Application of linarin in preparation of medicine for preventing or treating renal fibrosis

Abstract

The invention provides application of linarin in preparation of a medicine for preventing or treating renal fibrosis, and belongs to the technical field of medical application. Researches find that the linarin can down-regulate the expression levels of YAP, CTGF and inflammatory factors IL-6, IL-1beta and TNF-alpha, and on the basis, the linarin or the pharmaceutically acceptable salt, ester or solvate thereof can be used for preparing the medicine for preventing and treating renal fibrosis caused by unilateral ureter obstruction or fibroblast hyperplasia. According to the present invention, the pharmaceutical composition can effectively inhibit the one-side ureter obstruction, can reverse the kidney injury caused by the one-side ureter obstruction, can improve the renal dysfunction caused by the one-side ureter obstruction, can provide the new drug selection for the application scenario requiring the down-regulation of the expression levels of YAP, CTGF and the like, and can provide the important guiding significance for the prevention and treatment of the renal fibrosis and the kidney injury, the renal dysfunction and other diseases caused by the renal fibrosis. And the linarin has no obvious toxic or side effect, is definite in curative effect, safe and controllable, and has a relatively high practical application value.

Description

Technical Field

[0001] The present invention relates to the field of medical application technology, and in particular to the application of linaloside in preparing medicines for preventing or treating renal fibrosis. Background Art

[0002] Clinical and experimental studies have shown that renal fibrosis is a common final pathological process in most progressive chronic renal damage or poor adaptive repair. It is usually caused by an imbalance in the synthesis and degradation of the extracellular matrix, as well as excessive inflammatory responses and fibroblast proliferation. It is the main factor and final common pathway for chronic kidney disease (CKD) to develop into end-stage renal disease (ESRD). Therefore, preventing and delaying renal interstitial fibrosis is the key to delaying the progression of CKD. The emergence of renal fibrosis also means that renal damage is in the late stage. This may be the reason why anti-fibrosis is difficult to treat. The premise of early treatment is early detection. However, there is a lack of good biomarkers in the clinic to predict and evaluate renal fibrosis. For most CKD patients who reach end-stage renal disease, renal replacement therapy such as dialysis and renal transplantation is the only option. How to prevent and treat renal fibrosis is still an important problem faced by doctors and scientific researchers. Therefore, exploring potential drug targets for inhibiting renal fibrosis and developing safe and effective new anti-renal fibrosis drugs have important research significance and clinical value for the prevention and treatment of CKD.

[0003] The pathogenesis of renal fibrosis is mainly due to abnormal renal function, which is essentially different from other types of fibrotic diseases. There are many factors that cause renal fibrosis, and renal fibrosis caused by different factors often has different pathological mechanisms and treatment strategies. For example, renal fibrosis caused by hyperuricemia refers to the increase in uric acid levels in the blood due to hyperuricemia. When it exceeds the solubility limit, monosodium urate crystals will form and deposit, leading to kidney damage and activating a variety of cytokines and inflammatory pathways (such as signal transduction and activator of transcription factor 3 and reactive oxygen species, etc.), which can induce renal inflammation and renal fibrosis. In contrast, renal fibrosis caused by unilateral ureteral obstruction (UUO) is caused by structural or functional changes in the urinary tract that hinder normal urine flow (such as ureteral stones, trauma, stenosis and tumors, etc.). The obstruction caused by this structural or functional change makes it impossible for urine to be excreted normally, causing renal pelvic effusion, which in turn leads to loss of structure and function of renal tubules and glomeruli, and ultimately leads to renal tissue atrophy and fibrosis. Obviously, the initiating factors, pathological mechanisms and treatment strategies of renal fibrosis caused by hyperuricemia and unilateral ureteral obstruction are different. How to choose appropriate drugs is still the current research focus and difficulty.

