Potential biomarker for mesangial proliferative glomerulonephritis and application thereof

Abstract

The invention relates to a potential biomarker for mesangial proliferative glomerulonephritis and application thereof, and discovers that occurrence and development of mesangial proliferative glomerulonephritis, especially IgA nephropathy, are related to active sphingolipid metabolite sphingosine-1-phosphoric acid (S1P) signal disorder, and the S1P signal disorder is closely related to mesangial hyperplasia and inflammatory infiltration. Along with disorder of S1PRs receptor expression, the compound can be used as a new intervention target for mesangial proliferative glomerulonephritis, especially IgA nephropathy. According to the invention, a corresponding targeted drug is developed for regulation of S1P metabolism and an S1P signal channel, and possibility is provided for prevention, treatment and prognosis management of mesangial proliferative glomerulonephritis.

Description

Technical Field

[0001] The present invention relates to the field of biomedical technology, and in particular to a potential biomarker of mesangial proliferative glomerulonephritis and application thereof. Background Art

[0002] Mesangial proliferative glomerulonephritis (MsPGN) refers to diffuse proliferation of glomerular mesangial cells and mesangial matrix under light microscopy. Immunopathological examination can divide this type of disease into IgA nephropathy and non-IgA mesangial proliferative glomerulonephritis. Among them, IgA nephropathy is the most common primary glomerulonephritis and is more common in young and middle-aged people. About 20%-40% of IgA nephropathy patients will progress to end-stage renal disease (ESRD) within 10-20 years after diagnosis.

[0003] IgA nephropathy is confirmed by renal biopsy, with immunoglobulins mainly composed of IgA deposited in the glomeruli. Clinically, hematuria and proteinuria are the main manifestations. The pathogenesis of IgA nephropathy is still unclear. The quadruple hit theory is currently a more widely accepted hypothesis to explain the development of IgA nephropathy: Hit 1: production and accumulation of galactose-deficient IgA1 (Gd-IgA1); Hit 2: the autoimmune system recognizes Gd-IgA1 and produces autoimmune antibodies; Hit 3: after recognition by autoimmune antibodies, nephritis-causing immune protein complexes are formed; Hit 4: nephritis immune protein complexes are deposited in the kidneys and activate mesangial cells to cause mesangial hyperplasia, which in turn causes kidney damage. At present, conventional treatments for IgA nephropathy include supportive care, as well as the use of systemic glucocorticoids, immunosuppressants, etc. However, these methods have significant side effects, including severe infections, cardiovascular and metabolic abnormalities, etc. caused by systemic glucocorticoid treatment. In addition, the diagnosis of IgA nephropathy still requires invasive biopsy identification, and there is a lack of rapid and effective biomarkers for the diagnosis of IgA nephropathy. Finding and discovering valuable biomarkers is of great value for the early diagnosis, prognosis and development of targeted drugs for IgA nephropathy. As part of systems biology, metabolomics can achieve high-throughput detection of small molecules in standard prepared serum, plasma, urine and other biological samples. By integrating multivariate statistical analysis, it can ultimately screen out metabolic markers with significant differences, and thus deeply dialyze the pathological mechanism of the disease as a whole, and provide a scientific basis for the prevention and treatment of the disease.

[0004] Previous studies have shown that changes in the intestinal microbiome are involved in the pathogenesis of mesangial proliferative glomerulonephritis, but few studies have focused on metabolic disorders and the search for metabolic diagnostic markers for mesangial proliferative glomerulonephritis. Changes in the intestinal microbiome, immune system abnormalities, and renal cell dysfunction will inevitably lead to changes in metabolic pathways and abnormalities in the levels of corresponding metabolites, which will be reflected in the patient's tissues, blood, or urine, which also provides a theoretical basis for the search and identification of markers for mesangial proliferative glomerulonephritis. Summary of the invention

[0005] The purpose of the present invention is to provide an active sphingolipid metabolite sphingosine-1-phosphate as a potential biomarker for mesangial proliferative glomerulonephritis and its application in order to overcome the inability of the prior art to quickly and effectively diagnose IgA nephropathy.

