title: Up-regulation of the Ang II/AT1 receptor may compensate for the loss of gastric antrum ICC via the PI3k/Akt signaling pathway in STZ-induced diabetic mice.
abstract: The classic renin-angiotensin system (RAS) is a complex system in which angiotensin II (Ang II) has been identified as an important endogenous regulator that influences both smooth muscle contraction and cell growth. Although a local RAS is known to exist in the gastrointestinal tract, it is unclear whether Ang II is involved in the loss of gastric interstitial cells of Cajal (ICC) in diabetic mice. The present study was designed to investigate the effect of Ang II on ICC survival in streptozotocin (STZ)-induced diabetic mice. Western blot, immunofluorescence, isometric muscle recording, enzyme-linked immunosorbent assay (ELISA) and a cell counting kit-8 were used in this research. Our results demonstrate that the c-Kit and membrane-bound stem cell factor (mSCF) protein expression levels in gastric smooth muscle were decreased in STZ-induced diabetic mice. However, the angiotensin receptor type 1 (AT1R) expression levels in gastric smooth muscle and angiotensin-converting enzyme (ACE) expression levels in gastric mucosa were increased. The effect of Ang II on the tonic contraction of gastric smooth muscle was potentiated in diabetic mice, and the plasma Ang II level was enhanced. Ang II increased mSCF expression, cell proliferation, and Akt-Ser473 phosphorylation in cultured gastric smooth muscle cells (GSMCs). These effects were reduced by specific inhibitors ZD7155 (an AT1R antagonist) and LY294002 (a PI3-kinase inhibitor). Our results suggest that Ang II increases mSCF expression and cell proliferation in cultured GSMCs in a PI3K/Akt signaling-dependent manner. ACE and AT1R up-regulation in the stomach may help compensate for ICC loss in STZ-induced diabetic mice.
authors.affiliation: Department of Physiology, Shanghai Jiaotong University School of Medicine, Shanghai, 200240, China.
authors.forename: C M
authors.initials: CM
authors.lastname: Zhang
authors.affiliation: Department of Physiology, Shanghai Jiaotong University School of Medicine, Shanghai, 200240, China.
authors.forename: X
authors.initials: X
authors.lastname: Huang
authors.affiliation: Department of Physiology, Shanghai Jiaotong University School of Medicine, Shanghai, 200240, China.
authors.forename: H L
authors.initials: HL
authors.lastname: Lu
authors.affiliation: Department of Physiology, Shanghai Jiaotong University School of Medicine, Shanghai, 200240, China.
authors.forename: X M
authors.initials: XM
authors.lastname: Meng
authors.affiliation: Department of Physiology, Shanghai Jiaotong University School of Medicine, Shanghai, 200240, China.
authors.forename: D H
authors.initials: DH
authors.lastname: Liu
authors.affiliation: Department of Physiology, Chungbuk National University College of Medicine, Cheongju, Chungbuk, 361-763, Republic of Korea.
authors.forename: Young-Chul
authors.initials: YC
authors.lastname: Kim
authors.affiliation: Department of Physiology, Shanghai Jiaotong University School of Medicine, Shanghai, 200240, China. Electronic address: wenxiexu@sjtu.edu.cn.
authors.forename: W X
authors.initials: WX
authors.lastname: Xu
mesh_terms: D000804:Angiotensin II / Q000502:physiology; D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism* / Q000473:pathology; D005753:Gastric Mucosa / Q000378:metabolism; D056885:Interstitial Cells of Cajal / Q000502:physiology*; D008297:Male; D008813:Mice, Inbred ICR; D032389:Myocytes, Smooth Muscle / Q000502:physiology; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011706:Pyloric Antrum / Q000473:pathology; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013311:Streptozocin; D015854:Up-Regulation
chemical_list: D044140:Receptor, Angiotensin, Type 1; D000804:Angiotensin II; D013311:Streptozocin; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D007703:Peptidyl-Dipeptidase A
keywords: Angiotensin II; Diabetic gastroparesis; Gastric smooth muscle cells (GSMCs); Interstitial cell of Cajal (ICC); Membrane-bound stem cell factor (mSCF); Phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt)