High-fat diet amplifies renal renin angiotensin system expression, blood pressure elevation, and renal dysfunction caused by Ceacam1 null deletion

• Published in: American journal of physiology: endocrinology and metabolism Vol. 309; no. 9; p. E802
• Main Authors: Li, Caixia, Culver, Silas A, Quadri, Syed, Ledford, Kelly L, Al-Share, Qusai Y, Ghadieh, Hilda E, Najjar, Sonia M, Siragy, Helmy M
• Format: Journal Article
• Language: English
• Published: United States 01-11-2015
• Subjects: Animals; Blood Pressure - drug effects; Blood Pressure - genetics; Carcinoembryonic Antigen - genetics; Diet, High-Fat; Dietary Fats - pharmacology; Disease Progression; Gene Deletion; Hypertension - genetics; Hypertension - metabolism; Hypertension - physiopathology; Kidney - drug effects; Kidney - metabolism; Kidney - physiopathology; Kidney Diseases - genetics; Kidney Diseases - metabolism; Kidney Diseases - physiopathology; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Renin-Angiotensin System - drug effects; Renin-Angiotensin System - genetics; Up-Regulation - drug effects; Up-Regulation - genetics; carcinoembryonic antigen-related cell adhesion molecule 1; kidney; phosphatidylinositol 3′-kinase; renin-angiotensin system; high-fat diet
• ISSN: 1522-1555
• DOI: 10.1152/ajpendo.00158.2015

Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAMl), a substrate of the insulin receptor tyrosine kinase, regulates insulin action by promoting insulin clearance. Global null mutation of Ceacam1 gene (Cc1(-/-)) results in features of the metabolic syndrome, including insulin resistance, hyperinsulinemia, visceral adiposity, elevated blood pressure, and albuminuria. It also causes activation of the renal renin-angiotensin system (RAS). In the current study, we tested the hypothesis that high-fat diet enhances the expression of RAS components. Three-month-old wild-type (Cc1(+/+)) and Cc1(-/-) mice were fed either a regular or a high-fat diet for 8 wk. At baseline under regular feeding conditions, Cc1(-/-) mice exhibited higher blood pressure, urine albumin-to-creatinine ratio (UACR), and renal expression of angiotensinogen, renin/prorenin, angiotensin-converting enzyme, (pro)renin receptor, angiotensin subtype AT1 receptor, angiotensin II, and elevated PI3K phosphorylation, as detected by p85α (Tyr(508)) immunostaining, inflammatory response, and the expression of collagen I and collagen III. In Cc1(+/+) mice, high-fat diet increased blood pressure, UACR, the expression of angiotensin-converting enzyme and angiotensin II, PI3K phosphorylation, inflammatory response, and the expression of collagen I and collagen III. In Cc1(-/-) mice, high-fat intake further amplified these parameters. Immunohistochemical staining showed increased p-PI3K p85α (Tyr(508)) expression in renal glomeruli, proximal, distal, and collecting tubules of Cc1(-/-) mice fed a high-fat diet. Together, this demonstrates that high-fat diet amplifies the permissive effect of Ceacam1 deletion on renal expression of all RAS components, PI3K phosphorylation, inflammation, and fibrosis.