RU2695333C1 - Method for preventing ischemia-reperfusion renal injuries with an inhibitor of arginase ii in experiment - Google Patents

Method for preventing ischemia-reperfusion renal injuries with an inhibitor of arginase ii in experiment Download PDF

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RU2695333C1
RU2695333C1 RU2018133652A RU2018133652A RU2695333C1 RU 2695333 C1 RU2695333 C1 RU 2695333C1 RU 2018133652 A RU2018133652 A RU 2018133652A RU 2018133652 A RU2018133652 A RU 2018133652A RU 2695333 C1 RU2695333 C1 RU 2695333C1
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reperfusion
arginase
inhibitor
renal
ischemia
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Владислав Викторович Елагин
Олег Иванович Братчиков
Михаил Владимирович Покровский
Татьяна Григорьевна Покровская
Дарья Александровна Костина
Владимир Владимирович Гуреев
Михаил Викторович Корокин
Лилия Викторовна Корокина
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Федеральное государственное автономное образовательное учреждение высшего образования "Белгородский государственный национальный исследовательский университет" (НИУ "БелГУ")
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K38/00Medicinal preparations containing peptides
    • A61K38/16Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43Enzymes; Proenzymes; Derivatives thereof
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00Drugs for disorders of the urinary system
    • A61P13/12Drugs for disorders of the urinary system of the kidneys

Abstract

FIELD: medicine.SUBSTANCE: invention refers to medicine, namely to experimental pharmacology and urology, and concerns preventing ischemia-reperfusion renal injuries. For this purpose, Wistar rats 120 minutes before simulating renal ischemia by applying non-traumatic clamps on renal pedicles for 40 minutes followed by reperfusion of blood flow, arginase II KUD975 inhibitor 3 mg/kg is administered intragastrically through a probe.EFFECT: method provides effective prevention of renal ischemia-reperfusion injury, including due to endothelium-protective properties of the preparation administered at the experimentally established time.1 cl, 1 ex, 2 tbl

Description

The invention relates to medicine, in particular to experimental pharmacology and urology.

Over the past 25 years, the incidence of acute renal damage has increased 20 times and amounts to an average of 13-20% of all hospitalizations [Zamorsky II. Schudrova T.S. Linkova N.S. et al. Nephroprotective effect of the EDL peptide in acute kidney damage of various origins // Bulletin of Experimental Biology and Medicine. - 2017. - No. 3. - S. 376-381]. Along with the increase in the incidence of acute renal damage, disability and mortality from this condition increase. Ischemic damage to the kidney, aggravated subsequently by organ reperfusion, is the leading pathogenetic cause in the etiology of acute renal damage [Yankauskas S. S., Matsievsky D. D., Plotnikov E. Yu. et al. The use of high-frequency ultrasound Doppler technique for the study of renal blood flow during ischemia / reperfusion of the kidney. // Nephrology and dialysis. - 2014. - No. 1. - S. 169-173].

An important role in the pathogenesis of ischemic reperfusion damage to the kidneys is played by an enzyme that regulates the exchange of L-arginine and nitric oxide - arginase, which exists in two isoforms: arginase I and arginase II [Arginase-2 mediates renal ischemia-reperfusion injury / Raup-Konsavage WM, Gao T., Cooper TK, et al. // American Journal of Physiology-Renal Physiology. - 2017 .-- 313: 2. - F522-F534].

A known method for the prevention of ischemic-reperfusion injury of kidneys in an experiment (Arginase-2 mediates renal ischemia-reperfusion injury / Raup-Konsavage WM, Gao T., Cooper TK, et al. // American Journal of Physiology-Renal Physiology. - 2017. - 313: 2. - F522-F534), including modeling of pathology by applying atraumatic clamps to the renal legs of laboratory mice for 28 minutes. For the prevention of ischemic reperfusion injury, a single intraperitoneal administration of the non-selective arginase inhibitor S- (2-boronoethyl) -L-cysteine 18 hours before the ischemic stimulus was used. The method provides a reduction in the severity of histopathological changes, processes of oxidative stress and apoptosis, the synthesis of pro-inflammatory cytokines; increased the formation of nitric oxide and phosphorylation of eNOS, the expression of coactivator 1 alpha γ-receptor-activator of proliferation of peroxisomes and contributed to the preservation of mitochondrial ultrastructure.

