Oligopeptide modifier and application thereof in preparation of medicine for treating and / or improving kidney diseases

Abstract

The invention discloses an oligopeptide modifier and application thereof in preparation of a medicine for treating and / or improving kidney diseases. The oligopeptide modifier is obtained by replacing any amino acid of oligopeptide with D-type amino acid; the amino acid sequence of the oligopeptide is a conservative replacement variant obtained by adding 1-3 any amino acids to the N terminal and / or C terminal of the amino acid sequence shown as LNLYP or replacing less than 2 amino acids in the amino acid sequence shown as LNLYP with homologous polar amino acids. Experiments prove that compared with LP5, the stability of 145D-LP5 in plasma is remarkably improved, and 145D-LP5 can remarkably improve or treat chronic glomerulonephritis and diabetic nephropathy and inhibit accumulation of advanced glycation end products (AGEs) in kidney tissue.

Description

Technical Field

[0001] The present invention relates to a modified oligopeptide and application thereof in preparing a medicine for treating and / or improving kidney diseases, belonging to the field of polypeptides. Background Art

[0002] In the development of peptide drugs, plasma stability is one of the key bottlenecks that determines their drugability. Peptide molecules are susceptible to degradation by proteases widely present in plasma, resulting in a shortened drug half-life and significantly reduced bioavailability. The half-life of unmodified natural peptides in plasma is typically less than 10 minutes, severely limiting the maintenance of effective blood drug concentrations. Structural optimization strategies (such as cyclization, D-amino acid substitution, and fatty acid chain coupling) can significantly enhance their resistance to enzymatic degradation. For example, the clinically successful semaglutide has a half-life extended to 7 days after fatty acid modification. This improved stability not only reduces dosing frequency and improves patient compliance, but also reduces the risk of systemic toxicity by reducing the accumulation of metabolites. Diabetic nephropathy and chronic glomerulonephritis are the main causes of end-stage renal disease, and existing therapeutic drugs suffer from problems such as insufficient targeting and significant side effects. Previous studies have found that the natural oligopeptide LP5 (sequence LNLYP) derived from chicken gizzard lining can improve diabetic nephropathy by protecting the podocyte barrier and inhibiting oxidative stress. However, it is susceptible to proteolysis in plasma by proteases (such as neutral proteases and papain), resulting in a short half-life and limited efficacy. Previous studies have shown that the primary degradation site of LP5 in plasma is the Leu-Tyr bond, and its metabolites are Leu-Asn-Leu fragments, suggesting a stability deficiency. Existing technologies struggle to achieve a balance between stability and activity through simple sequence extension or chemical modification. While D-amino acid substitution is a potential strategy to improve peptide stability, it is important to avoid loss of activity due to conformational changes. Therefore, the development of LP5 derivatives that combine high plasma stability with therapeutic efficacy is an urgent technical challenge. Summary of the Invention

[0003] Purpose of the invention: The technical problem to be solved by the present invention is to provide a highly stable oligopeptide modification and its use in the preparation of drugs for treating and / or improving kidney diseases, to solve the problem of limited efficacy of existing LP5 due to plasma degradation, and to expand its indications.

[0004] Technical solution: To solve the above technical problems, the present invention provides an oligopeptide modification, in which any amino acid of the oligopeptide is replaced by a D-amino acid; the amino acid sequence of the oligopeptide is a sequence in which 1-3 arbitrary amino acids are added to the N-terminus and / or C-terminus of the amino acid sequence shown in LNLYP.

[0005] Among them, any amino acid of the oligopeptide is replaced by a D-type amino acid; the amino acid sequence of the oligopeptide is a conservative substitution variant in which less than two amino acids in the amino acid sequence shown by LNLYP are replaced by homologous polar amino acids.

[0006] Wherein, less than 2 amino acids in the amino acid sequence of the oligopeptide are replaced by conservative substitution variants of homologous polar amino acids; the amino acid sequence of the oligopeptide is LNLYP.

[0007] Wherein, any amino acid of the oligopeptide is replaced by a D-amino acid; and the amino acid sequence of the oligopeptide is LNLYP.

[0008] The oligopeptide modification is obtained by replacing amino acids 1, 4, and 5 of the oligopeptide with D-amino acids, and the sequence is DL-Asn-LDYDP.

[0009] The present invention also provides the use of an oligopeptide with an amino acid sequence such as LNLYP or a modified oligopeptide thereof in the preparation of a drug for treating and / or improving kidney disease.

