Renal function disorder improving agent

Abstract

To provide a renal function disorder preventing and / or improving agent that exhibits superior efficacy in preventing or improving renal function disorder.SOLUTION: A renal function disorder preventing and / or improving agent comprising 1-kestose as an active ingredient.SELECTED DRAWING: Figure 3

Description

[Technical Field]

[0001] The present invention relates to an agent for preventing and / or improving renal dysfunction that can be taken on a daily basis and has excellent effects for preventing and improving renal dysfunction. [Background technology]

[0002] The kidney contains glomeruli, which function to filter waste products and salt from the blood and excrete them as urine. Mesangial cells exist in the form of bundles of capillaries in the glomerulus, and together with the extracellular matrix, they form the mesangial region, which is involved in maintaining the structure of the glomerulus. They play an important role in maintaining glomerular function by synthesizing and decomposing the mesangial matrix and secreting various cellular factors.

[0003] Some kidney diseases involve mesangial proliferation, including mesangial cell proliferation or increased mesangial matrix. For example, IgA nephropathy is a mesangial proliferative disease characterized by granular deposition of IgA in the glomerular mesangial region. It is estimated that more than 30,000 patients in Japan are treated for IgA nephropathy annually, and approximately 30-40% of these patients will progress to end-stage renal failure over a 20-year period, with 11% of children progressing to end-stage renal failure over a 15-year period. Furthermore, chronic kidney diseases such as IgA nephropathy result in a gradual decline in renal function without noticeable symptoms, and once symptoms develop, recovery through treatment is often difficult.

[0004] Therefore, there is a need for the development of components that can be taken daily to prevent and improve renal dysfunction and to improve the prognosis after the onset of the disease. To date, it has been reported that seishinrenshiin extract (Patent Document 1) and polysaccharides derived from Aphanothece sacrum (Patent Document 2) have been shown to have an effect of improving renal function, but these documents do not examine the prevention of renal dysfunction or the improvement of prognosis. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] Japanese Patent Publication No. 2021-195358 [Patent Document 2] Japanese Patent Publication No. 2020-040900 Summary of the Invention [Problem to be solved by the invention]

[0006] An object of the present invention is to provide an agent for preventing and / or improving renal dysfunction that has excellent effects in preventing and improving renal dysfunction. [Means for solving the problem]

[0007] As a result of extensive research to solve the above-mentioned problems, the inventors discovered that taking 1-kestose can provide excellent preventive or ameliorative effects against renal dysfunction and can also improve the prognosis after onset, thereby completing the present invention.

[0008] The present invention includes the following aspects. [1] An agent for preventing and / or improving renal dysfunction, containing 1-kestose as an active ingredient. [2] The agent for preventing and / or improving renal dysfunction according to [1], wherein the renal dysfunction is mesangial proliferative nephritis or a disease causing mesangial proliferation. [3] The agent for preventing and / or improving renal dysfunction according to [2], wherein the mesangial proliferative disease is a disease selected from the group consisting of IgA nephropathy, IgA vasculitis, hepatic IgA nephropathy, lupus nephritis, amyloid nephropathy, MRSA infection-associated nephritis, HBV-associated nephropathy, HCV-associated nephropathy, C3 nephropathy, cryoglobulin nephropathy, immunotactoid nephropathy, and fibrillary glomerulonephritis. [4] The agent for preventing and / or improving renal dysfunction according to [2], wherein the disease causing mesangial proliferation is a disease selected from the group consisting of diabetic nephropathy, nephrosclerosis, focal segmental glomerulosclerosis, and amyloid nephropathy. [5] The agent for preventing and / or improving renal dysfunction according to any one of [1] to [4], which is a food or drink. [6] The agent for preventing and / or improving renal dysfunction according to any one of [1] to [4], which is a pharmaceutical product. [7] A drug for improving the prognosis of renal dysfunction containing 1-kestose as an active ingredient. [8] An enhancer for renal dysfunction improving agents containing 1-kestose as an active ingredient. [Effects of the Invention]

