Application of morusin compound in preparation of medicine for treating chronic kidney disease

Abstract

The invention belongs to the field of biological medicines, and particularly relates to application of morusin compounds in preparation of medicines for treating chronic kidney diseases. The morusin compound treats chronic kidney disease renal fibrosis by inhibiting a TGF-beta signal channel, reducing the expression of fibrosis related genes and proteins, reducing the fibrosis area and relieving renal tubule injury, provides a new choice for clinically treating the chronic kidney disease renal fibrosis, and has a good application prospect.

Description

Technical Field

[0001] The present invention belongs to the field of biomedicine, and particularly relates to the use of moracin compounds in the preparation of drugs for treating chronic kidney disease. Background Art

[0002] Chronic kidney disease (CKD) refers to a class of kidney diseases with persistent impairment of kidney structure or function. The national epidemiological survey from 2018 to 2019 showed that the prevalence rate in the adult population in China was as high as 8.2%. Without appropriate medical intervention, CKD can develop into renal failure, endangering the lives of patients. Clinically, the treatment of CKD mainly focuses on symptomatic treatment, including controlling blood sugar, blood pressure, blood lipids, etc., and there is no specific therapeutic drug yet. Renal fibrosis refers to the pathological phenotype of excessive accumulation of extracellular matrix in the renal tubulointerstitium and glomeruli. Fibrotic tissues can affect the function and survival of renal parenchymal cells in terms of spatial structure and cause damage to the overall renal function. Research shows that renal fibrosis is one of the core pathological features of CKD, and improving renal fibrosis can alleviate the impaired renal function. Therefore, anti-renal fibrosis is an important strategy for the treatment of CKD.

[0003] The TGF-β signal is the core signal regulating organ fibrotic lesions. The classical TGF-β signal starts with the sequential binding of extracellular TGF-β1 / 2 / 3 factors and membrane receptors TGFBR2 and TGFBR1, and then phosphorylates intracellular effector proteins Smad2 and Smad3 (which are also transcription factors). After Smad2 / 3 forms a complex with Smad4, it translocates into the nucleus to regulate the expression of genes related to the fibrotic process. In renal tissues of various types of CKD, the TGF-β signal shows excessive activation. In CKD animal models, inhibiting the TGF-β signal by gene modification or drug intervention can significantly reduce renal fibrosis and improve the impaired renal function. Therefore, targeting the TGF-β signal for the research and development of anti-renal fibrosis drugs is an important way for the development of new drugs for the treatment of CKD.

[0004] The traditional Chinese medicine Cortex Mori is the dried root bark of the mulberry tree (Morus alba L.) of the Moraceae family. It is cold in nature, sweet and pungent in taste, and belongs to the lung meridian. It has the effects of purging the lung to relieve asthma and promoting diuresis to reduce edema. It is commonly used to treat symptoms such as cough and asthma due to lung heat and oliguria with edema. Cortex Mori also has a therapeutic effect on obesity-related metabolic diseases and has effects such as lowering blood sugar, blood lipids, and improving insulin resistance. In the patent application (Mulberry bark extract for treating chronic kidney disease, its preparation method and use, CN202410256216.8), it is reported that Cortex Mori has significant anti-TGF-β signal drug activity and can be used to improve CKD-related renal fibrosis. However, the active drug components in Cortex Mori with anti-TGF-β signal activity and the ability to improve CKD renal fibrosis are still unclear.

[0005] Moracin compounds are a series of natural products extracted from plants of the Moraceae family, which have a wide range of biological activities, such as anti-tumor, antibacterial, antioxidant, etc., but there is no relevant report on the treatment of chronic kidney disease. SUMMARY OF THE INVENTION

[0006] In view of the problems of the prior art, the present invention provides the use of moracin compounds in the preparation of drugs for the treatment of chronic kidney disease.

[0007] The use of a compound represented by formula I, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a stereoisomer thereof, or a geometric isomer thereof, or an isotope-labeled compound thereof, or a crystal form thereof, or a prodrug thereof in the preparation of a drug for preventing and / or treating kidney disease;

[0008]

[0009] Wherein, ring A is selected from a substituted or unsubstituted 5- to 10-membered heterocycle, and the heteroatoms are selected from oxygen, sulfur, and nitrogen; the substituents are selected from hydroxyl, C1-C5 alkyl, and C1-C5 alcohol groups.

[0010] Preferably, the structural formula of the compound is as shown in formula II:

[0011]

[0012] Preferably, the structural formula of the compound is as shown in formula III:

[0013]

[0014] Preferably, the kidney disease is chronic kidney disease.

