Application of oligopeptide in preparation of medicine for treating and / or preventing diabetic nephropathy

Abstract

The invention discloses application of oligopeptide in preparation of a medicine for treating and / or preventing diabetic nephropathy. The oligopeptides comprise oligopeptides with the amino acid sequence of SEQ ID NO: 1: LNLYP and derivative sequences or conservative substitution variants of the oligopeptides. The oligopeptide can significantly improve renal function indexes of mice with diabetic nephropathy, such as UACR, serum creatinine, urea nitrogen and the like, enhance podocyte barrier integrity and inhibit accumulation of advanced glycosylation end products AGEs in kidney tissues, and provides a basis for development of novel drugs for treating diabetic nephropathy.

Description

Technical Field

[0001] The present invention relates to the use of an oligopeptide in preparing a medicine for treating and / or preventing diabetic nephropathy. Background Art

[0002] Chicken gizzard lining, the dried inner wall of the gizzard of the domesticated chicken, is a commonly used Chinese medicine in clinical practice. It has the benefits of strengthening the stomach and digestion, astringing spermatorrhea, and relieving stranguria and urinary tract infections. Patent number CN201910428295.5 discloses an active oligopeptide previously screened from chicken gizzard lining by the inventors, and describes its application in treating ulcerative colitis, nephrotic syndrome, and acute lung injury.

[0003] Diabetic kidney disease (DKD) refers to a condition characterized by structural and functional damage to the kidneys caused by chronic hyperglycemia. With prolonged disease progression, it can progress to end-stage renal disease, requiring dialysis or transplantation to maintain basic kidney function. It carries a high mortality rate and a poor prognosis. Clinical manifestations include albuminuria, hypertension, and edema, and in later stages, renal failure, electrolyte imbalance, and anemia, which pose a serious threat to human health. Treatment of DKD primarily relies on controlling blood sugar and blood pressure to slow disease progression. Angiotensin antagonists are commonly used to lower blood pressure and reduce glomerular pressure, but their benefits on renal function are limited. Currently, there is a lack of peptide drugs specifically designed to improve renal function in diabetic nephropathy. For example, liraglutide, exenatide, and benaglutide primarily rely on promoting insulin secretion, inhibiting glucagon, delaying gastric emptying, and suppressing appetite to improve blood sugar control. These drugs require subcutaneous administration, resulting in poor patient compliance. There is an urgent need to develop drugs that have stronger compliance and can more effectively improve the reduced kidney function caused by diabetic nephropathy. Summary of the Invention

[0004] Purpose of the invention: The purpose of the present invention is to provide an oligopeptide for use in the preparation of a drug for treating and / or preventing diabetic nephropathy.

[0005] Technical solution: The present invention discloses an oligopeptide for use in preparing a drug for treating and / or preventing diabetic nephropathy. The oligopeptide is an oligopeptide LP5 derived from chicken's gizzard lining, including an oligopeptide with an amino acid sequence of SEQ ID NO: 1: LNLYP.

[0006] The oligopeptide comprises a derivative sequence of 1-3 amino acids added to the N-terminus or C-terminus of the amino acid sequence SEQ ID NO: 1.

[0007] The oligopeptide comprises a conservative substitution variant in which less than two amino acids in the amino acid sequence SEQ ID NO: 1 are replaced by homologous polar amino acids.

[0008] Among them, diabetic nephropathy is a key pathological link in the progression from early stage to mid-stage, which is specifically manifested as metabolic disorders (hyperglycemia, insulin resistance) and early kidney damage (microalbuminuria, podocyte lesions).

[0009] Wherein, the application is that the oligopeptide improves the kidney function of diabetic nephropathy.

[0010] Among them, the application is that the oligopeptide reduces serum creatinine and urea nitrogen levels, improves glomerular filtration rate, maintains podocyte slit membrane protein expression, repairs filtration barrier, inhibits AGEs-RAGE signaling pathway, and reduces renal oxidative stress damage.

[0011] The administration method is oral, the administration lasts for 8 weeks, and the dosage is 10-40 mg / kg.

[0012] The present invention also discloses a pharmaceutical composition, which comprises the oligopeptide and a pharmaceutically acceptable carrier.

[0013] The dosage form of the pharmaceutical composition includes injection, oral preparation or transdermal absorption preparation.