[0006] Based on the above research background, the present invention utilizes metabolomics technology to analyze and determine the metabolic profile characteristics of patients with mesangial proliferative glomerulonephritis, conducts correlation analysis based on the renal function damage index and inflammatory factor levels of patients with mesangial proliferative glomerulonephritis, and performs effect verification in mouse glomerular mesangial cells, analyzes and identifies the induced pathological phenotype of mesangial proliferative glomerulonephritis, and thereby identifies potential biomarkers.

[0007] The purpose of the present invention can be achieved by the following technical solutions:

[0008] One of the technical solutions of the present invention is to provide an application of sphingosine-1-phosphate as a potential biomarker for mesangial proliferative glomerulonephritis.

[0009] The second technical solution of the present invention is to provide a potential biomarker combination for mesangial proliferative glomerulonephritis, wherein the potential biomarker combination includes sphingosine-1-phosphate;

[0010] The potential biomarker combination also includes any one or more of the renal function impairment indicators Scr, BUN, eGFR and the inflammatory factor levels IL-6, TNF-α, IL-17.

[0011] The third technical solution of the present invention is to provide the use of sphingosine-1-phosphate in preparing a kit for predicting and / or evaluating mesangial proliferative glomerulonephritis.

[0012] In some specific embodiments, the kit predicts and / or assesses the risk of mesangial proliferative glomerulonephritis based on the level of sphingosine-1-phosphate in the peripheral blood serum of the tested human subject.

[0013] A fourth technical solution of the present invention is to provide the use of sphingosine-1-phosphate in the preparation of a drug for preventing and / or treating and / or managing the prognosis of mesangial proliferative glomerulonephritis.

[0014] In some embodiments, the drug is a drug that degrades sphingosine-1-phosphate and / or blocks the synthesis of sphingosine-1-phosphate and / or converts sphingosine-1-phosphate.

[0015] A fifth technical solution of the present invention is to provide the use of sphingosine-1-phosphate antagonist FTY720 or its analogs in the preparation of drugs for preventing and / or treating and / or managing the prognosis of mesangial proliferative glomerulonephritis.

[0016] A sixth technical solution of the present invention is to provide the use of a sphingosine-1-phosphate receptor modulator in the preparation of a drug for preventing and / or treating and / or managing the prognosis of mesangial proliferative glomerulonephritis.

[0017] The seventh technical solution of the present invention is to provide the use of sphingosine-1-phosphate or its analogs or metabolic regulators in the preparation of a drug combination for preventing and / or treating and / or prognosis management of mesangial proliferative glomerulonephritis, wherein the metabolic regulator has the effect of degrading sphingosine-1-phosphate and / or blocking the synthesis of sphingosine-1-phosphate and / or converting sphingosine-1-phosphate.

[0018] In some embodiments, the pharmaceutical composition comprises a drug that degrades sphingosine-1-phosphate and / or blocks the synthesis of sphingosine-1-phosphate and / or converts sphingosine-1-phosphate.

[0019] Compared with the prior art, the present invention has the following beneficial effects:

[0020] (1) The present invention first discovered the important role of serum active sphingolipid metabolite sphingosine-1-phosphate (S1P) signal disorder in the occurrence and development of mesangial proliferative glomerulonephritis, especially IgA nephropathy. The present invention found that S1P was significantly increased in the mesangial proliferative glomerulonephritis patient group, and the correlation analysis with the patient's renal function damage index Scr (serum creatinine), BUN (urea nitrogen), eGFR (glomerular filtration rate), cell proliferation factors VEGF, PDFG and cell inflammatory factor levels IL-6, TNF-α, IL-17 all showed significant correlation, indicating its feasibility in diagnosing mesangial proliferative glomerulonephritis. S1P can be used as a high-throughput screening target for mesangial proliferative glomerulonephritis, especially IgA nephropathy, and can be used alone or in combination with other currently known biomarkers as a potential diagnostic target for the disease, thereby judging the occurrence of mesangial proliferative glomerulonephritis.