[0009] The agent for preventing and / or ameliorating renal dysfunction of the present invention contains a highly safe food ingredient as an active ingredient, and can be taken daily, and can effectively prevent or ameliorate renal dysfunction, and can also improve the prognosis after the onset of renal dysfunction. [Brief explanation of the drawings]

[0010] [Figure 1] FIG. 1 shows the administration schedule of 1-kestose and dextran sulfate sodium in an example. [Figure 2] FIG. 2 is a graph showing IgA concentrations. [Figure 3] Figure 3 is a graph showing the M score calculated from the number of mesangial cells present in the mesangial region when glomeruli of PAS-stained kidney tissue are observed under an optical microscope. In the figure, "*" indicates that the results of one-way ANOVA followed by Tukey's multiple comparisons test were 0.01≦p<0.05, and "**" indicates that the results were 0.001≦p<0.01. [Figure 4] FIG. 4 shows a fluorescent immunostained image of a glomerulus in kidney tissue. [Figure 5] Figure 5 is a graph showing the IgA deposition rate (%) in the glomeruli of kidney tissue. In the figure, "*" indicates that the Kruskal-Wallis test was performed followed by Dunnett's multiple comparison test, and the result was 0.01≦p<0.05. "**" indicates that the result was 0.001≦p<0.01. DETAILED DESCRIPTION OF THE INVENTION

[0011] The present invention will be described in detail below. The following description of the present invention may be based on preferred embodiments of the present invention, but the present invention is not limited to such embodiments. In this specification, the use of "to" to indicate a range of values ​​means that the values ​​before and after it are included as the lower and upper limits. As used herein, "prevention" means reducing the risk of developing a disease or condition. As used herein, "improvement" means one or more selected from the group consisting of suppression, alleviation, and recovery of the progression of a disease or symptom.

[0012] The agent for preventing and / or improving renal dysfunction of the present invention contains 1-kestose as an active ingredient. 1-kestose is a fructan formed by dehydration polymerization of D-fructose attached to the fructose side of sucrose via a β-(2→1) bond, and is represented by GF2 (G: glucose, F: fructose, n: fructose).

[0013] Ingestion of 1-kestose can effectively prevent and / or improve renal dysfunction in animals, including humans. Target renal dysfunction includes various renal diseases associated with impaired renal function, such as IgA nephropathy, IgA vasculitis, MRSA-associated nephritis, lupus nephritis, C3 nephropathy, amyloid nephropathy, HBV-associated nephropathy, HCV-associated nephropathy, hepatic IgA nephropathy, cryoglobulin nephropathy, monoclonal immunoglobulin deposition disease, immunotactoid nephropathy, fibrillary glomerulonephritis, diabetic nephropathy, nephrosclerosis, focal segmental glomerulosclerosis, acute nephritic syndrome, rapidly progressive nephritic syndrome, acute interstitial nephritis, chronic interstitial nephritis, renal tubular acidosis, recurrent or persistent hematuria, renal failure due to other causes, and kidney and urinary tract stones. These diseases can be prevented from developing into chronic kidney disease. Among these, mesangial proliferative diseases accompanied by an increase in mesangial cells or mesangial matrix are preferred, and examples thereof include mesangial proliferative nephritides such as IgA nephropathy, IgA vasculitis, hepatic IgA nephropathy, lupus nephritis, MRSA infection-associated nephritis, HBV-associated nephropathy, HCV-associated nephropathy, C3 nephropathy, cryoglobulin nephropathy, immunotactoid nephropathy, and fibrillary glomerulonephritis; and diseases causing mesangial proliferation such as diabetic nephropathy, nephrosclerosis, focal segmental glomerulosclerosis, and amyloid nephropathy.