[0004] Linarin (LR) is a natural flavonoid compound and an active ingredient of Chinese medicinal materials such as wild chrysanthemum, buddleja, and mint. It has multiple pharmacological activities such as anti-apoptosis, anti-inflammatory, antioxidant, anti-hypoxia, and anti-tumor. The prior art also discloses that linarin can regulate the expression level of uric acid secretion protein and is used to prepare drugs for treating hyperuricemia, but there is currently no related use of linarin in renal fibrosis (especially renal fibrosis caused by unilateral ureteral obstruction). Summary of the invention

[0005] In view of the technical problems existing in the background technology, the present application provides the use of mongoside in the preparation of drugs for preventing or treating renal fibrosis. The present application found through research that mongoside can downregulate the expression levels of YAP (Yes-associated protein), CTGF (connective tissue growth factor) and inflammatory factors IL-6, IL-1β, TNF-α, and is suitable for preventing and treating renal fibrosis caused by unilateral ureteral obstruction or fibroblast proliferation, and can reverse kidney damage caused by unilateral ureteral obstruction, and improve renal dysfunction caused by unilateral ureteral obstruction.

[0006] The embodiments of the present application provide the use of limonene or a pharmaceutically acceptable salt, ester or solvate thereof in the preparation of a drug for preventing or treating renal fibrosis.

[0007] In some embodiments, the renal fibrosis is renal fibrosis caused by unilateral ureteral obstruction.

[0008] In some embodiments, the renal fibrosis is renal fibrosis caused by fibroblast proliferation.

[0009] In some embodiments, the limonene glycoside or a pharmaceutically acceptable salt, ester or solvate thereof is used to down-regulate the expression levels of YAP, CTGF and inflammatory factors IL-6, IL-1β, TNF-α.

[0010] In some embodiments, the down-regulating effect of the limonene glycoside or a pharmaceutically acceptable salt, ester or solvate thereof on the expression levels of YAP, CTGF and inflammatory factors IL-6, IL-1β, TNF-α is dose-dependent.

[0011] In some embodiments, the dosage of the liuhuaside or its pharmaceutically acceptable salt, ester or solvate is 30-120 mg / kg calculated as liuhuaside.

[0012] In some embodiments, the limonene glycoside or a pharmaceutically acceptable salt, ester or solvate thereof is used to reverse kidney damage caused by unilateral ureteral obstruction.

[0013] In some embodiments, the limonene glycoside or a pharmaceutically acceptable salt, ester or solvate thereof is used to improve renal dysfunction caused by unilateral ureteral obstruction.

[0014] In some embodiments, the drug for preventing or treating renal fibrosis is a preparation prepared with limonene or its pharmaceutically acceptable salt, ester or solvate as the active ingredient and a pharmaceutically acceptable carrier or excipient.

[0015] In some embodiments, the dosage form of the preparation is a liquid preparation, a solid preparation or a semisolid preparation.

[0016] The beneficial effects of this application are:

[0017] The present application has found through research that mongoside can down-regulate the expression levels of YAP, CTGF and inflammatory factors IL-6, IL-1β, and TNF-α. Based on this, mongoside or its pharmaceutically acceptable salts, esters, or solvates can be used to prevent and treat renal fibrosis caused by unilateral ureteral obstruction or fibroblast proliferation, and can reverse kidney damage caused by unilateral ureteral obstruction, and improve renal dysfunction caused by unilateral ureteral obstruction, providing a new drug option for application scenarios that need to down-regulate the expression levels of YAP, CTGF and inflammatory factors IL-6, IL-1β, and TNF-α, and has important guiding significance for the prevention and treatment of renal fibrosis and the prevention and treatment of diseases such as kidney damage and renal dysfunction caused by renal fibrosis. In addition, mongoside has no obvious toxic and side effects, has a definite therapeutic effect, is safe and controllable, and has a high practical application value.

[0018] The above description is only an overview of the technical solution of the present application. In order to more clearly understand the technical means of the present application, it can be implemented in accordance with the contents of the specification. In order to make the above and other purposes, features and advantages of the present application more obvious and easy to understand, the specific implementation methods of the present application are listed below. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] In order to more clearly illustrate the technical solution of the present application, the following is a brief introduction to the drawings used in the present application. Obviously, the drawings described below are only some embodiments of the present application, and for ordinary technicians in this field, other drawings can be obtained based on these drawings without creative work.