[0021] (2) The present invention provides a new target for the treatment of mesangial proliferative glomerulonephritis, especially IgA nephropathy. The development of corresponding targeted drugs for the regulation of S1P metabolism and S1P signaling pathways provides possibilities for the prevention, treatment and prognosis management of the disease.

[0022] (3) The present invention provides a S1P antagonist FTY720 and its analogs, S1PRs receptor modulators and compounds with the same mechanism of action for the prevention of mesangial proliferative glomerulonephritis, especially IgA nephropathy. The present invention uses the metabolic marker S1P to verify its target effect of promoting cell proliferation and inflammatory infiltration in mouse glomerular mesangial cells. The biological effect of S1P can be reduced by using the S1P antagonist FTY720 and its analogs, and S1PRs receptor modulators. Therefore, mesangial proliferative glomerulonephritis, especially IgA nephropathy, can be improved by intervening in S1P signal transduction and regulating S1PRs receptors. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 PLS-DA model score diagram of serum metabolites detected by LC-MS (including positive and negative ion modes).

[0024] Figure 2 This is the OPLS-DA model score diagram of serum metabolites detected by LC-MS (including positive and negative ion modes).

[0025] Figure 3 The differential metabolites were obtained by non-targeted metabolomic analysis of serum.

[0026] Figure 4 This is a correlation analysis between the differential metabolites obtained from serum non-targeted metabolomics analysis and the indicators of renal function damage and the levels of inflammatory factors.

[0027] Figure 5 Receiver operating curve (ROC curve) of sphingosine-1-phosphate for the discovery set.

[0028] Figure 6 Receiver operating curve (ROC curve) of sphingosine-1-phosphate for the validation set.

[0029] Figure 7 This is the linear correlation analysis between sphingosine-1-phosphate and Scr.

[0030] Figure 8 This is the linear correlation analysis between sphingosine-1-phosphate and eGFR.

[0031] Fig. 9 To screen the concentration and time of action of sphingosine-1-phosphate on mouse glomerular mesangial cells.

[0032] Fig.10 This is the effect of sphingosine-1-phosphate and FTY720 on the expression levels of inflammatory factors in mouse glomerular mesangial cells.

[0033] Fig.11 This is the effect of sphingosine-1-phosphate and FTY720 on the expression level of mouse glomerular mesangial cell proliferation factor.

[0034] Fig.12 The effects of sphingosine-1-phosphate and FTY720 on the expression level of surface receptor S1PRs on mouse glomerular mesangial cells.

[0035] Fig.13 FTY720 improves the renal function indicators of mice with mesangial proliferative glomerulonephritis model.

[0036] Fig.14 Identification of a mouse model of mesangial proliferative glomerulonephritis (IgA deposition in the renal mesangial region). DETAILED DESCRIPTION

[0037] The present invention is described in detail below in conjunction with the accompanying drawings and specific embodiments. This embodiment is implemented based on the technical solution of the present invention, and provides a detailed implementation method and specific operation process, but the protection scope of the present invention is not limited to the following embodiments.

[0038] In the following examples and comparative examples, unless otherwise specified, raw materials or processing techniques are conventional commercially available raw materials or conventional processing techniques in the art.

[0039] The cell line was mouse glomerular mesangial cells (SV40 MES13) purchased from Wuhan Pronocell Life Science Co., Ltd. The cells were kept in a humidity of 95% and a CO 2 The cells were cultured in a 37°C incubator using a complete medium containing 5% fetal bovine serum and H-DMEM:F12 at a ratio of 3:1 (v:v).

[0040] Sphingosine-1-phosphate (S1P) was purchased from MCE Company, solid, white powder, with a purity of more than 98%. The molecular formula is: C 18 H 38 NO 5 P, molecular weight: 379.47.