[0014] The present invention also discloses the use of the pharmaceutical composition in preparing medicines for treating and / or preventing diabetic nephropathy.

[0015] Principle of the Invention: The present invention discloses the use of an oligopeptide in the preparation of a drug for treating and / or preventing diabetic nephropathy; the oligopeptide is LP5 and its derivative sequence or conservative substitution variant. In a DKD mouse model induced by STZ combined with a high-fat diet, LP5 improves glomerular filtration rate by reducing serum creatinine (SCr) and urea nitrogen (BUN) levels; maintains the expression of podocyte slit membrane proteins (nephrin, podocin) and repairs the filtration barrier; and inhibits the AGEs-RAGE signaling pathway to reduce renal oxidative stress damage. LP-5 can improve podocyte damage in diabetic nephropathy by regulating the Numb-NICD1 signaling pathway. LP-5 can also enhance proteasome activity and promote the clearance of AGEs in podocytes.

[0016] Beneficial effects: Compared with the existing technology, the present invention has the following significant advantages: the oligopeptide of the present invention can significantly improve the renal function indicators of diabetic nephropathy mice, effectively reduce the UACR, proteinuria and blood creatinine levels of DKD mice, and restore the creatinine clearance rate; the oral administration method enhances the patient's dependence, and the oligopeptide is of natural origin and has no liver and kidney toxicity, and has great application prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] Figure 1LP-5 improves renal function in diabetic nephropathy mice; A is the urine microalbumin-to-creatinine ratio of mice; B is the 12-h urine protein content of mice; C is the serum creatinine concentration of mice; D is the creatinine clearance rate of mice; E is the serum triglyceride level of mice; F is the serum total cholesterol level of mice; G is the serum low-density lipoprotein cholesterol level of 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.);

[0018] Figure 2 LP-5 improves glomerular hypertrophy and abnormal tubular morphology in diabetic nephropathy mice;

[0019] Figure 3 LP-5 improves glomerular mesangial proliferation and glycogen accumulation in diabetic nephropathy mice;

[0020] Figure 4 LP-5 improves glomerular collagen fiber proliferation in diabetic nephropathy mice;

[0021] Figure 5 LP-5 improves podocyte basement membrane thickening and foot process fusion in diabetic nephropathy mice;

[0022] Figure 6 LP-5 inhibits high glucose-induced podocyte barrier damage; A is the expression level of nephrin in podocytes; B is the expression level of podocin in podocytes; C is the expression level of podocalyxin in podocytes; D is the expression level of integrin α3β1 in podocytes; E is the expression level of WT1 in podocytes; F is the effect of LP-5 on high glucose-induced podocyte cytoskeleton remodeling; G is the effect of LP-5 on high glucose-induced podocyte albumin leakage (F&H green represents F-actin, blue represents cell nucleus. ×630, scale bar = 5 μm) (n = 4, #P < 0.05, ##P < 0.01, ###P < 0.001, compared with NG group; *P < 0.05, **P < 0.01, ***P < 0.001, compared with HG group.);

[0023] Figure 7Figure 5 shows that LP-5 inhibits podocyte damage caused by AGE accumulation; A shows the effect of LP-5 on high glucose-induced podocyte AGE accumulation; B shows the effect of LP-5 on high glucose-induced podocyte RAGE levels; C shows the effect of LP-5 on AGE-stimulated podocyte AGE accumulation; D shows the effect of LP-5 on AGE-stimulated podocyte RAGE levels; E shows the effect of LP-5 on AGE-stimulated podocyte Nephrin expression; F shows the effect of LP-5 on AGE-stimulated podocyte Podocin expression; G shows the effect of LP-5 on AGE-stimulated podocyte Desmin expression. H shows the effect of LP-5 on SMA expression in podocytes stimulated by AGEs; I shows the effect of LP-5 on skeletal remodeling in podocytes stimulated by AGEs (green represents F-actin, blue represents nucleus, ×630, scale bar = 5 μm); J shows the representative image of mitochondrial membrane potential in podocytes (×630, scale bar = 20 μm); K shows the level of mitochondrial membrane potential in podocytes; L shows the representative image of reactive oxygen species in podocytes (×630, scale bar = 20 μm); M shows the level of reactive oxygen species in podocytes (n = 4, #P < 0.05, ##P < 0.01, ###P < 0.001, compared with Control group; *P < 0.05, **P < 0.01, ***P < 0.001, compared with AGEs group.). DETAILED DESCRIPTION

[0024] The technical solution of the present invention is further illustrated below with reference to the examples. The test materials used in the examples can all be purchased through conventional channels. Among them, the amino acid sequence of the oligopeptide LP-5 is SEQ ID NO: 1: Leu-Asn-Leu-Tyr-Pro, which was synthesized by a commercial company. The sequence was confirmed by mass spectrometry and the purity was above 98%.