[0020] Figure 1 This is a comparison chart of the detection results of YAP and CTGF protein expression levels in the kidneys of mice in each group in the examples of this application;

[0021] Figure 2 This is a comparison chart of the levels of serum inflammatory factors IL-6, IL-1β, and TNF-α in mice of each group in the examples of this application;

[0022] Figure 3 This is a comparison of HE staining of the kidneys of mice in each group in the examples of this application;

[0023] Figure 4 This is a Masson staining comparison of the kidneys of mice in each group in the examples of this application;

[0024] Figure 5 This is a comparison chart of serum creatinine levels of mice in various groups in the examples of this application;

[0025] Figure 6 This is a comparison chart of the serum urea nitrogen levels of mice in each group in the examples of this application. DETAILED DESCRIPTION

[0026] The following embodiments of the technical solution of the present application are described in detail in conjunction with the accompanying drawings. The following embodiments are only used to more clearly illustrate the technical solution of the present application, and are therefore only used as examples, and cannot be used to limit the scope of protection of the present application.

[0027] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by technicians in the technical field to which this application belongs; the terms used herein are only for the purpose of describing specific embodiments and are not intended to limit this application; the terms "including" and "having" in the specification and claims of this application and the above-mentioned figure descriptions and any variations thereof are intended to cover non-exclusive inclusions.

[0028] Reference to "embodiments" herein means that a particular feature, structure, or characteristic described in conjunction with the embodiments may be included in at least one embodiment of the present application. The appearance of the phrase in various locations in the specification does not necessarily refer to the same embodiment, nor is it an independent or alternative embodiment that is mutually exclusive with other embodiments. It is explicitly and implicitly understood by those skilled in the art that the embodiments described herein may be combined with other embodiments.

[0029] The Hippo signaling pathway, also known as the Salvador / Warts / Hippo (SWH) pathway, was first discovered and elucidated in the screening of tumor suppressors in Drosophila mutants. It is highly conserved in mammals. In the Hippo signaling pathway, the kinase cascade plays a major regulatory role. When the body is stimulated by inflammation or injury, it interferes with the upstream kinase cascade, drives the downstream YAP / TAZ (Tafazzin) to dephosphorylate and translocate to the nucleus, and forms a complex with the nuclear transcription factor TEA domain 1-4 (TEAD1-4) to induce the expression of downstream target genes, such as connective tissue growth factor (CTGF) and epidermal growth factor receptor (EGFR), thereby exerting the biological function of the Hippo-YAP / TAZ signaling pathway. The Hippo signaling pathway has been widely studied as a key mechanism for controlling the size of animal organs. It can regulate cell apoptosis and proliferation as well as the self-renewal of stem cells, and at the same time plays an important role in regulating tissue regeneration, maintaining tissue homeostasis and fibrosis formation. Studies have found that YAP, as the main effector of the Hippo signaling pathway, is highly involved in the occurrence and development of renal fibrosis.

[0030] The present application found in the study that unilateral ureteral obstruction can induce the activation of YAP in mouse kidney myofibroblasts, and inhibition of YAP can hinder the activation of fibroblasts during renal fibrosis. Therefore, targeted regulation of YAP and its downstream transcription factors may be an effective way to alleviate renal fibrosis. At the same time, the present application study determined that Menghua glycosides can downregulate the expression levels of YAP, CTGF and inflammatory factors IL-6, IL-1β, and TNF-α. Based on this, Menghua glycosides can be used to prevent and treat renal fibrosis caused by unilateral ureteral obstruction or fibroblast proliferation, and can reverse kidney damage caused by unilateral ureteral obstruction, and improve renal dysfunction caused by unilateral ureteral obstruction.

[0031] Specifically, the embodiments of the present application provide the use of limonene glycosides or their pharmaceutically acceptable salts, esters or solvates in the preparation of drugs for the prevention or treatment of renal fibrosis. Wherein, the renal fibrosis may be renal fibrosis caused by unilateral ureteral obstruction, or renal fibrosis caused by fibroblast proliferation. Limonene glycosides can prevent fibroblast activation by downregulating the expression levels of YAP, CTGF and inflammatory factors IL-6, IL-1β, and TNF-α, and thus play a role in preventing or treating renal fibrosis caused by the above reasons. At the same time, renal fibrosis caused by unilateral ureteral obstruction can also cause kidney damage and abnormal renal function. Limonene glycosides or their pharmaceutically acceptable salts, esters or solvates can also play a role in reversing kidney damage and improving abnormal renal function.

[0032] Furthermore, the down-regulating effect of limonene or its pharmaceutically acceptable salts, esters or solvates on the expression levels of YAP, CTGF and inflammatory factors IL-6, IL-1β, TNF-α is dose-dependent.