[0015] Preferably, the chronic kidney disease is chronic kidney disease with renal fibrosis.

[0016] Preferably, the drug can reduce the expression of fibrosis genes.

[0017] Preferably, the fibrosis genes are selected from fibronectin, Col1a1, and α-SMA.

[0018] Preferably, the drug is used to inhibit TGF-β signal activity.

[0019] Preferably, the drug can reduce renal tubular injury.

[0020] The present invention also provides a pharmaceutical composition for preventing and / or treating kidney diseases, which is a preparation prepared from a compound represented by Formula I, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a stereoisomer thereof, or a geometric isomer thereof, or an isotope-labeled compound thereof, or a crystal form thereof, or a prodrug thereof as an active ingredient, or an active fraction of Morus alba L. root bark mainly composed of the above compound, plus pharmaceutically acceptable excipients; the structure of the compound represented by Formula I is:

[0021]

[0022] Wherein, ring A is selected from a substituted or unsubstituted 5- to 10-membered heterocyclic ring, and the heteroatom is selected from oxygen, sulfur, and nitrogen; the substituent is selected from a hydroxyl group, a C1-C5 alkyl group, and a C1-C5 alcohol group.

[0023] The chemical structural formula of moracin O is The chemical structural formula of moracin P is

[0024] The moracin compounds (moracin O, moracin P) of the present invention can treat renal fibrosis of chronic kidney diseases by inhibiting the TGF-β signal, reducing the expression of fibrosis-related genes and proteins, decreasing the fibrotic area, and alleviating the renal tubular injury caused by UUO, thus providing a new option for drugs for treating renal fibrosis of chronic kidney diseases clinically and having good application prospects.

[0025] Obviously, based on the above content of the present invention, according to the common general knowledge and conventional means in the art, without departing from the above basic technical idea of the present invention, various other forms of modifications, substitutions or changes can be made.

[0026] The above content of the present invention will be further described in detail below through specific embodiments in the form of examples. However, it should not be understood that the scope of the above subject matter of the present invention is limited to the following examples. All technologies implemented based on the above content of the present invention belong to the scope of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1Mulberroside O / P inhibits the TGF-β signaling activity in renal tubular epithelial TCMK1 cells. A - B. CCK8 assay was used to test the effects of different concentrations of mulberroside O and P on the viability of TCMK1 cells. The 90% cell viability range is marked by the dotted line in the figure. C. TCMK1 cells were pretreated with different concentrations of mulberroside O for 12 hours, and then stimulated with 5 ng / mL TGF-β1 for 30 min. Western blot was used to analyze the levels of Smad2, Smad3 and their phosphorylated forms. D - G are the quantitative analyses of the corresponding protein bands in Figure C. H. TCMK1 cells were pretreated with different concentrations of mulberroside P for 12 hours, and then stimulated with 5 ng / mL TGF-β1 for 30 min. Western blot was used to analyze the levels of Smad2, Smad3 and their phosphorylated forms. I - L are the quantitative analyses of the corresponding protein bands in Figure H.

[0028] Figure 2 Mulberroside O inhibits renal fibrosis in UUO mice. A. HE and Masson staining were used to analyze the renal tissue structure and collagen (blue) distribution, scale bar is 100μm. B. Tubular injury score based on HE staining. C. Quantitative analysis of fibrotic area based on Masson staining. D - F. RT-PCR was used to analyze the mRNA expression of fibronectin, Col1a1, α-SMA in renal tissue. G. Western blot was used to analyze the protein expression of fibrotic proteins fibronectin, Collagen I, α-SMA. H - J are the quantitative analyses of the corresponding protein bands in Figure G. Each point in the statistical graph represents an independent animal specimen. **p < 0.01 and ***p < 0.001 Vs. Sham. # p < 0.05, ## p < 0.01 and ### p < 0.001 Vs. UUO.

[0029] Figure 3 Mulberroside P inhibits renal fibrosis in UUO mice. A. HE and Masson staining were used to analyze the renal tissue structure and collagen (blue) distribution, scale bar is 100μm. B. Tubular injury score based on HE staining. C. Quantitative analysis of fibrotic area based on Masson staining. D - F. RT-PCR was used to analyze the mRNA expression of fibronectin, Col1a1, α-SMA in renal tissue. G. Western blot was used to analyze the protein expression of fibrotic proteins fibronectin, Collagen I, α-SMA. H - J are the quantitative analyses of the corresponding protein bands in Figure G. Each point in the statistical graph represents an independent animal specimen. **p < 0.01 and ***p < 0.001 Vs. Sham. # p < 0.05,## p < 0.01 and ### p < 0.001 Vs. UUO. Specific implementation manners

[0030] In the following examples and experimental examples, the reagents and raw materials not specifically described are all commercially available products.

