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
Introduction
Gastroparesis is a chronic disorder that is defined as the delayed gastric emptying of solids and liquids in the absence of physical obstruction (Parkman et al., 2004). Gastroparesis occurs in type 1 and type 2 diabetes mellitus patients (25%–55%) or can be idiopathic (Farrell and Keeffe, 1995, Kong et al., 1999, Parkman et al., 2011). Diabetic gastroparesis affects nutritional state, glycemic control and patient quality of life. Gastric motility requires interactions between smooth muscle, enteric and extrinsic autonomic nerves, and interstitial cells of Cajal (ICC) (Grover et al., 2011). Several factors contribute to gastroparesis, including acute hyperglycemia, dysregulation of gastrointestinal hormones, oxidative stress which induces the loss of neural nitric oxide synthase (nNOS) expression in the myenteric plexus and ICC network disturbances (Farrugia, 2008). Recent studies have been focused on the mechanism underlying ICC loss in diabetic gastroparesis.
ICC play critical roles in gastric motility, and damage to the ICC network is likely to contribute to gastropathy and gastroparesis (Vanormelingen et al., 2013). Stem cell factor (SCF)-Kit signaling is important for the maintenance of ICC phenotypes, proliferation, and differentiation (Torihashi et al., 1999). Membrane-bound SCF (mSCF) expressed by gastric smooth muscle cells (GSMCs) has been linked to smooth muscle myopathy and ICC depletion in murine diabetic gastroparesis. Exogenous SCF partially reverses the pathological changes in ICC in diabetic mice (Horváth et al., 2006).
With the exception of classical RAS, local RAS is present in various tissues, including kidney, brain, heart, and pancreas. Ang I can be converted to Ang II by angiotensin-converting enzyme (ACE) and then act on the angiotensin type 1 and 2 receptors (AT1R and AT2R) (de Gasparo et al., 2000, Touyz and Schiffrin, 2000). It is well known that angiotensin II (Ang II) is associated with increased gene expression and the production of growth factors, such as endothelial growth factor (EGF), platelet-derived growth factor (PDGF), insulin-like growth factor-1 (IGF-1), and platelet activating factor (PAF) (Ohtsu et al., 2006, Pan et al., 2010). Therefore, we hypothesized that Ang II might be involved in the production of mSCF. Different signal transduction cascades have been implicated in Ang II-mediated cell growth and migration, such as the mitogen-activated protein kinase (MAPK) cascade and the phosphatidylinositol 3-kinase (PI3K) pathways (Chiou et al., 2011). It has been reported that hyperglycemia caused by streptozotocin (STZ) strongly increases AT1 receptor expression in rat kidney and bladder (Harrison-Bernard et al., 2002, Tobu et al., 2012), but reports detailing its actions in the gastrointestinal tracts of diabetic mice are lacking. Our previous study showed that Ang II is an excitatory regulator of gastric motility (Lu et al., 2011). The presence of Ang II receptors at various levels of the gastrointestinal tract has been demonstrated in human, guinea pig and rat (Ino et al., 2006, Wang et al., 2005, Ewert et al., 2006). Here, we investigate the role of ACE-Ang II-AT1R alterations in diabetic gastroparesis and the Ang II signaling pathways in the production of mSCF and ICC survival.
Section snippets
Ethics
This study was conducted strictly according to the recommendations of the Guide for the Care and Use of Laboratory Animals of the Science and Technology Commission of P.R.C. (STCC Publication No. 2, revised 1988). The protocol was approved by the Committee on the Ethics of Animal Experiments of Shanghai Jiaotong University School of Medicine (Permit Number: Hu 686-2009).
Animals and the STZ-induced diabetic mouse model
Adult male ICR mice aged 5 wks weighing 30 ± 2 g were used for this study. The mice were fasted overnight and randomly divided
Body weight and blood glucose
Mice were used at the 8th week after injection of STZ. The blood glucose levels of the diabetic mice (29.2 ± 1.4 mmol/L, n = 50) were approximately 3 times higher than those of control mice (6.8 ± 0.6 mmol/L, n = 50, p < 0.05). The body weight of diabetic mice (23 ± 1.4 g, n = 50) was significantly decreased in comparison to that of control mice (40 ± 1.2 g, n = 50, p < 0.05).
c-Kit and mSCF expression in ICC and gastric smooth muscles
The c-Kit was used as a marker of ICC to investigate whether ICC networks were disrupted in STZ-induced diabetic mice.
Discussion
It has been recognized that ICC are pacemaker cells that generate spontaneous electrical slow waves and mediate motor neurotransmission in the gastrointestinal tract (Farrugia, 2008). ICC loss is one of the histological findings in diabetic gastroparesis (Horváth et al., 2006, Ordög et al., 2000, Takayama et al., 2002). In our study, we confirmed that the number of ICC was dramatically decreased and that their networks were destroyed in STZ-induced diabetic mice (Fig. 1). ICC loss results from
Acknowledgments
This work was supported by grants from the National Natural Science Foundation of China, NSFS (13ZR1423100) and NSFC (31171107; 31071011 and 31271236) and 2014CB910303.
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