[0033] In some embodiments of the present application, the dosage of the liuhua glycoside or its pharmaceutically acceptable salt, ester or solvate is 30-120 mg / kg calculated as liuhua glycoside.

[0034] In some embodiments of the present application, the drug for preventing or treating renal fibrosis is a preparation prepared by using limonene or its pharmaceutically acceptable salt, ester or solvate as an active ingredient and adding a pharmaceutically acceptable carrier or excipient, wherein the preparation is in the form of a liquid preparation, a solid preparation or a semi-solid preparation.

[0035] Some specific embodiments are listed below. It should be noted that the embodiments described below are exemplary and are only used to explain the present application, and should not be construed as limiting the present application. If specific techniques or conditions are not specified in the embodiments, the techniques or conditions described in the literature in this area or the product specifications are used. The reagents or instruments used without specifying the manufacturer are all conventional products that can be obtained commercially.

[0036] Example

[0037] In order to verify the effects of montanol on YAP, CTGF, inflammatory factors IL-6, IL-1β, TNF-α and kidneys, the following experiments were conducted:

[0038] Experiment 1: Establishment of unilateral ureteral obstruction model, drug administration and material collection methods

[0039] SPF male C57BL / 6J mice (8 weeks old, weight 20±2g) were intraperitoneally injected with 1% sodium pentobarbital at a dose of 0.1mL / 20g. After the mice were anesthetized, they were fixed on a small animal operating table with their abdomen facing up. The cortex and muscle layer were cut along the midline of the abdomen to expose the left kidney, and the left ureter was stripped. The upper and lower 1 / 3 of the ureter were ligated with 5-0 silk thread, and the ureter was cut between the two ligature points. The abdominal incision of the mouse was then sutured layer by layer. The ureter of the mice in the sham operation group was only stripped, but not ligated or cut, and then sutured layer by layer.

[0040] Mice were randomly divided into sham operation group (Sham NS), sham operation + 120 mg / kg LR group (Sham LR-120), UUO model group (UUO LR-0), UUO + LR group (LR doses were 30, 60, 120 mg / kg, respectively, denoted as UUO LR-30, UUO LR-60, UUO LR-120), 8 mice in each group. Menghua glycoside powder was suspended in normal saline, and 0.4 mL / 20 g was administered by gavage at 9 am the next day after the model was established. The LR doses were 30, 60, and 120 mg / kg / d, respectively. The sham operation group and UUO model group were given the corresponding volume of normal saline by gavage at 0.4 mL / 20 g for 14 consecutive days. Four hours after oral administration on the 14th day, blood was collected by removing the eyeballs, and the blood was centrifuged at 4000 rpm and 4°C for 10 min. The serum was collected and stored at -80°C for testing. After blood collection, the mice were killed by cervical dislocation, and the kidneys on both sides of the mice were removed on ice and weighed. The weight ratio of the obstructed kidney to the non-obstructed kidney was calculated, and the left obstructed kidney was cut cross-sectionally. A part of the kidney tissue was fixed in 4% paraformaldehyde, and the rest was stored at -80°C.

[0041] Experiment 2: Detection of YAP and CTGF protein expression levels in the kidneys obtained from Experiment 1

[0042] Add 1000 μL of lysis buffer {prepared from 10 μL cocktail (CST, #5871) and 990 μL RRIPA (CST, #9806)} for every 100 mg of tissue. Use ophthalmic scissors on ice to quickly chop and homogenize the tissue 3 times, stop for 10 seconds each time, then sonicate 10 times and place in an ice bath for 30 minutes. Centrifuge at 12000g, 4°C for 15 minutes, take the supernatant to a new EP tube to obtain the total protein product of the tissue. Dilute the protein sample with 10-fold double distilled water, and determine the protein concentration by BCA method. Adjust the protein concentration of each group with distilled water, add 2× loading buffer containing 2% β-mercaptoethanol (AMRESCO, #M0482), mix well, seal with sealing film, boil in boiling water for 10 minutes, and then place in an ice bath for 5 minutes. According to the protein concentration and the amount of protein required for each electrophoresis, divide the package and store at -80°C. 20-30 μg tissue protein samples were taken for gel electrophoresis, membrane transfer, blocking, primary antibody, membrane washing, secondary antibody, membrane washing, ECL (Beijing Pulilai Gene Technology Co., Ltd., P1050) color development, and optical density analysis was performed using ImageQuant LAS 4000 gel imager (GE ImageQuant, LAS4000). The results are shown in Figure 1 shown.