[0041] Embodiment 1:

[0042] The method for screening potential biomarkers of mesangial proliferative glomerulonephritis comprises the following steps:

[0043] (1) Peripheral blood samples were collected from 15 healthy donors (control group) and 27 patients with mesangial proliferative glomerulonephritis (experimental group) and stored in procoagulant blood collection tubes. The collection volume was 5 mL × 2 tubes / person and stored in procoagulant blood collection tubes. All samples signed informed consent for sample collection, and the processed samples followed the laboratory biosafety operation specifications and kept corresponding records.

[0044] The discovery set was divided into the following experimental groups: control group: HC group, peripheral blood of healthy donors, 15 cases; experimental group: MsPGN group, peripheral blood of patients with mesangial proliferative glomerulonephritis, 27 cases.

[0045] The blood sample in the procoagulant blood collection tube was centrifuged at 4°C and 3500 rpm for 10 min to separate the serum sample, which was then collected into a sterile centrifuge tube.

[0046] (2) Take 100 μL of serum from each sample at 4°C, add 20 μL of L-2-chlorophenylalanine (0.3 mg / mL, methanol) as the internal standard, fully dissolve, add 300 μL of pre-cooled methanol / acetonitrile solution (1:1, v / v), centrifuge at 12000g for 10 min at 4°C, take 300 μL of supernatant, vacuum dry, add 100 μL of acetonitrile aqueous solution (acetonitrile: water = 1:1, v / v) for re-dissolution, centrifuge at 12000g for 10 min at 4°C, take the supernatant and put it into a liquid phase vial for testing. QC samples were prepared by mixing equal volumes of all samples in each group, and the methanol solution was used as a blank sample.

[0047] (3) Non-targeted metabolomics based on ultra-high performance liquid chromatography-mass spectrometry was used to perform secondary separation of metabolites in the samples. The conditions were set as ACQUITY UHPLC HSS T3 column (2.1 mm × 100 mm, 1.8 μm); column temperature 35°C; mobile phase: mobile phase A was water (containing 0.1% formic acid, v / v); mobile phase B was acetonitrile (containing 0.1% formic acid, v / v); flow rate was 0.35 min / mL, and injection volume was 2 μL. Metabolite spectra were obtained in positive and negative ion modes, respectively, and mass spectrometry data of metabolites were obtained.

[0048] (4) Compound Discoverer software was used to identify, correct, and normalize the collected data. The data were then imported into SIMCA 14.1 software for PLS-DA and OPLS-DA modeling analysis. The results showed that the case group and the control group were well distinguished in both positive and negative ion modes (e.g. Figure 1 , 2 ).

[0049] (5) Metabolites with significant difference P value < 0.05, VIP value ≥ 1, and absolute value of difference fold (case group / control group) ≥ 1.5 were selected as differential metabolites between patients with mesangial proliferative glomerulonephritis and healthy donors; MetaboAnalyst5.0 and OmicStudio cloud platform, as well as HDMB, LIPID MAPS and METLIN metabolite databases were used for annotation; at the same time, the correlation analysis function of OmicStudio cloud platform was used to perform Pearson correlation analysis between the obtained differential metabolites and the clinical renal function indicators of patients with mesangial proliferative glomerulonephritis (such as Figure 3 ), and screened for differential metabolites that were significantly increased in the disease group (FC>1.5; P<0.05) and whose correlation values ​​with clinical renal function indicators were less than 0.05 (such as Figure 4 ), which is the active sphingolipid metabolite sphingosine-1-phosphate. The operating characteristic (ROC) curve was drawn to evaluate the diagnostic performance of the metabolite, and its AUC value = 0.995 (such as Figure 5 ), has a high diagnostic value, and sphingosine-1-phosphate is considered as a potential metabolic marker for patients with mesangial proliferative glomerulonephritis.

[0050] (6) Samples were collected again for validation (validation set). The control group was the HC group, with 30 healthy donors’ peripheral blood samples. The experimental group was the MsPGN group, with 35 patients’ peripheral blood samples. The ROC curve was calculated based on the peak values ​​of sphingosine-1-phosphate in the mesangial proliferative glomerulonephritis patient group and the healthy donor group. The AUC value was >0.8, which showed a high prediction accuracy and good sensitivity and specificity (e.g. Figure 6 ).