[0031] Example 1 Moracin O and moracin P can inhibit TGF-β signal activity

[0032] I. Experimental methods

[0033] 1. CCK8 cytotoxicity assay

[0034] Mouse renal tubular epithelial TCMK1 cells were seeded in 96-well plates, and the culture medium was DMEM (high glucose) + 10% FBS (fetal bovine serum). The culture conditions were 37 °C, 5% CO2 and 100% humidity. When the cell density was close to 80 - 90%, different concentrations (0.78 μg / mL, 1.56 μg / mL, 3.13 μg / mL, 6.25 μg / mL, 12.25 μg / mL, 25 μg / mL) of moracin O and moracin P were added to 0.5% FBS and the cells were treated for 24 hours. Then, the serum-free medium containing 10% CCK8 reagent (Sangon Biotech, product number: E606335) was replaced and incubated for 2 hours. The absorbance at 450 nm wavelength was measured using a multifunctional microplate reader, and the cell viability was calculated.

[0035] 2. Cell treatment of moracin O and moracin P against TGF-β signal activity

[0036] Mouse renal tubular epithelial TCMK1 cells were seeded in 6-well plates. When the cell density was close to 80 - 90%, different concentrations (1.56 μg / mL, 3.13 μg / mL, 6.25 μg / mL) of moracin O and moracin P were added to the 0.5% FBS medium and the cells were treated for 24 hours. Then, 5 ng / mL TGF-β1 was added to stimulate for 30 min. The cells were collected, proteins were extracted, and the expression levels of Smad2, Smad3, p-Smad2, and p-Smad3 were examined by western blot. β-actin was used as the internal reference. The antibodies used in western blot included rabbit anti-Smad2 (CST, product number 5339, USA, dilution ratio 1:1000), rabbit anti-Smad3 (CST, product number 9523, USA, dilution ratio 1:1000), rabbit anti-p-Smad2 (CST, product number 18338, USA, dilution ratio 1:1000), rabbit anti-p-Smad3 (Abcam, product number ab52903, USA, dilution ratio 1:1000), and mouse anti-β-actin (Abway, product number AB0011, China, dilution ratio 1:5000).

[0037] II. Experimental Results

[0038] The results are as Figure 1 (A, B) shown. After TCMK1 cells were treated with different concentrations of moracin O and moracin P for 24 hours, the CCK8 cell viability assay found that when the concentrations of moracin O and moracin P did not exceed 6.25 μg / mL, the cell viability could be maintained at about 90%. Therefore, in this example, three concentrations of 1.56, 3.13, and 6.25 μg / mL were used to test the effect of the drug on TGF-β signaling. As Figure 1 (C-L) shown, pretreatment of TCMK1 cells with 1.56, 3.13, and 6.25 μg / mL of moracin O and moracin P for 12 hours could dose-dependently inhibit the phosphorylation activation of Smad2 and Smad3 induced by transient (30 min) TGF-β1 stimulation, while the total protein levels of Smad2 and Smad3 were not affected. The results indicate that moracin O and moracin P block the activation of the TGF-β signaling pathway by inhibiting the phosphorylation of Smad2 and Smad3, thereby improving impaired renal function and reducing renal fibrosis.

[0039] Example 2 Moracin O can be used to treat renal fibrosis in chronic kidney disease

[0040] I. Experimental Methods

[0041] 1. Construction of unilateral ureteral obstruction (UUO) mouse model and drug treatment: Male C57BL / 6 mice aged 8-10 weeks were randomly divided into sham operation group (Sham), UUO model group, low-dose drug treatment group (Moracin O-L), and high-dose drug treatment group (Moracin O-H), with 7-8 mice in each group. The UUO surgical modeling process is as follows: After the mice were anesthetized with 40 mg / kg pentobarbital sodium, the hair on the back skin was shaved off. After disinfection, a 1 cm skin and body wall incision was made at the left kidney site. The renal ureter was dissected with blunt forceps and ligated with surgical suture, and then the tissue was replaced and the body wall and skin tissue were sutured. The mice in the Sham group underwent the same surgical procedure, but the ureter was not ligated. All animals were given wound disinfection with povidone iodine and intraperitoneal antibiotic injection to prevent infection after the operation, and were placed in a warm environment for recovery. The mice in the low-dose drug treatment group and the high-dose drug treatment group were intraperitoneally injected with 20 mg / kg (L, injection volume of 100 uL) and 40 mg / kg (H, injection volume of 200 uL) of Moracin O (MW 326.37, CAS No. 123702-97-6) respectively every day for 7 days after the operation. The mice in the model group and the Sham group were injected with the solvent (corn oil). At the end of the experiment, the mice were euthanized with 1 g / kg pentobarbital sodium, and the kidney tissues were collected for analysis of relevant indicators.

