title: Advanced oxidation protein products decrease the expression of calcium transport channels in small intestinal epithelium via the p44/42 MAPK signaling pathway.
abstract: Advanced oxidation protein products (AOPPs), novel protein markers of oxidative damage, accumulate in the plasma of patients with inflammatory bowel disease (IBD). Osteoporosis, which is closely related to the regulation of intestinal calcium transport channels (CTCs), is a prevalent extraintestinal complication of IBD and is associated with oxidative stress. However, the underlying mechanisms are unknown. The present study aimed to verify whether AOPPs inhibit CTCs in the small intestinal epithelium and to identify the underlying mechanisms that may contribute to IBD-associated osteoporosis. Normal Sprague-Dawley rats were treated with AOPP-modified rat serum albumin. The calcium ion level in serum was not significantly altered, while the duodenal expression of CTCs (e.g. transient receptor potential vanilloid [TRPV6], calbindin-D9k [CaBP-D9k], plasma membrane Ca(2+)-ATPase 1 [PMCA1], and Na(+)/Ca(2+) exchanger 1 [NCX1]) were decreased. In contrast, the levels of the related hormones that regulate calcium absorption including parathyroid hormone (PTH), 25-(OH)D₃, and 1,25-(OH)₂D₃ were increased, although the trend toward an increase in PTH levels was not significant. In order to further investigate the effects of AOPP exposure, we also evaluated the expression of CTCs (including the voltage-dependent L-type calcium channel [CaV1.3], TRPV6, CaBP-D9k, PMCA1, and NCX1) in cultured human colorectal adenocarcinoma cells (Caco-2). The expression levels of total CTC protein and mRNA, except for CaV1.3, were significantly down-regulated in a concentration- and time-dependent manner. Moreover, phosphorylation of p44/42 mitogen-activated protein kinase (MAPK) was observed in vivo and in vitro. The p44/42 inhibitor U0126 reversed the down-regulation of CTCs induced by AOPPs in the Caco-2 monolayer. Our results indicate that AOPPs down-regulate the expression of CTCs through p44/42 MAPK signaling mechanisms in the small intestinal epithelium. These data provide new insights regarding the molecular basis of AOPP-induced reductions in intestinal CTCs, and are relevant to understanding the mechanisms of IBD-associated osteoporosis. Further studies are needed to explore these mechanisms in greater detail.
authors: Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, China.
authors: Peiqun
authors: P
authors: Wu
authors: Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, China.
authors: Fang
authors: F
authors: Xie
authors: Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, China.
authors: Minmin
authors: M
authors: Xue
authors: Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, China.
authors: Xiaoping
authors: X
authors: Xu
authors: Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, China.
authors: Shuying
authors: S
authors: He
authors: Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, China.
authors: Minyi
authors: M
authors: Lin
authors: Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, China; Department of Huiqiao Building, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, China. Electronic address: bailan9@126.com.
authors: Lan
authors: L
authors: Bai
mesh_terms: D062107:Advanced Oxidation Protein Products / Q000378:metabolism*; D000818:Animals; D002070:Butadienes / Q000494:pharmacology; D018938:Caco-2 Cells; D002118:Calcium / Q000097:blood; D015220:Calcium Channels / Q000378:metabolism*; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism*; D007421:Intestine, Small / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009570:Nitriles / Q000494:pharmacology; D010281:Parathyroid Hormone / Q000097:blood; D010766:Phosphorylation; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction
chemical_list: D062107:Advanced Oxidation Protein Products; D002070:Butadienes; D015220:Calcium Channels; D004791:Enzyme Inhibitors; D009570:Nitriles; D010281:Parathyroid Hormone; C113580:U 0126; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D002118:Calcium
keywords: Advanced oxidation protein products; Calcium; Calcium transport channels; Intestinal epithelium; Mitogen-activated protein kinase