The effect of compound DM509 on kidney fibrosis in the conditions of the experimental model

Abstract

Kidney fibrosis is a key event in the development of chronic kidney disease, leading to end-stage renal failure. Unfortunately, there are now few drugs capable of preventing fibrosis in the kidneys, which is accompanied by the progression of chronic kidney disease in the terminal stage of renal failure. The results show the effectiveness of the use of a new dual-acting agent DM509 in the prevention of renal fibrosis using a model of unilateral obstruction of the ureter in mice. DM509 is both a farnesoid X-receptor agonist and a soluble epoxyhydrolase inhibitor. In this study, there were 8-12 week old C57BL/6J males undergoing surgery, which led to the development of unilateral ureteral obstruction and a control group. Mice received DM509 (10 mg/kg/day) or DM509-free solution together with drinking water for 10 days the day before surgery. Samples of kidney and blood tissues were collected at the end of the experiment. In the unilateral ureteral obstruction group, kidney dysfunction was detected, which was accompanied by increased urea nitrogen content in the blood compared to the control group (63 ± 7 vs. 34 ± 6 mg/d). The reduction of urea nitrogen in the blood by 36 % in mice with unilateral ureteral obstruction treated with DM509 is shown compared to mice with this pathology without treatment, which in turn proved the effectiveness of DM509 in preventing renal dysfunction. In mice with unilateral ureteral obstruction, which did not receive DM509, the development of kidney fibrosis with a high content of hydroxyproline in the kidneys and also increased collagen content in histological sections of the kidneys were detected. In the DM509 group, the renal and collagen hydroxyproline content was 34-66 % lower, indicating the effectiveness of this agent in the treatment of renal fibrosis. Thus, we have shown that the new DM509 is effective in preventing renal dysfunction and renal fibrosis using a murine model of unilateral ureteral obstruction.