[0042] 2. Histopathological staining: Paraffin-embedded kidney tissues were cut into 4-μm thick sections, dewaxed with conventional xylene and rehydrated with gradient ethanol. Then, HE staining (Beyotime, C0105, China) and Masson staining (Nanjing Jiancheng, D026-1-3, China) were performed using kits. After the stained sections were mounted with neutral balsam, they were observed and photographed under an upright bright-field microscope (Leica, DM500, Germany). Tubular injury scores were determined using HE-stained pictures. According to the presence or absence of cell degeneration and necrosis, tubular dilation, cast deposition, brush border loss or necrosis in the section fields of view, the following 5 scores were assigned: 0 points for normal; 1 point for less than 10% cortical involvement; 2 points for 10% - 25% cortical involvement; 3 points for 25% - 50% cortical involvement; 4 points for 50% - 75% cortical involvement; 5 points for more than 75% cortical involvement. For Masson staining, the proportion of positive staining (collagen) area was directly analyzed using Image J software. At least 3 randomly photographed fields of view were analyzed for each animal in each treatment group.

[0043] 3. RT-PCR: Total RNA was extracted from kidney tissues using the Trizol method. 1 μg of RNA was used to synthesize cDNA with M-MuLV reverse transcriptase (Sangon Biotech, B600005, China). The reaction steps were: 25°C for 5 min; 42°C for 60 min; 85°C for 5 min. RT-PCR amplification was performed using ChamQ Universal SYBR qPCR Master Mix (Vazyme, Q711-02, China), and the relative expression levels of genes between treatment groups were calculated using the 2 -△△Ct method. The primers used for RT-PCR included:

[0044] fibronectin, F: 5’-CTGGGACTGTACCTGCATCG-3’ (SEQ ID NO.1),

[0045] R: 5’-CCTCCACTTGTCGCCAATCT-3’ (SEQ ID NO.2);

[0046] Col1a1, F: 5’-ATCCAACGAGATCGAGCTCA-3’ (SEQ ID NO.3),

[0047] R: 5’-AAGGGAGCCACATCGATGAT-3’ (SEQ ID NO.4);

[0048] α-SMA, F: 5’-AGAGTTTTGTGCTGAGGTCCC-3’ (SEQ ID NO.5),

[0049] R: 5’-GGAGCATCATCACCAGCGAA-3’ (SEQ ID NO.6);

[0050] β-actin, F: 5’-AGAGGGAAATCGTGCGTGAC-3’ (SEQ ID NO.7),

[0051] R: 5’-CAATAGTGATGACCTGGCCGT-3’ (SEQ ID NO.8).

[0052] 4. Western blot: The renal tissue was lysed and the protein was extracted using IP lysis buffer. The protein concentration was determined by the Coomassie Brilliant Blue method. After the protein was denatured and lysed with SDS loading buffer, 20 μg of protein per lane was loaded onto a 10% SDS-PAGE gel for electrophoresis. After electrophoresis, the protein in the gel was transferred to a PVDF membrane, blocked with 5% non-fat milk or 2.5% BSA (for detecting phosphorylated proteins) for 1 h, incubated with the primary antibody overnight at 4°C, washed 3 times with TBST, 5 min each time, incubated with a species-matched horseradish peroxidase (HRP)-labeled secondary antibody for 1 h, and washed 3 times with TBST, 5 min each time. Then, signal exposure was performed using the SuperPico ECL Chemiluminescence Kit (Novizan, E422-01, China), and signal acquisition was performed using the ChemiScope 600EXp System (Qinxiang, China). The Western blot band signals were quantitatively analyzed using ImageJ software. The antibodies used in the experiments of this example included goat anti-Collagen I (SouthernBiothech, catalog number 1310-01, USA, dilution ratio 1:500), mouse anti-α-SMA (Boster, catalog number BM0002, China, dilution ratio 1:1000), rabbit anti-fibronectin (Abmart, catalog number T59537, China, dilution ratio 1:1000), and mouse anti-β-actin (Abway, catalog number AB0011, China, dilution ratio 1:5000).

