Abstract
Radiation-induced intestinal injuries (RIII) commonly occur in patients who suffer from pelvic or abdominal cancer. Nuclear factor-erythroid 2-related factor 2 (Nrf2) is a key transcriptional regulator of antioxidant, and the radioprotective role of Nrf2 is found in bone marrow, lung, and intestine, etc. Here, we investigated the effect of Nrf2 knockout on radiation-induced intestinal injuries using Nrf2 knockout (Nrf2−/−) mice and wild-type (Nrf2+/+) C57BL/6J mice following 13 Gy abdominal irradiation (ABI). It was found that Nrf2 knockout promoted the survival of irradiated mice, protected the crypt-villus structure of the small intestine, and elevated peripheral blood lymphocyte count and thymus coefficients. The DNA damage of peripheral blood lymphocytes and the apoptosis of intestinal epithelial cells (IECs) of irradiated Nrf2−/− mice were decreased. Furthermore, compared with that of Nrf2+/+ mice, Nrf2 knockout increased the number of Lgr5+ intestinal stem cells (ISCs) and their daughter cells including Ki67+ transient amplifying cells, Villin+ enterocytes, and lysozyme+ Paneth cells. Nuclear factor-κB (NF-κB) was accumulated in the crypt base nuclei of the small intestine, and the mRNA expression of NF-κB target genes Bcl-2, uPA, and Xiap of the small intestine from irradiated Nrf2−/− mice were increased. Collectively, Nrf2 knockout has the protective effect on small intestine damage following abdominal irradiation by prompting the proliferation and differentiation of Lgr5+ intestinal stem cells and activation of NF-κB.
Highlights
The small intestine is one of the most sensitive organs of the body to ionizing radiation (IR)
The speed of body weight recovery in Nuclear factor-erythroid 2-related factor 2 (Nrf2)−/− mice was significantly faster than that in Nrf2+/+ mice (p < 0.05) (Figure 1B). These results suggested that Nrf2 knockout improved the survival of mice treated with abdominal irradiation and their body weight recovered rapidly
The Nuclear factor-κB (NF-κB) target genes Bcl-2, uPA, and Xiap have the properties of anti-apoptosis and pro-survival. These results indicated that the activation of NF-κB and upregulation of NF-κB target genes in Nrf2−/− mice may be involved in the event that Nrf2 knockout alleviated radiation-induced intestinal injuries
Summary
The small intestine is one of the most sensitive organs of the body to ionizing radiation (IR). The major symptoms of radiation-induced intestinal injuries include diarrhea, nausea, bleeding, abdominal or rectal pain, and electrolyte loss, etc These adverse side effects of radiotherapy limit the effective radiation dosage applied to eradicate tumors. Nuclear factor-erythroid 2-related factor 2 (Nrf2), the redox sensitive transcriptional activating factor, is a member of the cap “n” collar (CnC) family that is composed of the transcription factors SKN-1, NRF1, NRF2, NFE2, NRF3, CncC, BACH1, and BACH2. These factors are characterized by a leucine zipper protein-protein dimerization domain, as well as CnC and basic domains that confer DNA binding activity [2]. Nrf heterodimerization with small musculoaponeurotic fibrosarcoma protein (sMaf) binds to cis antioxidant response elements (AREs) to govern the expression of Nrf target genes [3], which are involved in a wide range of antioxidant response and xenobiotic metabolism [4]
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