[0014] The agent for preventing and / or improving renal dysfunction of the present invention can be formulated by combining the above-mentioned active ingredient with a pharmaceutically acceptable carrier, if necessary. Examples of pharmaceutically acceptable carriers include glucose, lactose, starch, mannitol, dextrin, fatty acid glycerides, polyethylene glycol, hydroxyethyl starch, ethylene glycol, polyoxyethylene sorbitan fatty acid esters, amino acids, gelatin, albumin, water, and physiological saline. Furthermore, conventional additives such as stabilizers, humectants, emulsifiers, binders, isotonicity agents, and excipients can also be added as needed. The dosage form is not particularly limited, and examples include liquids, powders, granules, capsules, and tablets, which can be prepared according to conventional methods.

[0015] The agent for preventing and / or improving renal dysfunction of the present invention can be applied to mammals including humans, such as humans, dogs, cats, cows, pigs, chickens, sheep, horses, etc. The dosage is not particularly limited, but for example, the daily dosage for an adult is about 0.1 to 5 g per kg of body weight, preferably about 0.5 to 1 g per kg of body weight. In the case of dogs, cats, etc., the dosage is about 0.1 to 5 g per kg of body weight, preferably about 0.5 to 1 g per kg of body weight.

[0016] The agent for preventing and / or improving renal dysfunction of the present invention can also be in the form of a food or beverage, and is prepared by blending the above-mentioned active ingredient with known food additives and / or food ingredients according to a conventional method, and the form is not particularly limited, and examples thereof include starch-based foods such as bread, biscuits, pancakes, noodles, and tablet candy, sweets such as gum, candy, and Japanese sweets, meat foods such as ham and sausage, fish foods such as chikuwa and kamaboko, seafood foods, seasonings such as dressing, soy sauce, jam, and furikake, beverages such as tea, juice, soft drinks, and alcoholic beverages. Foods and beverages include foods for specified health uses and foods with functional claims that have been approved or notified to be labeled for the prevention and treatment of renal dysfunction.

[0017] The agent for preventing and / or ameliorating renal dysfunction of the present invention can be in the form of feed or pet food, and is prepared according to a conventional method by appropriately blending the above-mentioned active ingredient with known feed ingredients, gelling agents, shape-retaining agents, pH adjusters, seasonings, preservatives, nutritional supplements, etc. The form is not particularly limited, and any form such as pellets, flakes, or mash can be exemplified, and the agent can be used, for example, as feed for livestock such as cows, pigs, chickens, sheep, and horses, or as pet food for dogs, cats, etc.

[0018] The agent for improving the prognosis of renal dysfunction of the present invention can improve the prognosis after the onset of renal dysfunction and reduce the risk of initiating dialysis. Specific examples of target diseases, formulation methods, dosages, etc. are the same as those of the agent for preventing and / or improving renal dysfunction described above.

[0019] The potentiator of the present invention for the action of a therapeutic agent for renal dysfunction can potentiate the action of a known therapeutic agent for renal dysfunction. The known therapeutic agent for renal dysfunction is not particularly limited, and examples thereof include therapeutic agents for IgA nephropathy such as RAS inhibitors, SGLT2 inhibitors, corticosteroids, and immunosuppressants. Specific examples of target diseases, formulation methods, dosages, etc. are the same as those for the above-mentioned agent for preventing and / or improving renal dysfunction. [Example]

[0020] The present invention will be described in detail below by way of examples, but the present invention is not limited to these examples in any way.

[0021] Example 1 The effect of 1-kestose on renal dysfunction was investigated using IgA nephropathy model mice (HIGA mice).

[0022] (1) Samples and methods [sample] 1-Kestose (KES; manufactured by Itochu Sugar Co., Ltd., trade name: iKes Crystal) and dextran sodium sulfate (DSS; manufactured by MP Biomedicals, trade name: Dextran sodium sulfate MW 36,000-50,000) were used.