[0010] The present invention also provides the use of oligopeptides with an amino acid sequence such as LNLYP, or modified oligopeptides thereof, in the preparation of drugs for treating and / or ameliorating diabetic nephropathy and / or chronic glomerulonephritis (CGN). Experiments have shown that 145D-LP5 has a prolonged half-life in plasma and is resistant to hydrolysis by neutral proteases and papain. In animal models, it can reduce UACR, serum creatinine, and urea nitrogen levels, inhibit AGE deposition and the expression of inflammatory factors (TNF-α, IL-6, and IL-1β), and improve glomerular fibrosis.

[0011] The present invention also provides a drug for treating and / or improving kidney disease, which contains the oligopeptide or oligopeptide modification.

[0012] Wherein, the drug dosage form is selected from injection, oral preparation or transdermal absorption preparation.

[0013] The present invention also provides a pharmaceutical composition for treating and / or improving kidney disease, which contains the oligopeptide or oligopeptide modification or the drug.

[0014] Wherein, the dosage form of the pharmaceutical composition is selected from injection, oral preparation or transdermal absorption preparation.

[0015] This invention preserves and enhances the therapeutic activity of oligopeptides through structural modification, expanding their indications to chronic glomerulonephritis. Further elucidating their mechanisms of action through inhibition of oxidative stress (reducing MDA), regulation of fibrosis factors (TGF-β1, Cola1, FN1) and immune deposition (IgG / C3), provides a technical foundation for the development of novel drugs for the treatment of kidney diseases.

[0016] Beneficial effects: Compared with the existing technology, the present invention has the following significant advantages: (1) Significantly improved stability: 145D-LP5 is modified with D-amino acids to resist degradation by plasma proteases, prolong its half-life, overcome the defect of LP5 in the easy breakage of the Leu-Tyr bond, and greatly enhance its "drugability"; (2) Dual therapeutic advantages: In the models of diabetic nephropathy and chronic glomerulonephritis, it reduces urine protein, improves renal function indicators (Scr, BUN), and alleviates glomerular hypertrophy, fibrosis and inflammatory infiltration; (3) Multi-mechanism synergy: By inhibiting the accumulation of AGEs, reducing oxidative stress (MDA), regulating inflammatory factors (TNF-α, IL-6) and fibrosis pathways (TGF-β1), multi-target treatment is achieved; (4) Flexible dosage form: It is suitable for injection, oral or transdermal administration, improving clinical applicability. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] Figure 1 To investigate the stability of LP5 and its different modifications in plasma; Figure 2 To investigate the tolerance of LP5 and its modified product LP5-145D to different enzymes; Figure 3 LP5-145D improves weight loss in CGN mice (# P <0.05, ## P <0.01, ### P <0.001, compared with Control group;* P <0.05, ** P <0.01, *** P <0.001, compared with CGNgroup); Figure 4 The effect of LP5-145D on urine protein in CGN mice: A: urine protein level in 12-hour urine of mice; B: urine albumin to creatinine ratio (UACR) level of mice; C: urine protein to creatinine ratio (UPCR) level of mice (# P <0.05, ## P <0.01,### P <0.001, compared with Control group;* P <0.05, ** P <0.01, *** P <0.001, compared with CGN group); Figure 5The effect of LP5-145D on serum creatinine and urea nitrogen in CGN mice: A: serum creatinine concentration in mice; B: serum urea nitrogen level in mice (# P <0.05, ## P <0.01, ### P <0.001, compared with Controlgroup;* P <0.05, ** P <0.01, *** P <0.001, compared with CGN group); Figure 6 LP5-145D improves the renal tissue morphology of CGN mice (HE staining): (blue arrows indicate glomerular matrix proliferation, white arrows indicate renal tubular casts, and black arrows indicate inflammatory cell infiltration, ×400, scale bar 50 μm); Figure 7 145D-LP5 improves renal fibrosis in CGN mice (MASSON staining) (yellow arrows indicate renal tissue fibrosis, white arrows indicate renal tubular casts, ×400, scale bar 50 μm); Figure 8 Effects of LP-5 and LP5-145D on renal function in mice with diabetic nephropathy, where A: urine microalbumin-to-creatinine ratio of mice in each group; B: serum creatinine concentration of mice in each group; C: creatinine clearance rate of mice in each group; D: fractional urea nitrogen excretion of mice in each group (n=6, #P<0.05, ##P<0.01, ###P<0.001, compared with Control group; *P<0.05, **P<0.01, ***P<0.001, compared with DKD group.); Figure 9 LP5-145D improved the accumulation of advanced glycation end products in diabetic nephropathy mice (n=6, #P<0.05,##P<0.01, ###P<0.001, compared with Control group; *P<0.05, **P<0.01, ***P<0.001, compared with DKD group.). DETAILED DESCRIPTION

[0018] The technical solution of the present invention will be further described below with reference to the accompanying drawings.

