| Autor: |
Egorov ES; Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, Moscow, 119991, Russia., Kondratenko ND; Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, 119991, Russia.; Russian Clinical Research Center for Gerontology, Ministry of Health of the Russian Federation, Pirogov Russian National Research Medical University, Moscow, 129226, Russia., Averina OA; Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, 119991, Russia.; Institute of Functional Genomics, Lomonosov Moscow State University, Moscow, 119991, Russia.; Faculty of Chemistry, Lomonosov Moscow State University, Moscow, 119991, Russia., Permyakov OA; Institute of Functional Genomics, Lomonosov Moscow State University, Moscow, 119991, Russia.; Faculty of Chemistry, Lomonosov Moscow State University, Moscow, 119991, Russia., Emelyanova MA; Institute of Functional Genomics, Lomonosov Moscow State University, Moscow, 119991, Russia.; Faculty of Chemistry, Lomonosov Moscow State University, Moscow, 119991, Russia., Prikhodko AS; Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, Moscow, 119991, Russia.; Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, 119991, Russia., Zinovkina LA; Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, Moscow, 119991, Russia., Sergiev PV; Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, 119991, Russia.; Institute of Functional Genomics, Lomonosov Moscow State University, Moscow, 119991, Russia.; Faculty of Chemistry, Lomonosov Moscow State University, Moscow, 119991, Russia., Zinovkin RA; Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, 119991, Russia. roman.zinovkin@gmail.com.; HSE University, Moscow, 101000, Russia. |
| Abstrakt: |
Transcription factor NRF2 is involved in inflammatory reactions, maintenance of redox balance, metabolism of xenobiotics, and is of particular interest for studying aging. In the present work, the CRISPR/Cas9 genome editing technology was used to generate the NRF2 ΔNeh2 mice containing a substitution of eight amino acid residues at the N-terminus of the NRF2 protein, upstream of the functional Neh2 domain, which ensures binding of NRF2 to its inhibitor KEAP1. Heterozygote NRF2 wt/ΔNeh2 mice gave birth to homozygous mice with lower than expected frequency, accompanied by their increased embryonic lethality and visual signs of anemia. Mouse embryonic fibroblasts (MEFs) from the NRF2 ΔNeh2/ΔNeh2 homozygotes showed impaired resistance to oxidative stress compared to the wild-type MEFs. The tissues of homozygous NRF2 ΔNeh2/ΔNeh2 animals had a decreased expression of the NRF2 target genes: NAD(P)H:Quinone oxidoreductase-1 (Nqo1); aldehyde oxidase-1 (Aox1); glutathione-S-transferase A4 (Gsta4); while relative mRNA levels of the monocyte chemoattractant protein 1 (Ccl2), vascular cell adhesion molecule 1 (Vcam1), and chemokine Cxcl8 was increased. Thus, the resulting mutation in the Nfe2l2 gene coding for NRF2, partially impaired function of this transcription factor, expanding our insights into the functional role of the unstructured N-terminus of NRF2. The obtained NRF2 ΔNeh2 mouse line can be used as a model object for studying various pathologies associated with oxidative stress and inflammation. |