[0025] Example 1

[0026] Evaluation of the efficacy of LP-5 in improving diabetic nephropathy:

[0027] 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 to the environment for one week before the experiment and housed in an SPF-grade animal room at room temperature of 22-24°C, 12 hours of light and 12 hours of darkness, with free access to food and water. They were randomly divided into a blank control group and a model group. After two weeks of high-fat diet feeding, the model group was intraperitoneally injected with 50 mg / kg of streptozotocin daily for five consecutive days. The control group was fed a normal diet and received an equal amount of vehicle intraperitoneally. At five weeks after modeling, the fasting blood glucose levels of the mice were measured, and urine was collected in metabolic cages to measure urine creatinine, urine protein, and urine microalbumin concentrations, and urine protein electrophoresis analysis was performed.

[0028] After the diabetic nephropathy model was successfully established, mice in the model group were randomly divided into groups. Each group was given daily oral administration of 10, 20, or 40 mg / kg LP-5 (LP-5 low, medium, and high dose groups); 20 mg / kg losartan potassium (positive drug group 1); and 1000 mg / kg Huangkui capsule (positive drug group 2). In addition, mice in the blank and model groups were given an equal volume of normal saline daily by oral administration for 8 weeks.

[0029] After dosing, mice were placed in metabolic cages and fasted for 12 hours. Urine was collected and volume calculated, then centrifuged at 3500 rpm for 15 minutes at 4°C. Urine creatinine, protein, and microalbumin were measured using kits, and samples were stored at -80°C. Blood was collected from the eyeballs of the mice, allowed to stand at room temperature for 1 hour, and then centrifuged at 3500 rpm for 15 minutes at 4°C to separate serum. The serum was aliquoted and stored at -80°C. Immediately after blood collection, the kidneys were removed, the renal capsule removed, and weighed. The left kidney was placed in 4% paraformaldehyde and allowed to stand at room temperature for 24 hours. Half of the kidney was embedded in paraffin and sectioned for pathological staining. The other half was dehydrated in 30% sucrose solution, embedded in OCT gel, and frozen sections were prepared for later use. Paraffin sections: Half of the left kidney was paraffin-embedded, and 3 μm thick paraffin sections were prepared. Hematoxylin and eosin (HE), PAS, and MASSON staining were performed (contracted by Nanjing Freese Biotechnology Co., Ltd.). Full-length scans were taken using a pathology scanner, and images were visualized and analyzed using NDP.view software. Frozen sections: Dehydrate half of the left kidney and rapidly freeze in OCT gel. Cut sections to 4 μm thickness using a microtome. Immediately mount the sections to prevent curling and store at -20°C for renal tissue immunofluorescence experiments. Electron microscopy specimens: Obtain a 2 mm × 2 mm block of tissue from the renal cortex and fix it in glutaraldehyde fixative for 2 hours at room temperature in the dark. Transfer to 4°C for storage, prepare the specimen, and photograph it.

[0030] The experimental results are as follows:

[0031] like Figure 1As shown, the urinary microalbumin-to-creatinine ratio (UACR) of diabetic nephropathy mice was significantly increased (P < 0.001). Compared with the model group, the UACR levels of mice in the LP-5 10 / 20 / 40 mg / kg groups and the losartan potassium and Huangkui capsule groups were significantly decreased (P < 0.01). The 12-hour urine protein content of diabetic nephropathy mice was significantly increased (P < 0.01). Compared with the model group, the urinary protein levels of mice in the LP-5 10 / 20 / 40 mg / kg groups and the losartan potassium and Huangkui capsule groups were significantly decreased (P < 0.05). Serum triglyceride, total cholesterol, and low-density lipoprotein cholesterol levels in diabetic nephropathy mice were significantly increased (P < 0.001). Administration of LP5 significantly reduced these levels (P < 0.05). Compared with the normal control group, the diabetic nephropathy mice had significantly elevated serum creatinine (P < 0.01). The LP-5 10 / 20 / 40 mg / kg group, as well as the losartan potassium and Huangkui capsule positive drug groups, significantly reduced serum creatinine levels (P < 0.05). The diabetic nephropathy mice also had significantly decreased creatinine clearance (P < 0.001), indicating reduced glomerular filtration capacity. The LP-5 10 / 20 / 40 mg / kg group and the losartan potassium positive drug group significantly increased creatinine clearance (P < 0.05).