[0053] II. Experimental Results

[0054] The in vivo anti-renal fibrosis efficacy of moracin O was analyzed in the UUO mouse model. HE staining showed that moracin O intervention significantly improved the abnormal renal tissue structure in UUO and reduced the renal tubular injury score. Masson staining showed that the extracellular collagen area in the renal tissue of moracin O-treated mice was significantly reduced ( Figure 2(A-C). RT-PCR analysis of renal tissues revealed that compared with the UUO model group, the expression levels of the renal fibrosis genes fibronectin, Col1a1, and α-SMA mRNA were significantly inhibited by moracin O. Figure 2 (D-F). Western blot analysis further confirmed that moracin O treatment reduced the expression levels of the fibrosis proteins fibronectin, Collagen I, and α-SMA. Figure 2 (G-J). The results showed that moracin O could treat renal fibrosis in chronic kidney disease by reducing the expression of fibrosis-related genes and proteins, decreasing the fibrotic area, and alleviating renal tubular injury induced by UUO.

[0055] Example 3 Moracin P can be used to treat renal fibrosis in chronic kidney disease

[0056] I. Experimental methods

[0057] 1. Construction of unilateral ureteral obstruction (UUO) mouse model and drug treatment: Male C57BL / 6 mice aged 8 - 10 weeks were randomly divided into a sham operation group (Sham), a UUO model group, a low-dose drug treatment group (Moracin P-L), and a high-dose drug treatment group (Moracin P-H), with 7 - 8 mice in each group. The UUO surgical modeling process was as follows: After anesthesia with 40 mg / kg pentobarbital sodium, the back skin hair of the mice was shaved, and after disinfection, a 1-cm skin and body wall incision was made at the left kidney site. The renal ureter was dissected with blunt forceps and ligated with surgical suture, and then the tissue was repositioned, and the body wall and skin tissue were sutured. The mice in the Sham group underwent the same surgical procedure, but the ureter was not ligated. All animals were given wound disinfection with iodophor and intraperitoneal antibiotic injection to prevent infection after the operation and were placed in a warm environment for recovery. The mice in the low-dose drug treatment group and the high-dose drug treatment group were intraperitoneally injected with 20 mg / kg (L, injection volume 100 μL) and 40 mg / kg (H, injection volume 200 μL) of Moracin P (MW 326.37, CAS No. 102841-43-0) respectively every day for 7 days after the operation. The mice in the model group and the Sham group were injected with the solvent (corn oil). At the end of the experiment, the mice were euthanized with 1 g / kg pentobarbital sodium, and the kidney tissues were collected for relevant index analysis.

[0058] 2. Histopathological staining: The paraffin-embedded kidney tissues were cut into 4-μm thick sections, dewaxed with conventional xylene, and rehydrated with gradient ethanol. Then, HE staining (Beyotime, C0105, China) and Masson staining (Nanjing Jiancheng, D026-1-3, China) were performed using kits. After the stained sections were sealed with neutral balsam, they were observed and photographed under an upright bright-field microscope (Leica, DM500, Germany). Tubular injury scores were determined using HE-stained pictures. According to the presence or absence of cell degeneration and necrosis, tubular dilation, cast deposition, brush border loss or necrosis in the section fields of view, the following 5 scores were assigned: 0 for normal; 1 for less than 10% cortical involvement; 2 for 10% - 25% cortical involvement; 3 for 25% - 50% cortical involvement; 4 for 50% - 75% cortical involvement; 5 for more than 75% cortical involvement. For Masson staining, the proportion of positive staining (collagen) area was directly analyzed using Image J software. At least 3 randomly photographed fields of view were analyzed for each animal in each treatment group.

[0059] 3. RT-PCR: Total RNA was extracted from kidney tissues using the Trizol method. 1 μg of RNA was reverse-transcribed into cDNA using M-MuLV reverse transcriptase (Sangon Biotech, B600005, China). The reaction steps were: 25°C for 5 min; 42°C for 60 min; 85°C for 5 min. RT-PCR amplification was performed using ChamQ Universal SYBR qPCR Master Mix (Vazyme, Q711-02, China). The relative expression levels of genes between treatment groups were calculated using the 2 -△△Ct -ΔΔCt method. The primers used for RT-PCR were the same as those in Example 2.