[0019] Example 1: Plasma Stability Study of LP-5 Modified Derivatives Methods: LP-5 oligopeptide (Leu-Asn-Leu-Tyr-Pro) and its different modifications N-LP5 (Ac-Leu-Asn-Leu-Tyr-Pro), LP5-C (H-Leu-Asn-Leu-Tyr-Pro-NH2), N-LP5-C (Ac- The following amino acids (Leu-Asn-Leu-Tyr-Pro-NH2), ω-aminooctanoic acid-LP5 (ω-N-LP5), 15D-LP5 (D-Leu-Asn-Leu-Tyr-D-Pro), 145D-LP5 (D-Leu-Asn-Leu-D-Tyr-D-Pro), 3D-LP5 (Leu-Asn-D-Leu-Tyr-Pro), 4D-LP5 (Leu-Asn-Leu-D-Tyr-Pro), and 45D-LP5 (Leu-Asn-Leu-D-Tyr-D-Pro) were synthesized by Nanjing GenScript Biotechnology Co., Ltd. Sequences were confirmed by mass spectrometry and showed a purity exceeding 98%. LP-5 and its modified derivatives were accurately weighed and dissolved in physiological saline to prepare 1 mg / mL stock solutions for later use.

[0020] 100 μL of each modification working solution was taken, and 900 μL of plasma was added to make a final concentration of 100 μg / mL. After mixing, the mixture was placed on a metal bath and incubated. At the incubation time points of 0 min, 2 min, 5 min, 10 min, 15 min, and 30 min, 100 μL of incubation solution was taken out, and 3 times the amount of ice-cold methanol was added to terminate the enzyme reaction. The mixture was vortexed and centrifuged at 12000 rpm at 4°C for 10 min. The supernatant was filtered through a 0.22 μm filter membrane and subjected to LC-MS / MS detection.

[0021] Result 1: Metabolism of LP-5 and its modifications in plasma Figure 1As shown in the figure, the metabolic rates of LP-5 and its modifications are as follows: LP-5 = LP5-C > 4D-LP5 > 45D-LP5 > N-LP5 > N-LP5-C > ω-N-LP5 > 3D-LP5 > 15D-LP5 > 145D-LP5. C-terminal amidation did not significantly improve stability, and the metabolic rate in plasma was almost the same as that of LP-5. N-terminal modification, as well as simultaneous N- and C-terminal modifications, slightly improved stability compared to LP-5. Furthermore, linking the N-terminus to ω-aminocaprylic acid also slightly improved metabolic stability in plasma. By replacing D-amino acids at positions 3, 4, 4 and 5, 1 and 5, and 1, 4 and 5, we obtained 3D-LP5, 4D-LP5, 45D-LP5, 15D-LP5, and 145D-LP5 modifications. Among them, the metabolic stability of 4D-LP5 and 45D-LP5 did not show significant improvement, while the metabolic stability of 3D-LP5, 15D-LP5, and 145D-LP5 were all significantly improved. Among them, 145D-LP5 was metabolized the slowest in plasma.

[0022] Example 2: Investigation of the tolerance of LP5 and its modified product 145D-LP5 to different enzymes Methods: LP5 and 145D-LP5 stock solutions were prepared as in Example 1. Aladdin reagents were used for pepsin (optimum pH: 1.5-2.0), trypsin (optimum pH: 8.0), alkaline protease (optimum pH: 10.0), neutral protease (optimum pH: 7.0), and papain (optimum pH: 8.0). Protease powders were dissolved in their respective optimal pH solutions. LP5 and 145D-LP5 stock solutions (1 mg / mL) were diluted to 100 μg / mL with the respective protease solutions. The solutions were incubated for 2 h under the optimal conditions for each protease. After incubation, 100 μL of each incubation solution was aspirated, 300 μL of ice-cold methanol was added to terminate the enzymatic reaction, and the samples were filtered through a 0.22 μm filter before being loaded into an HPLC system. The residual amounts of LP5 and 145D-LP5 in the system were determined.