[0032] like Figure 2 As shown, HE staining of renal tissue revealed that glomeruli in the normal control group were normal in size and had clear outlines. The surrounding renal tubules were morphologically normal, with a central brush border (green arrow). In the model group, the central brush border was lost, glomeruli were enlarged (white arrow), and numerous vacuolar lesions (black arrow) were present in renal tubular cells, typical of diabetic nephropathy. Compared to the model group, glomeruli in the LP-5 10 / 20 / 40 mg / kg and losartan potassium groups were normal in size, but some tubular epithelial cells still showed vacuolar degeneration.

[0033] PAS staining results of renal tissue Figure 3 As shown in the figure, the glomeruli of mice in the normal control group were normal in size and well-defined, with normal surrounding tubular morphology and no obvious glycogen accumulation. Kidney sections from mice with diabetic nephropathy showed significant PAS-positive staining, suggesting abnormal glycogen accumulation in the renal tissue. Furthermore, the glomeruli of mice in the DKD group were abnormally enlarged (white arrows), with mild mesangial proliferation (red arrows), and numerous vacuolar lesions (black) in the renal tubular epithelial cells. Compared with the model group, the glomeruli of mice in the LP-5 10 / 20 / 40 mg / kg groups and the losartan potassium-positive drug group were normal in size, but some tubular epithelial cells still showed vacuolar degeneration. The glomeruli of mice in the LP-5 10 mg / kg group still showed mild mesangial proliferation and glycogen accumulation. No obvious glycogen accumulation or mesangial proliferation was observed in the other drug-treated groups.

[0034] The results of MASSON staining of mouse kidney tissue are as follows Figure 4 As shown in the figure, the glomeruli of mice in the normal control group were normal in size, with brush-bordered renal tubules and no obvious collagen fiber proliferation. The model group mice showed glomerular hypertrophy (white arrows), extensive vacuolar degeneration of renal tubular epithelial cells, and cavities of varying sizes within the cytoplasm of renal tubular epithelial cells (black arrows). Significant collagen fiber proliferation was observed in the glomeruli, which appeared dark blue under MASSON staining (blue arrows). Compared with the model group, the glomeruli of mice in the LP-5 10 / 20 / 40 mg / kg groups, losartan potassium, and Huangkui capsule positive drug groups were normal in size, with no obvious collagen fiber staining, although some renal tubular epithelial cell vacuolar lesions were still present.

[0035] like Figure 5 As shown, the podocyte foot processes of mice in the blank control group were numerous and relatively independent, with normal basement membrane thickness. In contrast, the podocyte basement membrane of mice in the model group was thickened (white arrows), foot process fusion (black arrows), and the number of foot processes was reduced. The podocyte basement membrane thickness of mice in the LP-510 / 20 / 40 mg / kg groups was normal, while the podocyte basement membrane of mice in the losartan potassium group was thickened, with no significant difference from the model group. Compared with the model group, the number of podocyte foot processes in mice in all treatment groups was significantly increased, and foot process fusion was improved.

[0036] Example 2

[0037] LP-5 improves podocyte injury induced by high glucose and AGEs

[0038] Podocyte injury is the primary cause of proteinuria and glomerular filtration barrier dysfunction in diabetic nephropathy. By establishing a podocyte injury model, we evaluated the therapeutic effect of LP-5 on podocyte barrier injury using Western blotting, immunofluorescence, and Transwell assays.

