affected ileum (inflamed CD cases, n=36) and unaffected ileum (non-inflamed CD cases, n=45 and controls, n=20). Immunohistochemistry for angiotensinogen was also performed. The study was of case-control design in a tertiary care setting.. Ileal expression of AGT was lower in CD cases compared to controls (p<0.0001), in inflamed CD samples (p=0.017) and current smokers (p=0.02). HIF1α expression was lower in non-inflamed CD biopsy samples than controls (p=0.006). The presence of disease-associated NOD2 variants was associated with increased expression of markers of angiogenesis (HIF1α p=0.009; MCAM p=0.007) in inflamed CD samples. Angiotensinogen immunohistochemical staining supported the quantitative RT-PCR expression findings.. Angiotensinogen expression is down regulated in human ileal CD, particularly in the presence of inflammation and current cigarette smoking, implicating the mesenteric vasculature and mucosal hypoxia as co-factors in ileal CD pathogenesis. A novel reduction in HIF1α expression in non-inflamed ileal mucosa in CD patients was also demonstrated.

Topics: Adult; Aged; Angiogenic Proteins; Angiotensinogen; Case-Control Studies; CD146 Antigen; Crohn Disease; Female; Gene Expression Regulation; Genotype; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Ileum; Immunohistochemistry; Male; Middle Aged; Neovascularization, Pathologic; Nod2 Signaling Adaptor Protein; Phenotype; Real-Time Polymerase Chain Reaction; RNA, Messenger; Smoking; Young Adult

Angiotensin peptides may act locally as cytokines in several organ systems with elevated mucosal levels present in Crohn's disease. A variant in the angiotensinogen gene promoter results in increased peptide production, while transforming growth factor beta1 (TGFbeta1) codon 25 variants demonstrate variable peptide production, predisposing to fibrosis in several organs.. Conduct an Australian-based analysis of the angiotensinogen-6 variant in two independent inflammatory bowel disease (IBD) cohorts, and examine the role of angiotensinogen-6 and TGFbeta1 codon 25 variants in shaping Crohn's disease phenotype.. IBD Patients (Crohn's disease = 347, ulcerative colitis = 147) and CD families (n = 148) from two cohorts, together with 185 healthy controls were genotyped for angiotensinogen-6. Genotype-phenotype analyses were performed for both angiotensinogen-6 and TGFbeta1 codon 25.. Angiotensinogen-6 AA genotype was significantly associated with Crohn's disease (p = 0.007, OR = 2.38, CI = 1.32-4.32) in cohort 1, but not in the smaller cohort 2 (p = 0.19). The association remained significant when the two cohorts were combined (p = 0.008), and in a TDT family analysis (p = 0.03). TGF 1 codon 25 was associated with stricturing Crohn's disease (p = 0.01, OR = 2.63, CI = 1.16-5.88) and a shorter time to intestinal resection (p = 0.06).. The association of the angiotensinogen-6 variant with Crohn's disease supports a potential role for angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonists in disease treatment.

Topics: Adolescent; Adult; Angiotensinogen; Australia; Case-Control Studies; Cohort Studies; Colitis, Ulcerative; Crohn Disease; Female; Gene Frequency; Genetic Predisposition to Disease; Genetic Variation; Genotype; Humans; Inflammatory Bowel Diseases; Linkage Disequilibrium; Male; Phenotype; Polymorphism, Genetic; Promoter Regions, Genetic; Transforming Growth Factor beta1