title: Targeted deletion of murine CEACAM 1 activates PI3K-Akt signaling and contributes to the expression of (Pro)renin receptor via CREB family and NF-κB transcription factors.
abstract: The carcinoembryonic antigen-related cell adhesion molecule 1 regulates insulin sensitivity by promoting hepatic insulin clearance. Mice bearing a null mutation of Ceacam1 gene (Cc1(-/-)) develop impaired insulin clearance followed by hyperinsulinemia and insulin resistance, in addition to visceral obesity and increased plasma fatty acids. Because insulin resistance is associated with increased blood pressure, we investigated whether they develop higher blood pressure with activated renal renin-angiotensin system and whether this is mediated, in part, by the upregulation of renal (pro)renin receptor (PRR) expression. Compared with age-matched wild-type littermates, Cc1(-/-) mice exhibited increased blood pressure with increased activation of renal renin-angiotensin systems and renal PRR expression. Cytoplasmic and nuclear immunostaining of phospho-PI3K p85α and phospho-Akt was enhanced in the kidney of Cc1(-/-) mice. In murine renal inner medullary collecting duct epithelial cells with lentiviral-mediated small hairpin RNA knockdown of carcinoembryonic antigen-related cell adhesion molecule 1, PRR expression was upregulated and phosphorylation of PI3K (Tyr508), Akt (Ser473), NF-κB p65 (Ser276), cAMP response element-binding protein/activated transcription factor (ATF)-1 (Ser133), and ATF-2 (Thr71) was enhanced. Inhibiting PI3K with LY294002 or Akt with Akt inhibitor VIII attenuated PRR expression. In conclusion, global null deletion of Ceacam1 caused an increase in blood pressure with increased renin-angiotensin system activation together with upregulation of PRR via PI3K-Akt activation of cAMP response element-binding protein 1, ATF-1, ATF-2, and NF-κB p65 transcription factors.
authors.affiliation: Division of Endocrinology and Metabolism, University of Virginia Health System, P.O. Box 801409, Charlottesville, VA 22908-1409, USA.
authors.forename: Jiqian
authors.initials: J
authors.lastname: Huang
authors.forename: Kelly J
authors.initials: KJ
authors.lastname: Ledford
authors.forename: William B
authors.initials: WB
authors.lastname: Pitkin
authors.forename: Lucia
authors.initials: L
authors.lastname: Russo
authors.forename: Sonia M
authors.initials: SM
authors.lastname: Najjar
authors.forename: Helmy M
authors.initials: HM
authors.lastname: Siragy
mesh_terms: D051697:Activating Transcription Factor 1 / Q000378:metabolism; D000818:Animals; D002272:Carcinoembryonic Antigen / Q000502:physiology*; D017362:Cyclic AMP Response Element-Binding Protein / Q000502:physiology*; D006973:Hypertension / Q000209:etiology; D007333:Insulin Resistance; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D011956:Receptors, Cell Surface / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D051996:Transcription Factor RelA / Q000502:physiology*; D000093342:Prorenin Receptor
chemical_list: D051697:Activating Transcription Factor 1; C497100:Atf1 protein, mouse; D002272:Carcinoembryonic Antigen; C486183:Ceacam1 protein, mouse; C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D011956:Receptors, Cell Surface; D051996:Transcription Factor RelA; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D000093342:Prorenin Receptor
keywords: (pro)renin receptor; CEACAM1; CREB protein; kidney; renin-angiotensin system