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

A. Stavniichuk, O. Savchuk, Abdul Hye Khan, Wojciech K. Jankiewicz, John D. Imig, Daniel Merk
Taras Shevchenko National University of Kyiv, Kyiv; Taras Shevchenko National University of Kyiv, Kyiv; Department of Pharmacology & Toxicology The Medical College of Wisconsin, Milwaukee, WI; Department of Pharmacology & Toxicology The Medical College of Wisconsin, Milwaukee, WI; Department of Pharmacology & Toxicology The Medical College of Wisconsin, Milwaukee, WI; Institute of Pharmaceutical Chemistry, Goethe-University of Frankfurt, Frankfurt am Main

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.

Keywords


soluble epoxide hydrolase inhibitor, farnesoid x receptor agonist, kidney fibrosis

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Rece ed in the editorial: 16.01.2020

Received are vised version: 17.02.2019

Signed in the press: 17.02.2019




DOI: http://dx.doi.org/10.17721/1728_2748.2020.80.10-15

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