The main disadvantage of this method is that for prophylaxis a non-selective inhibitor of the arginase enzyme is used as a pharmacological agnet, which reduces the activity of both arginase II and arginase I. As a result of the suppression of the activity of arginase I, side effects such as hyperammonemia, manifested in insufficiency of the urea enzyme cycle and leading to ammonia poisoning of the body, which can aggravate the symptoms of accumulation of other nitrogen metabolism products in acute renal respiration - creatinine and urea.

Closest to the claimed is a method of preventing ischemic reperfusion injury of the kidneys in the experiment (Lempiäinen J, Finckenberg P, Levijoki J, Mervaala E. AMPK activator AICAR ameliorates ischaemia reperfusion injury in the rat kidney. // British Journal of Pharmacology. - 2012. - 2012. 166 (6). - 1905-1915. Doi: 10.1111 / j.1476-5381.2012.01895.x.), Including reproduction of the pathology model by applying atraumatic clamps to the kidney legs for 40 minutes, followed by reperfusion and 5-amino administration to the laboratory animal -4-imidazolecarboxamide riboside-1-β-D-ribofuranoside at a dose of 500 mg / kg once, moreover, 5-amino-4-imidazolecarbox Mid-riboside 1-β-D-ribofuranoside administered intravenously 30 minutes before ischemia simulations and severity nephroprotective properties produce once after 24 hours of reperfusion without assessing the severity of changes in the glomeruli and morphometry.

The main disadvantage of this method is that the prevention of ischemia during histological examination is confirmed only by a semi-quantitative assessment of acute tubular necrosis without taking into account the severity of changes in the cortical substance of the kidneys, which is responsible for glomerular filtration and the lack of process evaluation on the third day of the experiment, when pathological changes reach their maximum, which is not allows you to fully talk about the effective prevention of ischemic reperfusion damage to the kidneys in the experiment.

On the other hand, 5-amino-4-imidazole carboxamide riboside-1-β-D-ribofuranoside in clinical trials of the third phase has not proved its effectiveness in ischemic and reperfusion heart injuries that have a similar pathogenesis with the studied model [Pokrywka A, Cholbinski P, Kaliszewski P, et al. Metabolic modulators of the exercise response: Doping control analysis of an agonist of the peroxisome proliferator-activated receptor δ (GW16) and 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR). - J Physiol Pharmacol. - 2014 .-- 65 (4). - 469-76.]. In addition, isoflurane, which according to the literature has nephroprotective activity, was used as an anesthetic, which could distort the results of the study [Carraretto, A.R. et al. Does propofol and isoflurane protect the kidney against ischemia / reperfusion injury during transient hyperglycemia ?. Acta Cir. Bras. [online]. 2013, vol. 28, n.3, pp. 161-166.].

The objective of the invention is to provide a more effective method of preventing ischemic reperfusion damage to the kidneys using an arginase II KUD975 inhibitor in the experiment.

This object is achieved by the fact that a method for the prevention of ischemic-reperfusion damage to the kidneys using an arginase II KUD975 inhibitor is proposed, including prophylaxis with a drug by a single administration of its solution to a white laboratory animal, followed by modeling of pathology by applying atraumatic clamps to the kidney legs for 40 minutes, followed by reperfusion blood flow in the kidneys, and Wistar white rats are used as laboratory animals as a drug and used inhibitor of arginase II KUD975, administered at a dose of 3 mg / kg intragastrically by gavage for 120 minutes to simulate ischemia, and renal protection properties evaluation performed after 24 and 72 hours of reperfusion.

The technical result of the invention is an effective method for the prevention of ischemic reperfusion damage to the kidneys using an arginase II KUD975 inhibitor in an experiment, confirmed by the results of a histological study with morphometry of the epithelial height in the proximal and distal portions of the nephron, the cross-sectional area of the renal corpuscle and vascular glomerulus.

 The substance KUD975 under study is a synthesized compound of a phenolic nature - methyl ester (2 - ((1-hydroxynaphthalen-2-yl) thio) acetyl) -D-proline.

The main advantage of the proposed method is that the introduction of an arginase II KUD975 inhibitor at a dose of 3 mg / kg once 120 minutes before the induction of ischemia leads to a pronounced prevention of ischemic reperfusion damage to the kidneys in the experiment, which is confirmed by the results of a histological study with morphometry.

