Effect of Carnosine on the Activity of Matrix Metalloproteinase-2 and Oxidative Stress in the Kidneys in Experimental Urate Nephrolithiasis.

The effect of carnosine on MMP-2 activity and oxidative stress in the kidneys in experimental urate nephrolithiasis was studied. Urate nephrolithiasis was modeled in Wistar rats by intragastric administration of a mixture of oxonic and uric acids. Carnosine was administered intragastrically through a tube in a dose of 15 mg/kg. In rats treated with carnosine, the concentration of MMP-2 in the urine decreased by 3.7 times, and the excretion of MMP-2 with urine decreased by 4.3 times. In the homogenate of the kidneys from rats treated with carnosine, the concentration of TBA-reactive substances decreased by 5 times and the concentration of MMP-2 decreased by 12.7%. After treatment with carnosine, the number of histologically confirmed cases of urate nephrolithiasis decreased by 2 times, while the mean size of urate deposits decreased by 2.7 times. Thus, carnosine inhibits MMP-2 and reduces the intensity of oxidative stress in the kidneys, which prevents the development of urate nephrolithiasis.

Nephroprotective Effect of Leu-Ile-Lys Tripeptide in Experimental Diabetes Mellitus.

We studied the effect of tripeptide Leu-Ile-Lys on kidney function in rats with experimental diabetes mellitus modeled by single intraperitoneal administration of streptozotocin (65 mg/kg). The tripeptide was intragastrically administrated in a dose of 11.5 mg/kg from week 5 to week 8 of the pathological process. The concentrations of glucose, protein, and creatinine in the urine were measured before and then weekly throughout the experiment. In 8 weeks, the markers of activity of the free radical oxidation process (concentration of TBA-reactive substances, total prooxidant activity, and total antioxidant activity, as well as activities of catalase, superoxide dismutase, and glutathione peroxidase) were assayed and a morphological study was conducted. After administration of the tripeptide Leu-Ile-Lys for 4 weeks, glucose concentration in the urine decreases by 3-44 times (p<0.001) and protein concentration by 2.3-3.7 times (p=0.007). The concentration of TBA-reactive substances decreased by 1.3 times (p<0.001), and the total antioxidant activity increased by 2.3 times (p<0.001). Administration of the tripeptide Leu-Ile-Lys to animals with experimental diabetes mellitus led to significant improvement of the renal function against the background of significant alleviation of oxidative damage and an increase in the antioxidant protection of the renal tissues. Improvement of the morphofunctional state of tissues and cells of the renal glomerulus was confirmed histologically, in particular, an increase in the number of podocytes by 1.5 times was observed.

Effect of Carnosine on the Course of Experimental Urate Nephrolithiasis.

The prospect of using the antioxidant dipeptide carnosine for the treatment of urate nephrolithiasis was evaluated. Urate nephrolithiasis was modeled in rats by intragastric administration of a mixture of oxonic and uric acids. Carnosine was administered intragastrically through a tube in a dose of 15 mg/kg. In rats treated with carnosine, the concentration of TBA-reactive products decreased by 1.4 times, the total antioxidant activity increased by 1.4 times, and catalase activity increased by 1.3 times. By the end of the experiment, the lactate dehydrogenate level in experimental rats was 2-fold lower than in the control, and the number of urate deposits decreased by 1.6 times with a concomitant alleviation of the inflammatory processes. Thus, the use of direct peptide antioxidant carnosine attenuated the manifestations of urate nephrolithiasis.

Experience of Using Tripeptide Leu-Ile-Lys for Experimental Therapy of Chronic 16-Week Oxalate Nephrolithiasis in Rats.

We studied the effect of tripeptide Leu-Ile-Lys on the course of chronic 16-week oxalate nephrolithiasis in rats modeled by administration of 1% ethylene glycol solution in drinking water for 16 weeks. The tripeptide Leu-Ile-Lys obtained by chemical synthesis (sample purity ≥98%) was administered intragastrically through a probe in a dose of 11.5 mg/kg in 1 ml saline. It was found that during tripeptide Leu-Ile-Lys significantly alleviated the course of experimental pathology, which was confirmed by characteristic biochemical and morphological indicators. We observed a decrease in the concentration of calcium ions by 4.4 times, weakening of oxidative stress in the renal tissue due to a decrease in the total prooxidant activity by 1.2 times, normalization of increased catalase activity, and reduction of superoxide dismutase activity by 2.4 times relative to disease control. Histological signs of nephrolithiasis were recorded in 9% cases (vs. 75% cases in disease control).

Effect of Tripeptide Leu-Ile-Lys on the Course of Experimental Nephrolithiasis.

We studied the effect of Leu-Ile-Lys tripeptide on the course of experimental oxalate nephrolithiasis modeled in rats by administration of 1% ethylene glycol solution instead of drinking water for 6 weeks. The Leu-Ile-Lys tripeptide obtained by chemical synthesis (purity ≥98%) was administered through a gastric tube (11.5 mg/kg in 1 ml saline). Administration of Leu-Ile-Lys tripeptide against the background of experimental oxalate nephrolithiasis significantly alleviated the course of experimental pathology, which was confirmed by typical biochemical and morphological changes: decrease in urinary activity of γ-glutamyltransferase (by 2.1 times in comparison with the initial level) and intensity of oxidative stress (the content of TBA-reactive products decreased by 1.3 times in comparison with that in untreated animals) and increase in glutathione peroxidase activity by 1.8 times; no histological signs of nephrolithiasis were found in animals treated with the tripeptide.

[The features of the pathologic changes in chronic oxalate stone disease after 16 week of experimental phase].