[0023] [Experimental animals] 11-week-old HIGA mice (Japan SLC, Inc.) were housed under specific pathogen-free (SPF) conditions. From 12 weeks of age, mice were housed under the following conditions (i) and (ii) to obtain the SW-treated and DSS-treated groups, respectively (see Figure 1). (i) Mice were allowed free access to sterilized water until they were 12 to 25 weeks old (SW-administered group). (ii) From 14 weeks of age, the mice were given free access to 3% DSS aqueous solution for 7 days, from 17 weeks of age to 2% DSS aqueous solution for 7 days, and from 20 weeks of age to 2% DSS aqueous solution for 7 days. Except for the above periods, the mice were given free access to sterilized water from 12 to 25 weeks of age (DSS-administered group). As treatment groups, the mice were kept under the conditions (iii) and (iv) below to obtain an SW+KES administration group and a DSS+KES administration group, respectively (see FIG. 1). (iii) Mice were reared with free access to 5% 1-kestose and sterilized water from 12 to 25 weeks of age (SW+KES administration group). (iv) From 12 to 25 weeks of age, the mice were allowed to freely consume 5% 1-kestose. From 14 weeks of age, they were given free access to 3% DSS aqueous solution for 7 days, from 17 weeks of age, they were given free access to 2% DSS aqueous solution for 7 days, and from 20 weeks of age, they were given free access to sterilized water for the remaining period from 12 to 25 weeks of age (DSS+KES administration group).

[0024] [IgA concentration] Under isoflurane anesthesia, blood was collected from the orbital venous plexus of mice using a hematocrit tube. The collected blood was centrifuged at 14,000 rpm for 5 minutes, and the supernatant was stored as serum at -80°C. Serum IgA concentrations were measured in mice at 14, 17, 20, 23, and 25 weeks of age using a commercially available IgA ELISA kit (Invitrogen, product name: IgA Mouse Uncoated ELISA Kit).

[0025] [PAS staining] Mice from each group were sacrificed, and kidney tissue was collected. The collected kidney tissue was fixed, and sections were obtained from the fixed kidney tissue. The sections were stained with Periodic Acid Schiff (PAS). The stained glomeruli of the kidney tissue were observed under a light microscope. According to the Oxford International Classification of IgA Nephropathy, mesangial hypercellularity is defined as the presence of four or more cell nuclei in the mesangial region of a single segment in a 3 μm section under a light microscope, and is classified as follows based on the number of cells in the mesangial region with the highest number of cells: Normal: 3 or less Mild: 4 to 5 Moderate: 6~7 pieces Altitude (severe): 8 or more Similarly, the mesangial hypercellularity score (M score), which is the average score for all glomeruli according to the definition below, is known to be a prognostic factor independent of clinical parameters. The M scores for each group are shown in Figure 3. <4: Mesangial cells / mesangial area = 0 4-5: Mesangial cell / mesangial area = 1 6-7: Mesangial cells / mesangial area = 2 ≧8: Mesangial cells / mesangial area = 3