[0051] Compared with the control group, the content of the metabolite sphingosine-1-phosphate was significantly increased in the experimental group.

[0052] Sphingosine-1-phosphate, a potential biomarker of mesangial proliferative glomerulonephritis, is one of the serum metabolites that participates in the sphingomyelin metabolic pathway and participates in functions such as cell proliferation, migration, survival, and intercellular signal transduction.

[0053] Embodiment 2:

[0054] The experimental groups were set as follows: control group: HC group, peripheral blood of healthy donors, 30 cases; experimental group: MsPGN group, peripheral blood of patients with mesangial proliferative glomerulonephritis, 35 cases.

[0055] The blood sample in the procoagulant blood collection tube was centrifuged at 4°C and 3500 rpm for 10 min to separate the serum sample and collect it in a sterile centrifuge tube. The renal function indicators serum creatinine (Scr) and glomerular filtration rate (eGFR) of the two groups of serum samples were measured using a fully automatic biochemical analyzer, and the peak values ​​of sphingosine-1-phosphate in the mesangial proliferative glomerulonephritis patient group and the healthy donor group obtained in the validation set of Example 1 were linearly correlated with Scr and eGFR (as shown in Figure 1). Figure 7 ,like Figure 8 ), it can be seen that sphingosine-1-phosphate showed a good significant positive correlation (P=0.0265) and a significant negative correlation (P=0.0011) with Scr and eGFR, respectively, indicating the uniqueness of the metabolite S1P in diagnosing mesangial proliferative glomerulonephritis and a more sensitive diagnosis.

[0056] Embodiment 3:

[0057] To detect the biological effects of sphingosine-1-phosphate on glomerular mesangial cells.

[0058] Mouse glomerular mesangial cells in the logarithmic growth phase were digested with trypsin and made into single cell suspension and counted under a microscope. The number of cells was calculated according to the counting formula:

[0059] Number of cells in cell suspension / mL = total number of cells in four grids / 4×10 4 × Dilution factor

[0060] After calculating the number of cells in the cell suspension, 10,000 cells were seeded into each well of a 96-well cell culture plate and placed in an incubator for overnight culture to allow the cells to adhere.

[0061] Starve for 24 hours using serum-free H-DMEM:F12=3:1 (v:v) medium; dilute 1mM S1P stock solution to final concentrations of 0.05μM, 0.5μM, 1μM, 1.5μM, 2μM, and 5μM S1P working solution using complete medium, and then stimulate mouse glomerular mesangial cells for 24h, 48h, and 72h, and set up a blank control group (Control). After the addition of drugs, continue to culture in an incubator.

[0062] Add 20uL of MTT solution (concentration of 5mg / mL, prepared with PBS) to each well, continue incubation for 4h, terminate the culture, carefully remove the culture supernatant in the well, and then add 150uL of DMSO to each well, shake and oscillate for 10min to fully dissolve the crystals.

[0063] Then, the light absorption value of each well was measured using an ELISA reader at a wavelength of 570 nm, and the cell proliferation rate was calculated. Cell inhibition rate (%) = (OD S1Pgroup –OD Control group ) / OD S1P group ×100.

[0064] The results showed that after incubation with different concentrations of S1P for 24h, 48h and 72h, the proliferation-promoting effect of mouse glomerular mesangial cells first increased and then weakened as the concentration of S1P increased (e.g. Fig. 9 ).

[0065] The proliferation and survival of cells were detected by MTT method, and the concentration and action time with the greatest proliferation promoting effect on mouse glomerular mesangial cells were selected as the optimal S1P action conditions. Fig. 9 As shown, when the S1P concentration reached 1.5 μM and intervened for 24 hours, the S1P-induced mouse glomerular mesangial cell hyperproliferation and inflammatory infiltration effects were the strongest, significantly higher than the normal cell level.