[0043] exist Figure 1 From left to right, they are sham operation group, sham operation + 120 mg / kg LR group, UUO model group, and UUO + LR group (30, 60, 120 mg / kg). Figure 1 It can be seen that the expression levels of YAP and CTGF proteins in the renal tissue of UUO mice were significantly increased, while limonene glycosides could reduce their expression in a dose-dependent manner, indicating that limonene glycosides could inhibit the increase of YAP protein expression levels in the kidneys of mice induced by UUO.

[0044] Experiment 3: The serum obtained in Experiment 1 was tested for inflammatory factors IL-6 (Wuhan Elaruite Biotechnology Co., Ltd., E-MSEL-M0001), IL-1β (Wuhan Elaruite Biotechnology Co., Ltd., E-MSEL-M0003), and TNF-α (Wuhan Elaruite Biotechnology Co., Ltd., E-MSEL-M0002)

[0045] ①Preparation before testing: Prepare washing solution, standard working solution, biotinylated antibody working solution and enzyme conjugate working solution in sequence according to the instructions of each kit (except for the sample, the other liquids and materials are provided by the kit).

[0046] ② Sample addition: Take out the 96-well ELISA plate provided by the kit, set the standard wells, blank wells and sample wells. Add 50μL of the gradient diluted standard to the standard wells, 50μL of the standard or sample diluent to the blank wells, and 50μL of the mouse serum sample to be tested to the remaining wells. Cover the ELISA plate with a film and incubate at 37℃ for 120min.

[0047] ③ Add biotinylated antibody: Drain the liquid in the wells without washing. Add 50 μL of biotinylated antibody working solution to each well, cover the ELISA plate with a film, and incubate at 37°C for 1 hour.

[0048] ④ Washing: discard the liquid in the well and drain on absorbent paper. Add 350μL of washing solution to each well, soak for 40s, discard the liquid in the ELISA plate, and drain. Repeat this washing step three times.

[0049] ⑤ Add enzyme conjugate: Add 50 μL of enzyme conjugate working solution to each well, cover the ELISA plate with a film, and incubate at 37°C for 30 minutes.

[0050] ⑥ Washing: Wash the plate 3 times as in ④ washing step above.

[0051] ⑦ Color development: Add 50 μL of substrate solution to each well, cover the ELISA plate with a film, and incubate at 37°C in the dark for 15 minutes.

[0052] ⑧Termination and detection: Add 25 μL of stop solution to each well to terminate the reaction, and immediately detect the absorbance value of each well at 450 nm using a full-wavelength microplate reader (Molecular Devices, SpectraMax 190).

[0053] ⑨Calculation: Draw a standard curve based on the concentration of the standard and the corresponding absorbance value, and calculate the concentration of IL-6, IL-1β, and TNF-α in the sample to be tested based on the absorbance value of the sample. Figure 2 shown.

[0054] exist Figure 2 In the figure, from left to right are sham operation group, sham operation + 120 mg / kg LR group, UUO model group, UUO + LR group (30, 60, 120 mg / kg), where ns means no significant difference. Compared with the sham operation group, ### P<0.001; compared with the UUO group, ** P<0.01, *** P<0.001. Figure 2 It can be seen that limonene glycosides can significantly inhibit the significant increase in the levels of inflammatory factors IL-6, IL-1β, and TNF-α in the serum of UUO mice, and have a certain dose dependence, indicating that limonene glycosides can improve the inflammatory response of UUO mice.

