Stavniichuk A. Development of fibrosis and inflammation of the kidneys in mice under the conditions of the introduction of new bifunctional molecules.

The thesis is devoted to study the development of inflammation and fibrosis in the kidney using a mouse UUO model of renal fibrosis. In this thesis, studies are also carried out to investigate the anti-inflammatory and anti-fibrotic effects of sEH inhibitor, agonists of nuclear receptors (PPAR- and FXR), and the novel bifunctional molecules RB394 and DM509. Biochemical, histological and immunohistochemical data confirmed renal fibrosis from renal ECM protein accumulation and elevated renal hydroxyproline content. Renal fibrosis was accompanied by increased renal inflammation, tubular and vascular injuries and oxidative stress in the UUO mice. When we investigated RB394, our data revealed that among all the substances (sEH inhibitor, PPAR- agonist, and their combination) the novel bifunctional molecule RB394 was the most effective in reducing fibrosis, inflammation, oxidative stress, and injury in the kidney of UUO mice. We also investigated anti-inflammatory, anti-fibrotic and kidney protective effects of another bifunctional molecule DM509 in the mice with UUO. DM509 demonstrated anti-inflammatory, anti-fibrotic and kidney protective effects in UUO mice. Our findings demonstrated the development of renal inflammation and fibrosis in a UUO mice model. Most importantly, we demonstrated robust anti-fibrotic and anti-inflammatory potentials of two novel bifunctional molecules RB394 and DM509 in a mouse UUO model of renal fibrosis.