Loss of parietal cell superoxide dismutase leads to gastric oxidative stress and increased injury susceptibility in mice

Abstract

Jones MK, Zhu E, Sarino EV, Padilla OR, Takahashi T, Shimizu T, Shirasawa T. Loss of parietal cell superoxide dismutase leads to gastric oxidative stress and increased injury susceptibility in mice. Am J Physiol Gastrointest Liver Physiol 301: G537-G546, 2011. First published June 30, 2011 doi:10.1152/ajpgi.00177.2011Mitochondrial superoxide dismutase (SOD2) prevents accumulation of the superoxide that arises as a consequence of oxidative phosphorylation. However, SOD2 is a target of oxidative/nitrosative inactivation, and reduced SOD2 activity has been demonstrated to contribute to portal hypertensive gastropathy. We investigated the consequences of gastric parietal cell-specific SOD2 deficiency on mitochondrial function and gastric injury susceptibility. Mice expressing Cre recombinase under control of the parietal cell Atpase4b gene promoter were crossed with mice harboring loxP sequences flanking the sod2 gene (SOD2 floxed mice). Cre-positive mice and Cre-negative littermates (controls) were used in studies of SOD2 expression, parietal cell function (ATP synthesis, acid secretion, and mitochondrial enzymatic activity), increased oxidative/nitrosative stress, and gastric susceptibility to acute injury. Parietal cell SOD2 deficiency was accompanied by a 20% (P Ͻ 0.05) reduction in total gastric SOD activity and a 93% (P Ͻ 0.001) reduction in gastric SOD2 activity. In SOD2-deficient mice, mitochondrial aconitase and ATP synthase activities were impaired by 36% (P Ͻ 0.0001) and 44% (P Ͻ 0.005), respectively. Gastric tissue ATP content was reduced by 34% (P Ͻ 0.002). Basal acid secretion and peak secretagogue (histamine)-induced acid secretion were reduced by 43% (P Ͻ 0.0001) and 40% (P Ͻ 0.0005), respectively. There was a fourfold (P Ͻ 0.02) increase in gastric mucosal apoptosis and 41% (P Ͻ 0.001) greater alcohol-induced gastric damage in the parietal cell SOD2-deficient mice. Our findings indicate that loss of parietal cell SOD2 leads to mitochondrial dysfunction, resulting in perturbed energy metabolism, impaired parietal cell function, and increased gastric mucosal oxidative stress. These alterations render the gastric mucosa significantly more susceptible to acute injury.

Ink4a/Arf-Dependent Loss of Parietal Cells Induced by Oxidative Stress Promotes CD44-Dependent Gastric Tumorigenesis

“…The accumulation of ROS triggers the p38 MAPK -p16 INK4a /p19 ARF signaling pathway selectively in parietal cells and the consequent induction of parietal cell loss. In fact, parietal cells have been reported to contain abundant mitochondria (32), a major source of intrinsic ROS production, and have been considered to be highly susceptible to oxidative stress (33). Together, oxidative stressdependent p38…”

Role of NRF2 in protection of the gastrointestinal tract against oxidative stress

“…( 5 ) Thus, reflux of gastric luminal acid into the esophageal lumen readily causes esophageal mucosal injury, manifested clinically as reflux esophagitis. It has been reported that H + not only injures epithelial cells, but also causes free radical generation in their mitochondria, ( 6 – 8 ) exacerbating acid-induced injury and inflammation. ( 9 ) This suggests that free radicals generated by luminal H + contribute to the pathophysiology of reflux esophagitis.…”

Profiling cellular bioenergetics, glutathione levels, and caspase activities in stomach biopsies of patients with upper gastrointestinal symptoms

“…Bioenergetic studies on the gastric epithelium are relatively limited, especially with respect to investigating human stomach diseases and the use of compound biomarkers [8,10,11,[20][21][22][23][24][25][26][27][28][29][30] . The main purpose of this study was to examine the suitability of using biochemical parameters (cellular respiration, ATP, GSH, and caspase activity) as biomarkers for the gastric mucosa.…”

“…Bioenergetics of the gastric epithelium was investigated in specimens collected from animal and human tissues [8,10,11,20] . In the bullfrog gastric mucosa, cellular mitochondrial O2 consumption was increased and cellular ATP was decreased in the presence of acetylsalicylic acid [8] .…”