[0055] Experiment 4: Histopathological examination of the kidneys obtained in Experiment 1

[0056] Hematoxylin-Eosin staining: After the tissue was fixed with 4% paraformaldehyde overnight, it was rinsed with running water for 24 hours, and then dehydrated, transparent and waxed in a tissue embedding machine (Wuhan Hairui Technology Co., Ltd., HBM-200LF): 60%, 70%, 80%, 90%, and 95% ethanol were soaked for 30 minutes respectively; anhydrous ethanol was soaked twice, each for 1 hour; xylene was transparent for 40 minutes; paraffin was soaked twice, each for 1 hour. Paraffin was embedded in the tissue embedding machine, and the tissue was cut into paraffin sections with a thickness of 5μm using a tissue ultrathin slicer (Leica, RM2245). After drying at 65℃ for 2 hours, the sections were dewaxed in xylene three times, each for 15 minutes; anhydrous ethanol was used twice, each for 5 minutes, 95%, 85%, and 75% ethanol were soaked for 5 minutes each, and distilled water was used for 3 minutes. Stain with hematoxylin (Shanghai Biotech Co., Ltd., C0107) for 6 min, rinse in double distilled water for 30 s, differentiate with 1% hydrochloric acid for 10 s, blue with PBS (Beijing Lanjieke Technology Co., Ltd., BL302A) for 3 min, wash with tap water for 30 s, stain with eosin solution (Shanghai Biotech Co., Ltd., C0109) for 2 min, then rinse with PBS for transparency, soak in anhydrous ethanol for 5 min, soak in xylene twice, 5 min each, and add neutral gum (Beijing Solebold Technology Co., Ltd., G8590) to seal the slide. Observe and photograph under an upright biological microscope (Olympus, BX53), 200×.

[0057] Masson staining: wax sections were dewaxed with xylene three times, 15 min each time; anhydrous ethanol twice, 5 min each, 95%, 85%, 75% ethanol soaked for 5 min each, and distilled water soaked for 3 min. Staining was performed according to the instructions of Nanjing Jiancheng Kit (Nanjing Jiancheng Bioengineering Institute, D026): nuclear staining solution staining for 60 s, rinse with rinse solution for 30 s, pulp staining solution staining for 40 s, rinse with rinse solution for 30 s, color separation solution color separation for 8.5 min, no need to rinse, directly add counterstain solution to stain for 4 min, rinse with anhydrous ethanol, blow dry the slide, and add neutral gum to seal the slide. Observe and take pictures under an upright biological microscope (Olympus, BX53), 200×.

[0058] The kidney pathological changes were observed under a microscope. The results of kidney Hematoxylin-Eosin and Masson staining were as follows: Figure 3 , Figure 4 shown.

[0059] like Figure 3As shown in the figure, compared with the sham operation group, renal tubular dilatation and inflammatory cell infiltration were observed in UUO model mice (the black arrows in the figure represent renal tubular dilatation, and the blue arrows represent inflammatory cell infiltration). Menghua glycosides can significantly alleviate the above pathological changes, indicating that Menghua glycosides can significantly improve the renal damage caused by unilateral ureteral obstruction; Figure 4 As shown, compared with the sham operation group, there was collagen deposition in the tubular interstitium of UUO model mice (the black arrows in the figure represent tubular dilatation, and the red arrows represent collagen deposition). Collagen fiber deposition was significantly reduced after administration of lignoceramide, indicating that lignoceramide can reverse collagen deposition and renal fibrosis caused by unilateral ureteral obstruction.

[0060] Experiment 5: Testing the serum creatinine and urea nitrogen levels in the serum obtained in Experiment 1

[0061] The serum obtained by centrifugation was placed on ice, and the serum creatinine and serum urea nitrogen levels of mice were detected according to the instructions of Nanjing Jiancheng Kit (Nanjing Jiancheng Bioengineering Institute, C011-2-1 and Nanjing Jiancheng Bioengineering Institute, C013-2-1). The results were as follows: Figure 5 , Figure 6 shown. Figure 5 , Figure 6 ns means no significant difference compared with the sham operation group. ## P<0.01; compared with the UUO group, * P<0.05, *** P<0.001.

[0062] Depend on Figure 5 , Figure 6 It can be seen that compared with the sham operation group, the serum creatinine and urea nitrogen levels in the model group were significantly increased, indicating that UUO mice had obvious renal damage. Compared with the model group, the 30, 60, and 120 mg / kg doses of mongoside groups could significantly reduce serum creatinine ( Figure 5 ), while the 60 and 120 mg / kg doses of linalool groups could significantly reduce the level of serum urea nitrogen ( Figure 6 ), improve renal function abnormalities caused by unilateral ureteral obstruction.