AIM: to study the pathologic features of chronic oxalate stone disease. MATERIALS AND METHODS: a model of the experimental oxalate stone disease was done in rats that drank the 1% ethylene glycol solution for 16 weeks. The pathologic analysis of the rats kidneys was done. RESULTS: After 16 weeks of oxalate stone disease modeling in all parts of kidneys the large crystals deposits were found, which plugged renal tubules. Moreover, purulent calculous pyelonephritis developed complicated by fibrosis.

Morphological Evaluation of the Influence of the Peptide Complex from Tissue of Porcine Kidneys on the Experimental Urolithiasis.

We performed morphological analysis of the effect of the peptide complex from porcine kidneys on the course of experimental urolithiasis modeled in rats by treatment with 1% ethylene glycol solution (in drinking water) for 6 weeks. The peptide complex obtained by acetic acid extraction was administered in a dose of 15 mg. Administration of the peptide complex to animals with experimental kidney stone disease leads to 100% destruction of large and medium stones to the "dust" granularity.

The Role of Free Radical Oxidation in the Development of Experimental Urate Nephropathy.

We studied the dynamics of activity of antioxidant enzymes under conditions of experimental urate kidney damage in rats. Combined administration of uric (0.145 g) and oxonium (0.3 g) acids to laboratory animals modulated free radical oxidation in the kidneys, and especially, in the blood. During the week 1, activity of free radical processes decreased, which was probably determined by the antioxidant effect of increasing blood concentration of uric acid. After 2-3 weeks of experimental pathology, the development of oxidative stress was observed, probably due to predominance of prooxidant activity of uric acid.

[Comparative estimation of antilithogenic activity of porcine kidney derived biomedical substance and sodium citrate in experimental urolithiasis].

AIM: to compare the anti-lithogenic activity of biomedical substance derived from freeze-dried porcine kidney and sodium citrate. MATERIALS AND METHODS: The experiments were conducted on Wistar rats divided into three groups of 15 animals each: control group (disease control), comparison group (sodium citrate treatment) and experimental group (treatment with biomedical substance from porcine kidneys). Experimental urolithiasis was modeled using the ethylene glycol model. On every 7th day of the 6 week experiment testing was done calcium and oxalate urine concentration and the activity of marker enzymes of renal epithelial damage: lactate dehydrogenase (LDH), -glutamyl transferase (GGT), and N-acetyl--D-glucosaminidase (NAG). At the end of the experiment, a part of the rats were decapitated and the renal tissue was tested for the oxidant status indicators of (renal thiobarbiturate reactive product content, TBRP, and total prooxidant activity, TPA) and antioxidant enzyme activities: glutathione peroxidase (GPO), superoxide dismutase (SOD) and catalase (CAT). To measure the number and size of calcium deposits formed in the renal papillary area, the Koss histochemical method was used. RESULTS: The experimental findings showed developing oxalate nephrolithiasis in the control group, as indicated by urinary supersaturation of oxalate ion, increased activity of marker enzymes, oxidative stress and the formation of numerous calcium deposits in the renal papillary area. In the comparison group, the 3-week use of sodium citrate contributed to a significant decrease in nephrolithiasis: a 3 to 4-fold decrease in the activity of marker enzymes in the urine, a 3.8-fold increase in the concentration of TBRP, normalization of GPO activity; the number and size of urinary calcium deposits decreased by 3.4 and 1.9 times, respectively. In the experimental group, using biomedical substance led to an even greater therapeutic effect. LDH activity and concentration of TPRP showed 1.9 times and by 26.2% greater decrease than in the comparison group, respectively, SOD and CAT activity almost doubled, there were 3.6 times fewer calcium deposits in the field of view and their mean size was 1.7 times smaller than in the comparison group. CONCLUSION: The study findings showed that the porcine kidney derived biomedical substance provide significantly greater antilithogenic effect than sodium citrate.

Development of Endoplasmic Reticulum Stress during Experimental Oxalate Nephrolithiasis.

Morphological and ultrastructural study of the kidney was performed in rats with oxalate nephrolithiasis. Specific features of endoplasmic reticulum stress were evaluated during nephrolithiasis and treatment with α-tocopherol. We observed the signs of endoplasmic reticulum stress with activation of proapoptotic pathways and injury to the cell lining in nephron tubules and collecting ducts. Ultrastructural changes were found in the organelles, nuclei, and cell membranes of epitheliocytes. A relationship was revealed between endoplasmic reticulum stress and oxidative damage, which developed at the early state of lithogenesis.

Activation of P-450-Dependent Monooxygenases Modulates the Diuretic Effect of Histochrome in Rats.

We studied the role of the liver monooxygenase system in pharmacological activity of histochrome, a pharmaceutical form of echinochrome A. In experiments on rats, benzonal, an inductor of the monooxygenase system of phenobarbytal type, significantly potentiated the diuretic effect of histochrome. Benzonal withdrawal was followed by a natriuretic reaction. In view of the known inverse relation between the biological effect of the drug and the rate of its metabolism, our findings suggest that the effects of echinochrome A on some kidney excretory function parameters are produced not by native agent, but one of its metabolites.

Expression of renal crystallization inhibitors in experimental nephrolithiasis.

The expression of renal inhibitors of crystallization (Tamm-Horsefall protein, osteopontin, bikunin) in experimental nephrolithiasis was studied in rats receiving 1% ethylene glycol solution for drinking for 3 weeks. The expression of Tamm-Horsefall protein increased, while osteopontin and bikunin expression decreased in experimental nephrolithiasis.