[0026] [Fluorescent immunostaining] Mice from each group were sacrificed, and kidney tissue was collected. The collected kidney tissue was embedded in an embedding medium for frozen tissue sectioning (OCT compound, Tissue-Tec) and stored at -80°C. The obtained frozen sections were immersed in ethanol at -30°C for 10 minutes and then washed three times with phosphate-buffered saline (PBS). The fixed tissue was then placed in blocking buffer (5% goat serum, 0.5% BSA, 0.05% Tween PBS) and incubated at room temperature (25°C) for 1 hour. After incubation, the tissue was then placed in primary antibody diluted in blocking buffer (primary antibody / blocking buffer = 1 / 100) (Goat anti-Mouse IgG H&L-Alexa Fluor 405, Abcam) and incubated at room temperature (25°C) for 1 hour in the dark. After incubation, the tissue was washed twice for 5 minutes with PBS-T and rinsed twice for 5 minutes with PBS. Subsequently, the primary antibody diluted in blocking buffer (primary antibody / blocking buffer = 1 / 200) (Goat anti-Mouse IgA-FITC, Southern Biotech) was placed in primary antibody diluted in blocking buffer and incubated at room temperature (25°C) for 1 hour in the dark. After incubation, the tissue was washed twice with PBS-T for 5 minutes each in the dark and rinsed twice with PBS for 5 minutes each. Subsequently, primary antibody diluted in blocking buffer (primary antibody / blocking buffer = 1 / 50) (Rat anti-Mouse C3, Santa Cruz Biotechnology) was placed on the tissue and incubated for 1 hour at room temperature (25°C) in the dark. After incubation, the tissue was washed twice with PBS-T for 5 minutes each in the dark and rinsed twice with PBS for 5 minutes each. After rinsing, the tissue was placed in a secondary antibody diluted in blocking buffer (secondary antibody / blocking buffer = 1 / 500) (Goat anti-Rat IgG (H+L) Highly Cross-Adsorbed Secondary Antibody, Alexa Fluor Plus 647, Thermo Fisher Scientific) and left to stand at room temperature (25°C) for 30 minutes in the dark. After standing, the tissue was washed twice for 5 minutes with PBS-T and rinsed twice for 5 minutes with PBS. After rinsing, the tissue was mounted in mounting medium and allowed to dry. The glomeruli of the kidney tissue obtained by the above procedure were observed using a fluorescence microscope (BZ-X800, manufactured by Keyence Corporation). Images of the glomeruli of the kidney tissue are shown in Figure 4. Furthermore, the IgA deposition area (μm 2 ) and Bowman's capsule area (μm 2The IgA deposition rate (%) was calculated from the average value of the IgA deposition area (μm 2 ) / Bowman's capsule area (μm 2 The results are shown in Figure 5.

[0027] (2) Results As shown in Figure 3, the M score was reduced in the DSS+KES group compared to the DSS group. Also, as shown in Figure 5, the IgA deposition rate in the glomeruli of kidney tissue was reduced in the DSS+KES group compared to the DSS group. The above results indicate that administration of 1-kestose inhibits mesangial cell proliferation in the glomeruli of the kidney, as well as inhibits IgA deposition in the mesangial region. [Industrial Applicability]

[0028] The agent for preventing and / or improving renal dysfunction of the present invention is a highly safe food ingredient that can be taken on a daily basis and has excellent preventive and improving effects against renal dysfunction, and therefore can be used as a medicine, food, etc. for preventing and improving renal dysfunction.

Claims

1. An agent for preventing and / or improving renal dysfunction, comprising 1-kestose as an active ingredient.

2. 2. The agent for preventing and / or improving renal dysfunction according to claim 1, wherein the renal dysfunction is mesangial proliferative nephritis or a disease causing mesangial proliferation.

3. The agent for preventing and / or improving renal dysfunction according to claim 2, wherein the mesangial proliferative nephritis is a disease selected from the group consisting of IgA nephropathy, IgA vasculitis, hepatic IgA nephropathy, lupus nephritis, MRSA infection-associated nephritis, HBV-associated nephropathy, HCV-associated nephropathy, C3 nephropathy, cryoglobulin nephropathy, immunotactoid nephropathy and fibrillary glomerulonephritis.

4. 3. The agent for preventing and / or improving renal dysfunction according to claim 2, wherein the disease causing mesangial proliferation is a disease selected from the group consisting of diabetic nephropathy, nephrosclerosis, focal segmental glomerulosclerosis and amyloid nephropathy.

5. 3. The agent for preventing and / or improving renal dysfunction according to claim 1 or 2, which is a food or drink.

6. 3. The agent for preventing and / or improving renal dysfunction according to claim 1 or 2, which is a pharmaceutical.

7. An agent for improving the prognosis of renal dysfunction, comprising 1-kestose as an active ingredient.

8. An agent for enhancing the effect of a renal dysfunction treatment agent, which contains 1-kestose as an active ingredient.

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