[0039] Methods: Conditionally immortalized mouse podocyte cell line MPC5 cells were cultured in RPMI-1640 medium containing 10% fetal bovine serum and 1% penicillin-streptomycin solution in a cell culture incubator at 37°C and 5% CO2. The number of cell passages used in all experiments was controlled between 4 and 10. High glucose injury model: MPC5 cells with a confluence of 80% were taken and plated at 1×10 5 Each well of a six-well plate was inoculated with 100 μg / mL of MPC5 cells. The cells were cultured in an incubator for 12 hours to allow them to adhere to the wall. The medium was then replaced with serum-free and glucose-free medium for 12 hours for synchronization. The cells were then treated with medium containing normal glucose (NG; 11 mM glucose), high mannitol (MA; 11 mM glucose + 19 mM mannitol), high glucose (HG; 30 mM glucose), or high glucose plus LP-5 (0.1, 1, 10 μM) for 24 hours. AGEs damage model: MPC5 cells with a confluence of 80% were taken and plated at 1×105 Cells were seeded into each well of a six-well plate. Cultured in an incubator for 12 hours to allow attachment, then synchronized for 12 hours using serum-free, glucose-free medium. Cells were divided into six groups: control, BSA control (50 μg / mL BSA), AGEs (50 μg / mL AGEs), and AGEs plus LP-5 (0.1, 1, and 10 μM) groups. Cultures were continued in the incubator for 24 hours.

[0040] The experimental results are as follows:

[0041] LP-5 inhibits high glucose-induced podocyte barrier damage: podocyte slit membrane proteins Nephrin and Podocin, apical membrane protein Podocalyxin, and basement membrane protein α3β1 are involved in maintaining podocyte barrier function. Figure 6 As shown in Figures AD, high glucose culture significantly reduced the expression of podocyte Nephrin, Podocin, Podocalyxin, and α3β1 (P < 0.05); compared with the model group, LP-5 (1, 10 μM) significantly increased the expression of podocyte Nephrin, Podocin, Podocalyxin, and α3β1 (P < 0.05). WT1 is an important regulatory factor in podocyte life activities, and it participates in the regulation of the transcription and translation of podocyte proteins Nephrin, Podocin, and Podocalyxin. Figure 6 As shown in Figure E, the expression of WT1 protein in podocytes cultured in high glucose was significantly reduced (P < 0.05); compared with the model group, LP-5 (0.1, 1, 10 μM) could significantly increase the expression of WT1 protein (P < 0.05).

[0042] The podocyte skeleton affects the podocyte morphology and regulates most of the life activities of the podocyte. External stimuli cause the podocyte skeleton to remodel and damage the podocyte barrier function. Figure 6 As shown in middle F, the podocyte skeleton in the normoglucose group was in parallel bundles throughout the cell, while the podocyte skeleton in the high glucose group showed obvious cell membrane marginalization and significantly reduced actin expression in the cytoplasm; the podocyte skeleton morphology of the LP-5 (10 μM)-treated group was significantly restored, with typical parallel bundles of actin fibers.