[0023] Results: Enzyme resistance results are as follows Figure 2 As shown in the figure, none of the five proteases hydrolyzed 145D-LP5. Compared with the prototype drug LP-5, the modified 145D-LP5 had significantly improved resistance to neutral proteases and papain.

[0024] Example 3: Evaluation of the efficacy of 145D-LP5 in improving chronic glomerulonephritis (CGN) Methods: SPF-grade BALB / c male mice, 6 weeks old and weighing 18-21 g, were purchased from the Center for Comparative Medicine of Yangzhou University under license number SCXK (Su) 2022-0009. The animals were housed in an SPF-grade experimental animal room with recirculating ventilation, a day-night cycle, and free access to food and water. They were acclimated for 1 week before the experiment, and animal handling was in accordance with the Guide for the Care and Use of Laboratory Animals. Six-week-old BALB / c mice were acclimated for 1 week and then divided into a control group and a model group. The model group received multiple subcutaneous injections of 100 mg / kg of a cationic bovine serum albumin (cBSA) solution (100 mg / mL in 0.1 M PBS) emulsion with incomplete Freund's adjuvant (1:1, v:v). The control group received an equal volume of saline emulsion with incomplete Freund's adjuvant (1:1, v:v). One week later, the model group received cBSA injections via the tail vein every other day for four weeks, with the first injection at a dose of 6.5 mg / kg, the second at a dose of 13 mg / kg, and subsequent injections at a dose of 26 mg / kg. The control group received an equal volume of saline via the tail vein every other day. After the final injection week, the mice were placed in metabolic cages for urine collection. Urine was collected for 12 hours, and the volume was calculated. The supernatant was centrifuged at 3000 rpm and 4°C for 15 minutes. Urine protein, microalbumin, and creatinine were measured according to the kit instructions. Urine protein was measured using the Coomassie Brilliant Blue method, microalbumin was measured using an ELISA method, and creatinine was measured using the sarcosine oxidase method. After the CGN model was successfully established, 145D-LP5 was administered orally (5, 10, or 20 mg / kg) once daily for four weeks. Losartan potassium (20 mg / kg), a commonly used drug in CGN clinical practice, was used as a positive control agent. The efficacy of 145D-LP5 on CGN mice was assessed by examining renal tissue pathology, serum, and renal biochemical parameters. Results are presented as mean ± SEM. Intergroup comparisons were performed using one-way ANOVA or two-way ANOVA with Bonferroni's post-hoc tests using Microsoft Excel software. P < 0.05 was considered statistically significant. Data were processed using Excel software, and graphs were generated using Graphpad and PowerPoint.

[0025] Result 1: 145D-LP5 significantly improved the condition and body weight of CGN mice: After modeling, mice showed symptoms such as dry and yellow hair, significant weight loss, decreased activity, and mental depression. Compared with the model group, the 145D-LP5 10 or 20 mg / kg and losartan potassium administration groups significantly increased the body weight of mice ( Figure 3). Among them, 145D-L, 145D-M, and 145D-H represent dosages of 5, 10, and 20 mg / kg, respectively.

[0026] Result 2: 145D-LP5 significantly improved urinary protein in CGN mice: like Figure 4 As shown in A, the total amount of urinary protein in CGN mice increased significantly in 12 h (P < 0.001). Compared with the model group, 10 or 20 mg / kg 145D-LP5 and losartan potassium significantly reduced the total amount of urinary protein in CGN mice in 12 h (P < 0.05). There was no significant difference between the low-dose 145D-LP5 group and the model group. Figure 4 As shown in B, UACR in CGN mice was significantly increased (P < 0.001); compared with the model group, 145D-LP5 (5, 10, or 20 mg / kg) and losartan potassium significantly reduced UACR levels in CGN mice (P < 0.01). Figure 4 As shown in C, the UPCR of CGN mice was significantly increased (P < 0.01). Compared with the model group, the UPCR of mice in the 145D-LP5 (10, 20 mg / kg) and losartan potassium groups was significantly decreased (P < 0.01), and there was no significant difference between the low-dose 145D-LP5 group and the model group.