[0060] 4. Western blot: The renal tissues were lysed and proteins were extracted using IP lysis buffer. The protein concentration was determined by the Coomassie Brilliant Blue method. After the proteins were denatured and lysed with SDS loading buffer, 20 μg of protein per lane was loaded onto a 10% SDS-PAGE gel for electrophoresis. After electrophoresis, the proteins in the gel were transferred to a PVDF membrane, blocked with 5% non-fat milk or 2.5% BSA (for detecting phosphorylated proteins) for 1 h, incubated with the primary antibody overnight at 4°C, washed 3 times with TBST for 5 min each time, incubated with a species-matched horseradish peroxidase (HRP)-labeled secondary antibody for 1 h, and washed 3 times with TBST for 5 min each time. Then, the signal was exposed using the SuperPico ECL Chemiluminescence Kit (Novizan, E422-01, China), and the signal was collected using the ChemiScope 600EXp System (Qinxiang, China). The Western blot band signals were quantitatively analyzed using ImageJ software. The antibodies used in this experiment were the same as those in Example 2.

[0061] II. Experimental Results

[0062] The in vivo anti-renal fibrosis efficacy of sanggenin P was analyzed in the UUO mouse model. HE staining showed that sanggenin P intervention significantly improved the abnormal renal tissue structure in UUO and reduced the tubular injury score. Masson staining showed that the extracellular collagen area in the renal tissues of mice intervened with sanggenin P was significantly decreased ( Figure 3 A-C). RT-PCR analysis of renal tissues found that compared with the UUO model group, the expression levels of fibrosis-related genes fibronectin, Col1a1, and α-SMA mRNA in the renal tissues intervened with sanggenin P were significantly inhibited ( Figure 3 D-F). Western blot analysis further confirmed that sanggenin P intervention reduced the expression levels of fibrosis proteins fibronectin, Collagen I, and α-SMA ( Figure 3 G-J). The results showed that sanggenin P could treat renal fibrosis in chronic kidney disease by reducing the expression of fibrosis-related genes and proteins, decreasing the fibrosis area, and alleviating tubular injury caused by UUO.

[0063] In summary, the sanggenin compounds (sanggenin O, sanggenin P) of the present invention can treat renal fibrosis in chronic kidney disease by inhibiting the TGF-β signal, reducing the expression of fibrosis-related genes and proteins, decreasing the fibrosis area, and alleviating tubular injury caused by UUO, providing a new option for drugs for treating renal fibrosis in chronic kidney disease clinically and having good application prospects.

Claims

Use of a compound represented by Formula I, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a stereoisomer thereof, or a geometric isomer thereof, or an isotope-labeled compound thereof, or a crystal form thereof, or a prodrug thereof in the preparation of a drug for preventing and / or treating kidney diseases; Among them, Ring A is selected from substituted or unsubstituted 5- to 10-membered heterocycles, and the heteroatoms are selected from oxygen, sulfur, and nitrogen; the substituents are selected from hydroxyl, C1-C5 alkyl, and C1-C5 alkoxy.

2. The use according to claim 1, characterized in that: The structural formula of the compound is as shown in Formula II:

3. The use according to claim 1, characterized in that: The structural formula of the compound is as shown in Formula III:

4. The use according to claim 1, characterized in that: The kidney disease is chronic kidney disease.

5. The use according to claim 4, characterized in that: The chronic kidney disease is a chronic kidney disease with renal fibrosis.

6. The use according to claim 1, characterized in that: The drug can reduce the expression of fibrosis genes.

7. The use according to claim 6, characterized in that: The fibrosis genes are selected from fibronectin, Col1a1, and α-SMA.

8. The use according to claim 1, characterized in that: The drug is used to inhibit TGF-β signaling activity.

9. The use according to claim 1, characterized in that: The drug can alleviate renal tubular injury.

10. A pharmaceutical composition for preventing and / or treating kidney diseases, characterized in that: It is a preparation prepared with a compound represented by Formula I, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a stereoisomer thereof, or a geometric isomer thereof, or an isotope-labeled compound thereof, or a crystal form thereof, or a prodrug thereof as the active ingredient, or with the active part of mulberry bark containing the above compound as the main component, plus pharmaceutically acceptable excipients; the structure of the compound represented by Formula I is: Wherein, Ring A is selected from substituted or unsubstituted 5- to 10-membered heterocycles, and the heteroatoms are selected from oxygen, sulfur, and nitrogen; the substituents are selected from hydroxyl, C1-C5 alkyl, and C1-C5 alkoxy.

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