[0043] LP-5 inhibits podocyte damage caused by AGEs accumulation: Figure 7As shown in middle A, high glucose culture significantly increased the level of AGEs in podocytes (P < 0.05); compared with the model group, low, medium, and high doses of LP-5 (0.1, 1, and 10 μM) significantly reduced the accumulation of AGEs in podocytes (P < 0.05). RAGE is a cell membrane surface receptor for AGEs. When AGEs increase, RAGE is activated, inducing downstream oxidative stress signals and promoting further increase in RAGE protein expression, leading to the AGEs-RAGE signal cascade effect. Figure 7 As shown in Figure B, high glucose culture significantly increased the level of RAGE in podocytes (P < 0.01); compared with the model group, low, medium, and high doses of LP-5 (0.1, 1, and 10 μM) significantly reduced the protein expression of RAGE in podocytes (P < 0.05; P < 0.01; P < 0.01). Figure 7 As shown in middle C, AGEs stimulation significantly increased the level of AGEs in podocytes (P < 0.01); compared with the model group, low, medium, and high doses of LP-5 (0.1, 1, and 10 μM) significantly reduced the accumulation of AGEs in podocytes (P < 0.05; P < 0.05; P < 0.01). Figure 7 As shown in Figure D, AGEs stimulation significantly increased the level of RAGE in podocytes (P < 0.05); compared with the model group, low, medium, and high doses of LP-5 (0.1, 1, and 10 μM) significantly reduced the level of RAGE in podocytes (P < 0.05). Figure 7 As shown in Figures E and F, AGEs stimulation significantly reduced the expression of podocyte slit diaphragm proteins Nephrin and Podocin (P < 0.05; P < 0.01), and non-glycosylated BSA had no significant effect on the protein levels of Nephrin and Podocin (P > 0.05). Compared with the model group, LP-5 (0.1, 1, 10 μM) significantly increased the expression of Nephrin in podocytes (P < 0.05), and LP-5 (1, 10 μM) significantly increased the expression of Podocin in podocytes (P < 0.05). Figure 7 As shown in G and H, AGEs stimulation significantly increased the expression of podocyte EMT markers Desmin and SMA (P < 0.05), and non-glycosylated BSA had no significant effect on the expression of Desmin and SMA (P > 0.05); compared with the model group, LP-5 (0.1, 1, 10 μM) significantly reduced the expression of Desmin and SMA in podocytes (P < 0.05). Figure 7 As shown in Figure I, the podocyte skeleton in the control group was bundled and ran through the entire cell, while the podocyte skeleton in the AGEs group was restructured, with obvious cell membrane marginalization and a significant decrease in the expression of the cytoskeleton inside the cell. In the LP-5 (10 μM)-treated group, the podocyte skeleton showed the morphology of actin fibers running through the cell. Figure 7As shown in J and K, the mitochondrial membrane potential (MMP) of podocytes in the AGEs group was significantly lower than that in the control group (P < 0.05); compared with the model group, the MMP level of podocytes in the LP-5 (10 μM) group was significantly increased (P < 0.01). This indicates that LP-5 inhibits AGEs-induced mitochondrial depolarization and protects podocyte mitochondrial function. Figure 7 As shown in L, M, the level of reactive oxygen species in podocytes of the AGEs group was extremely significantly increased (P < 0.001), which was 3.5 times that of the normal control group; LP-5 (10 μM) treatment significantly inhibited the AGEs-induced ROS level in podocytes (P < 0.01).

[0044] Therefore, the oligopeptides of the present invention are used in the preparation of drugs for the treatment and / or prevention of diabetic nephropathy, and can improve the glomerular filtration rate by lowering serum creatinine and urea nitrogen levels; maintain the expression of podocyte slit membrane proteins and repair the filtration barrier; and inhibit the AGEs-RAGE signaling pathway to reduce renal oxidative stress damage; among them, LP-5 can effectively inhibit the accumulation of podocyte AGEs and the activation of the AGEs-RAGE signaling pathway caused by AGEs in the extracellular environment, and LP-5 can effectively restore the expression of podocyte slit membrane proteins, inhibit the expression of podocyte EMT-related proteins, inhibit podocyte skeletal remodeling and mitochondrial oxidative stress damage, thereby improving AGEs-induced podocyte damage, significantly improving the renal function indicators of diabetic nephropathy, and has great clinical application prospects.

Claims

1. Use of an oligopeptide in the preparation of a drug for treating and / or preventing diabetic nephropathy, characterized in that: The oligopeptide includes an oligopeptide with an amino acid sequence of SEQ ID NO: 1: LNLYP.

2. The use according to claim 1, characterized in that The oligopeptide comprises a derivative sequence of 1 to 3 amino acids added to the N-terminus or C-terminus of the amino acid sequence SEQ ID NO:

1.

3. The use according to claim 1, characterized in that The oligopeptide includes a conservative substitution variant in which less than two amino acids in the amino acid sequence SEQ ID NO: 1 are replaced by homologous polar amino acids.

4. The use according to claim 1, characterized in that The diabetic nephropathy is a stage of progression from early stage to mid-stage, specifically metabolic disorders and early kidney damage.

5. The use according to claim 1, characterized in that The application is that the oligopeptide improves the kidney function of diabetic nephropathy.

6. The use according to claim 1, characterized in that The application is that the oligopeptide reduces serum creatinine and urea nitrogen levels, improves glomerular filtration rate, maintains podocyte slit membrane protein expression, repairs filtration barriers, inhibits AGEs-RAGE signaling pathway, and reduces renal oxidative stress damage.

7. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises the oligopeptide according to claim 1 and a pharmaceutically acceptable carrier.

8. The pharmaceutical composition according to claim 7, characterized in that The dosage form of the pharmaceutical composition includes injection, oral preparation or transdermal absorption preparation.

9. Use of the pharmaceutical composition according to claim 7 in the preparation of a drug for treating and / or preventing diabetic nephropathy.

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