[0027] Result 3: 145D-LP5 significantly downregulated the levels of blood creatinine and urea nitrogen in CGN mice; like Figure 5 As shown in A, Scr was significantly increased in CGN mice ( P <0.01); Compared with the model group, the Scr levels of mice in the 145D-LP5 (5, 10, 20 mg / kg) and losartan potassium groups were significantly decreased ( P <0.05). Figure 5 As shown in B, BUN in CGN mice was significantly increased ( P <0.05); compared with the model group, the BUN of mice in the 145D-LP5 (10, 20 mg / kg) and losartan potassium groups decreased significantly ( P <0.05), there was no significant difference between the 145D-LP5 low-dose group and the model group.

[0028] Result 4: 145D-LP5 significantly improved glomerular matrix proliferation and renal tubular casts in the kidney tissue of CGN mice: like Figure 6 As shown, the results of HE staining of renal tissue showed that the glomeruli of mice in the normal control group were normal in size, with clear outlines, prominent glomeruli, and normal morphology of surrounding renal tubules. The glomeruli of mice in the model group (CGN group) were enlarged, with blurred outlines, glomerular adhesions, mesangial proliferation, and insertion into endothelial cells, making the glomeruli appear lobed, and the mesangial matrix was significantly increased ( Figure 6blue arrow); renal tubules are deformed and casts are obvious ( Figure 6 White arrow); Inflammatory cell infiltration can be seen in the interstitium ( Figure 6 Black arrows). Compared with the model group, the glomerular and tubular structures were significantly improved in the 145D-LP5 (10, 20 mg / kg) and losartan potassium groups, but the low-dose 145D-LP5 group still showed obvious mesangial matrix proliferation and renal tubular casts.

[0029] Result 5: 145D-LP5 significantly improved glomerular hypertrophy and fibrosis in CGN mice: like Figure 7 The results of MASSON staining of renal tissue showed that the glomeruli of mice in the normal control group were normal in size and the surrounding renal tubules were normal in morphology. The glomeruli of mice in the model group were enlarged and fibrosis was significantly increased ( Figure 7 Yellow arrows, staining shows increased blue); renal tubules are deformed and casts are obvious ( Figure 7 (White arrows). Compared with the model group, the 145D (10, 20 mg / kg) and losartan potassium groups showed significant improvement in glomerular and tubular structure, and significantly reduced fibrosis. However, fibrosis and protein casts were still observed in the low-dose 145D group.

[0030] Example 4: Evaluation of the efficacy of 145D-LP5 in improving diabetic nephropathy (DKD) Experimental Methods: SPF-grade C57BL / 6J male mice, 6-8 weeks old, weighing 20-22 g, were purchased from Beijing Biotechnology Co., Ltd. (license number: SCXK (Beijing) 2019-0010). Animals were acclimated for one week before the experiment and housed in an SPF animal room at 22-24°C, 12 h light / 12 h dark, with free access to food and water. After one week of adaptive feeding, the mice were divided into a blank control group and a model group. The model group was fed a high-fat diet (D12492) for two weeks and then intraperitoneally injected with 50 mg / kg streptozotocin (STZ) daily for five consecutive days. The control group was fed a normal diet and intraperitoneally injected with an equal volume of vehicle (citrate buffer, pH 4.5). At five weeks after modeling, fasting blood glucose levels were measured, and urine was collected from mice in metabolic cages for analysis of urine creatinine, urine protein, and urine microalbumin concentrations. Mice were weighed, and blood was collected by tail clipping for fasting blood glucose measurement using a glucometer. After a successful diabetic nephropathy model was established in mice, LP-5 (40, 20, or 10 mg / kg) or 145D-LP5 (20 mg / kg) was administered orally once daily for 8 weeks. Losartan potassium (20 mg / kg) and Huangkui capsule (HKC), commonly used drugs in CGN clinical practice, were used as positive agents. Mice were placed in metabolic cages and fasted, but not watered. Urine was collected for 12 hours. After volume measurement, urine was centrifuged at 3500 rpm at 4°C for 15 minutes. Urine creatinine, protein, and microalbumin were measured according to the kit instructions. Creatinine was measured using the sarcosine oxidase method, protein using the Coomassie Brilliant Blue method, and microalbumin using the ELISA method.

[0031] Renal tissue pathological staining and transmission electron microscopy were used to observe changes in the physiological and pathological structure of the kidneys. The relevant biochemical indicators in the blood and urine of mice were detected to judge the damage and recovery of renal function. The changes in the levels of factors related to kidney damage in mice were explored to evaluate the therapeutic effect of 145D-LP5 on diabetic nephropathy.