[0063] In summary, the present application provides the application of mongoside in the preparation of drugs for the prevention or treatment of renal fibrosis, which belongs to the field of medical application technology. The present application has found through research that mongoside can down-regulate the expression levels of YAP, CTGF and inflammatory factors IL-6, IL-1β, and TNF-α. Based on this, mongoside or its pharmaceutically acceptable salt, ester or solvate can be used to prepare drugs for the prevention and treatment of renal fibrosis caused by unilateral ureteral obstruction or fibroblast proliferation, and can reverse the kidney damage caused by unilateral ureteral obstruction, and improve the abnormal renal function caused by unilateral ureteral obstruction, which provides a new drug selection for the application scenarios that need to down-regulate the expression levels of YAP, CTGF, etc., and has important guiding significance for the prevention and treatment of diseases such as renal fibrosis and kidney damage and abnormal renal function caused by it. And mongoside has no obvious toxic and side effects, definite efficacy, safety and controllability, and has a high practical application value.

[0064] It should be noted that the present application is not limited to the above-mentioned embodiments. The above-mentioned embodiments are only examples, and the embodiments having the same structure as the technical idea and exerting the same effect within the scope of the technical solution of the present application are all included in the technical scope of the present application. In addition, without departing from the scope of the main purpose of the present application, various modifications that can be thought of by those skilled in the art to the embodiments and other methods of combining some of the constituent elements in the embodiments are also included in the scope of the present application.

Claims

1. Use of limonene or its pharmaceutically acceptable salts, esters or solvates in the preparation of drugs for preventing or treating renal fibrosis.

2. Use of limonene or its pharmaceutically acceptable salt, ester or solvate according to claim 1 in the preparation of a medicament for preventing or treating renal fibrosis, characterized in that: The renal fibrosis is renal fibrosis caused by unilateral ureteral obstruction.

3. Use of the linaloside or its pharmaceutically acceptable salt, ester or solvate according to claim 1 in the preparation of a medicament for preventing or treating renal fibrosis, characterized in that: The renal fibrosis is renal fibrosis caused by fibroblast proliferation.

4. Use of limonene or its pharmaceutically acceptable salt, ester or solvate according to claim 1 in the preparation of a medicament for preventing or treating renal fibrosis, characterized in that: The limonene glycoside or its pharmaceutically acceptable salt, ester or solvate is used to down-regulate the expression levels of YAP, CTGF and inflammatory factors IL-6, IL-1β, and TNF-α.

5. Use of limonene or its pharmaceutically acceptable salt, ester or solvate according to claim 4 in the preparation of a medicament for preventing or treating renal fibrosis, characterized in that: The down-regulating effect of the limonene glycoside or its pharmaceutically acceptable salt, ester or solvate on the expression levels of YAP, CTGF and inflammatory factors IL-6, IL-1β and TNF-α is dose-dependent.

6. Use of limonene or its pharmaceutically acceptable salt, ester or solvate according to claim 5 in the preparation of a medicament for preventing or treating renal fibrosis, characterized in that: The dosage of the limonene glycoside or its pharmaceutically acceptable salt, ester or solvate is 30-120 mg / kg based on limonene glycoside.

7. Use of limonene or its pharmaceutically acceptable salt, ester or solvate according to claim 2 in the preparation of a medicament for preventing or treating renal fibrosis, characterized in that: The limonene glycoside or its pharmaceutically acceptable salt, ester or solvate is used to reverse kidney damage caused by unilateral ureteral obstruction.

8. Use of limonene or its pharmaceutically acceptable salt, ester or solvate according to claim 2 in the preparation of a medicament for preventing or treating renal fibrosis, characterized in that: The limonene glycoside or its pharmaceutically acceptable salt, ester or solvate is used to improve renal dysfunction caused by unilateral ureteral obstruction.

9. Use of the linaloside or its pharmaceutically acceptable salt, ester or solvate according to claim 1 in the preparation of a medicament for preventing or treating renal fibrosis, characterized in that: The medicine for preventing or treating renal fibrosis is a preparation prepared by taking limonene or its pharmaceutically acceptable salt, ester or solvate as active ingredient and adding pharmaceutically acceptable carriers or excipients.

10. Use of limonene glycoside or its pharmaceutically acceptable salt, ester or solvate according to claim 9 in the preparation of a medicament for preventing or treating renal fibrosis, characterized in that: The dosage form of the preparation is a liquid preparation, a solid preparation or a semisolid preparation.

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