The method is carried out as follows.

The experiments were carried out on 70 male Wistar rats weighing 180-220 g. For the study, rats without external signs of the disease that have passed the quarantine regimen were taken.

The choice of male rats in the experiment is associated with the presence of cyclic hormonal changes in females and the renoprotective effects in estrogens, which can affect the purity of the experiment.

Each group included 10 rats. The first group - a group of false-operated animals, the second group - with modeling of ischemic reperfusion damage to the kidneys (control, 24 hours), the third group - with modeling of ischemic reperfusion damage to the kidneys (control, 72 hours), the fourth group - with pathology correction by an arginase II inhibitor KUD975 (24 hours of reperfusion), the fifth group - with pathology correction by an arginase II inhibitor KUD975 (72 hours of reperfusion), the sixth group - with correction of pathology L-norvaline (comparison drug, 24 hours of reperfusion), the seventh group - with correction th pathology of L-norvaline (comparison drug, 72 hours of reperfusion).

Simulation of ischemic reperfusion damage to the kidneys was performed as follows: under general anesthesia (chloral hydrate, 300 mg / kg ip), median laparotomy was performed, kidney legs were isolated, and atraumatic vascular clamps were sequentially applied to both legs with an ischemic period of 40 minutes under the control of microcirculation. Then clamps were removed, the abdominal cavity was washed with 0.9% sodium chloride solution and the wound was sutured in layers. 24 or 72 hours after the experiment, the animals were euthanized, followed by kidney collection for morphological examination.

In the fourth and fifth experimental groups, animals were injected with an arginase inhibitor II KUD975 at a dose of 3 mg / kg once intragastrically through a probe 120 minutes before the application of vascular clamps. In the sixth and seventh experimental groups, animals were injected with L-norvaline at a dose of 100 mg / kg once intraperitoneally 30 minutes before the application of vascular clamps.

The severity of the protective effect was judged by the results of a histological study with morphometry of the height of the epithelium in the proximal and distal parts of the nephron, the cross-sectional area of the renal corpuscle and vascular glomerulus after 24 or 72 hours of the reperfusion period.

For histological examination, the obtained cadaver material was fixed in a 10% neutral buffered formalin solution. Upon completion of fixation, a tissue site measuring 1x1 cm was excised from the biomaterial, embedded in paraffin according to the standard method, and sections 5–7 μm thick were made.

The obtained histological sections were stained with hematoxylin and eosin, according to the method of Van Giesonn, according to Mallory.

Microscopy and photographing was carried out using an optical system consisting of a Leica CME microscope and a DCM-510 eyepiece camera. The morphometric study included the determination of the following parameters: on microphotographs using the Imago J program, we measured the height of epithelial cells in the proximal and distal parts of the nephron, measured cross-sectional area of the renal corpuscle and vascular glomerulus.

The reliability of changes in the absolute parameters was determined by the difference method of variation statistics with finding the average values of the shifts, the arithmetic mean and the probability of a possible error (p) according to Student tables. Differences were evaluated as significant at p <0.05. For calculations, we used the statistical analysis program Microsoft Excel.

EXAMPLE OF SPECIFIC PERFORMANCE

Microscopic examination of histological sections of the kidney in false-operated animals showed normal morphometric indices: the height of the epithelium in the proximal tubules was 11.28 ± 1.56 μm, in the distal tubules - 7.08 ± 1.43 μm. The cross-sectional area of the renal corpuscle and vascular glomerulus was 10318.97 ± 83.74 μm 2 and 6449.95 ± 40.42 μm 2, respectively. These indicators indicate a normal microscopic picture in the cortical and medulla of the kidneys.

One day after surgery, the height of proximal epithelial cells decreased 1.4 times in comparison with falsely operated animals. By the 3rd day, a significant (p≤0.05) decrease in height was already 1.7 times (6.56 ± 0.74 μm). In the distal parts of the nephron, a change in the height of the epithelium had the same tendency. Moreover, the maximum decrease in the height of epithelial cells by 1.7 times (p≤0.05) occurred 3 days after surgery and amounted to 4.24 ± 0.73 μm.