[0032] Result 1: LP5-145D significantly improved renal function in diabetic nephropathy (DKD) mice: The microalbumin-to-creatinine ratio (UACR) is widely used in clinical diagnosis of renal injury. Figure 8 As shown, both LP-5 and 145D-LP5 significantly reduced proteinuria in DKD mice. Elevated serum creatinine and decreased creatinine clearance are also markers of renal impairment. Creatinine clearance (CCr) = (urine creatinine * minute urine volume / serum creatinine) / body weight, reflecting glomerular filtration rate (GFR). Decreased creatinine clearance indicates advanced diabetes, acute or chronic renal failure, and other conditions.

[0033] Fractional urea nitrogen excretion (FEUN) = (urine urea nitrogen to creatinine ratio) / (blood urea nitrogen to creatinine ratio) * 100. Elevated FEUN is considered a marker of acute renal failure and renal tubular necrosis. Both LP-5 and LP5-145D significantly reduce FEUN. Therefore, administering LP-5 or LP5-145D to mice partially restores the ability of the renal tubules to recycle urea nitrogen, indicating that both LP-5 and LP5-145D possess tubular protective effects. At the same concentration, LP5-145D significantly improved some indicators compared to LP5.

[0034] Result 2: LP5-145D significantly improved the accumulation of advanced glycation end products in diabetic nephropathy mice: Advanced glycation end products (AGEs) are a key factor in kidney damage in diabetic nephropathy. AGEs are products of the advanced glycation of proteins. Sustained high blood sugar levels in diabetic nephropathy promote their massive production. However, because AGEs are cleared very slowly, excessive accumulation binds to the receptor for advanced glycation end products (RAGE) on the cell membrane, activating downstream inflammatory and oxidative stress signals and promoting renal structural and functional damage. Inhibiting AGE levels can improve diabetic nephropathy.

[0035] like Figure 9 As shown in the results, the serum levels of advanced glycation end products in diabetic nephropathy mice were significantly increased (P < 0.05); the serum AGEs levels in the positive drug group and LP-5 or LP5-145D oligopeptide groups were significantly reduced compared with the model group (P < 0.05). At the same concentration, the inhibitory effect of LP5-145D was better than that of LP-5.

Claims

1. A modified oligopeptide, characterized in that The method is to replace any amino acid of the oligopeptide with a D-type amino acid; the amino acid sequence of the oligopeptide is to add 1-3 arbitrary amino acids to the N-terminus and / or C-terminus of the amino acid sequence shown in LNLYP.

2. The oligopeptide modified substance according to claim 1, characterized in that The method is to replace any amino acid of the oligopeptide with a D-type amino acid; the amino acid sequence of the oligopeptide is a conservative substitution variant in which less than two amino acids in the amino acid sequence shown by LNLYP are replaced with homologous polar amino acids.

3. The oligopeptide modified substance according to claim 1, characterized in that The oligopeptide modification is to replace the amino acids at positions 1, 4, and 5 of the oligopeptide with D-type amino acids; the amino acid sequence of the oligopeptide is to add 1-3 arbitrary amino acids to the N-terminus and / or C-terminus of the amino acid sequence shown in LNLYP.

4. The oligopeptide modified substance according to claim 2, characterized in that The oligopeptide modification is a variant in which amino acids at positions 1, 4, and 5 of the oligopeptide are replaced by D-type amino acids; the amino acid sequence of the oligopeptide is a conservative substitution variant in which less than two amino acids in the amino acid sequence shown in LNLYP are replaced by homologous polar amino acids.

5. Use of an oligopeptide having an amino acid sequence as represented by LNLYP or a modified oligopeptide according to any one of claims 1 to 4 in the preparation of a drug for treating and / or improving kidney disease.

6. The application according to claim 5, characterized in that The kidney disease includes diabetic nephropathy or chronic glomerulonephritis.

7. A drug for treating and / or improving kidney disease, characterized in that: It contains an oligopeptide or a modified oligopeptide according to any one of claims 1 to 4.

8. The drug according to claim 6, characterized in that The pharmaceutical dosage form is selected from injection, oral preparation or transdermal absorption preparation.

9. A pharmaceutical composition for treating and / or improving kidney disease, characterized in that: It contains an oligopeptide or the oligopeptide modification according to any one of claims 1 to 4 or the drug according to claim 7.

10. The pharmaceutical composition according to claim 9, characterized in that The dosage form of the pharmaceutical composition is selected from injection, oral preparation or transdermal absorption preparation.

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