Regarding changes in the cross-sectional area of the renal corpuscle and vascular glomerulus, it was revealed that against the background of a slight decrease in the size of the renal corpuscle, the decrease in the parameters of the area of the vascular glomerulus was significantly (p≤0.05) less by 1.7 times, which is quite understandable by an increase in field of view of the renal corpuscle with shrunken vascular glomeruli.

Against the background of arginase II inhibitor KUD975 correction, after 24 hours of reperfusion, the epithelial height of the proximal and distal tubules increased to 9.4 ± 0.09 μm and 6.61 ± 0.09 μm, respectively. The area of the vascular glomerulus increased to 5848.69 ± 80.87 μm 2 with a parallel increase in the area of the renal body to 9929.89 ± 113 μm 2 .

Against the background of correction with L-norvaline after 24 hours of reperfusion, the epithelial height of the proximal and distal tubules increased to 8.38 ± 0.1 μm and 6.5 ± 0.08 μm, respectively. The area of the vascular glomerulus increased to 5690.58 ± 88.22 μm 2 with a parallel increase in the area of the renal corpuscle to 9882.41 ± 104.55 μm 2 .

A similar dynamics was also observed after 72 hours of reperfusion: the height of the epithelium of the proximal and distal tubules increased to 8.57 ± 0.1 μm and 6.19 ± 0.1 μm, respectively, significantly differing from the control group and L-norvaline (p≤0, 05). The area of the vascular glomerulus also increased to 4867.97 ± 62.17 μm 2 with a parallel increase in the area of the renal corpuscle to 9952.29 ± 128.88 μm 2 .

Against the background of correction with L-norvaline, after 72 hours of reperfusion, the epithelial height of the proximal and distal tubules increased to 7.98 ± 0.1 μm and 5.55 ± 0.1 μm, respectively, significantly differing from the control group (p≤0.05). The area of the vascular glomerulus increased to 4240.73 ± 54.92 μm 2 with a parallel increase in the area of the renal corpuscle to 9587.35 ± 134.13 μm 2 . The dynamics of the results of morphometry of the structures of the kidneys are presented in tables 1 and 2.

Table 1

Dynamics of the results of morphometry of the height of the tubule epithelium in the experimental groups (μm, M ± m, n = 10)

Figure 00000001

Note: a - p <0.05 in comparison with the group of false-operated animals; b - p <0.05 compared with the ischemia-reperfusion group.

table 2

Dynamics of the results of morphometry of glomerular structures in experimental groups (μm 2 , M ± m, n = 10)

Figure 00000002

Note: a - p <0.05 in comparison with the group of false-operated animals; b - p <0.05 compared with the ischemia-reperfusion group.

Thus, in the proposed method, intragastric administration of an arginase II KUD975 inhibitor at a dose of 3 mg / kg once 120 minutes before the induction of ischemia leads to a more pronounced prevention of ischemic reperfusion damage to the kidneys than administration of L-norvaline at a dose of 100 mg / kg, which is confirmed results of a histological examination with morphometry after 24 and 72 hours of the reperfusion period.

Claims (1)

  1. A method for the prevention of ischemic-reperfusion damage to the kidneys using an arginase II KUD975 inhibitor, comprising prophylaxis with a drug by a single injection of its solution in a white laboratory animal, followed by modeling of pathology by applying atraumatic clamps to the kidney legs for 40 minutes, followed by reperfusion of blood flow in the kidneys, characterized in that Wistar white rats are used as laboratory animals, an arginase II KU inhibitor is used as a medicine D975, administered at a dose of 3 mg / kg intragastrically through a probe 120 minutes before ischemia modeling, and nephroprotective properties are assessed in dynamics after 24 and 72 hours of reperfusion with the exception of side effects characteristic of small and non-selective arginase inhibitors.
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Cited By (1)

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RU2716596C1 (en) * 2019-09-06 2020-03-13 федеральное государственное бюджетное учреждение "Национальный медицинский исследовательский центр имени В.А. Алмазова" Министерства здравоохранения Российской Федерации Method for reducing the size of ischemic-reperfusion myocardial injury with the use of quinacrine

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2716596C1 (en) * 2019-09-06 2020-03-13 федеральное государственное бюджетное учреждение "Национальный медицинский исследовательский центр имени В.А. Алмазова" Министерства здравоохранения Российской Федерации Method for reducing the size of ischemic-reperfusion myocardial injury with the use of quinacrine

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