[0066] Embodiment 4:

[0067] As shown in Example 3, the active sphingolipid metabolite S1P acts on mouse glomerular mesangial cells at a final concentration of 1.5 μM, and after 24 hours of intervention, it significantly promotes the excessive proliferation and inflammatory infiltration of mouse glomerular mesangial cells. Under the optimal S1P action conditions, the RT-PCR method was further used to detect the expression levels of cell inflammatory factors and cell proliferation factors.

[0068] After the metabolite S1P acted on mouse glomerular mesangial cells, the expression levels of inflammatory factors IL-6, TNF-α, and IL-1β were significantly increased compared with normal cells (such as Fig.10 ), the expression levels of cell proliferation factors VEGF and PDFG were also significantly increased (such as Fig.11 ).

[0069] Since S1P mainly exerts its signal transduction effect through the G protein-coupled receptor S1PRs on the cell surface, the expression level of S1PRs is related to the main pathway of S1P action. RT-PCR was used to detect the expression level of S1PRs receptors under the optimal S1P action conditions.

[0070] After the metabolite S1P acted on mouse glomerular mesangial cells, the expression levels of cellular S1PRs (1-5) were increased compared with normal cells, especially promoting the expression of S1PR3 (such as Fig.12 ).

[0071] The RT-PCR primers used are shown in Table 1 below:

[0072] Table 1 RT-PCR primers for S1P-related cellular inflammatory factors, cell proliferation factors, and receptors

[0073]

[0074] Embodiment 5:

[0075] The S1P antagonist FTY720 was used to act on S1P-induced mouse glomerular mesangial cells to detect the effects on cell proliferation and inflammatory infiltration as well as the changes in the levels of expressed S1PRs receptors.

[0076] The mesangial proliferative glomerulonephritis mouse model was established using Bacb / c mice. 18 male Balb / c mice were randomly divided into normal control group, model group and FTY720 treatment group, with 6 mice in each group. First, the mesangial proliferative glomerulonephritis disease model was established in the mice in the model group and FTY720 treatment group. The modeling method was as follows: each mouse was given 800 mg / kg bovine serum albumin (BSA) by oral gavage every other day for 9 weeks; castor oil and CCl 4 The two drugs were mixed in a volume ratio of 5:1, and 0.1 mL was injected subcutaneously once a week. At the 6th and 8th weeks, 0.05 mg of lipopolysaccharide (LPS) was injected into the tail vein of each mouse. Each mouse in the normal control group was gavaged with the corresponding dose of distilled water, and physiological saline was used for subcutaneous injection and tail vein injection. During the experiment, all mice had free access to food and water. At the end of the 9th week, 2 mice were randomly selected from the control group and the modeling mice to determine whether the modeling was successful. Mouse kidney tissue samples were collected, and the IgA deposition in the mouse kidneys was detected by immunofluorescence. The IgA deposition in the glomerular mesangial area of ​​the model group mice was positive and diffusely granular (such as Fig.14 ), proving that the mesangial proliferative glomerulonephritis model mouse was successfully established.

[0077] From the 10th week, each mouse in the FTY720 treatment group was intragastrically treated with 0.5 mg / kg FTY720 once a day for 4 weeks. The normal control group and the model group were given distilled water at corresponding doses.

[0078] After the intervention, the 24-hour urine samples of each group of mice were collected by metabolic cage method, and the supernatant was collected by centrifugation at 4°C and 3000rpm for 5 minutes. The urine renal function indicators urine creatinine, urea nitrogen, uric acid, and urine protein were further tested. The results showed that the S1P antagonist FTY720 could significantly reduce the levels of urine creatinine, urea nitrogen, uric acid, and urine protein in the model mice (such as Fig.13 ), significantly improved the abnormal renal function indicators of model mice, and had a beneficial effect on mesangial proliferative glomerulonephritis (such as Figure 9-12 ).

[0079] The results show that when the S1P receptor is regulated, the biological effect of S1P on mesangial cells will be weakened. Based on this, preventive and therapeutic drugs targeting S1P receptor regulation can be developed and then applied to mesangial proliferative glomerulonephritis, especially IgA nephropathy.

[0080] The above description of the embodiments is to facilitate the understanding and use of the invention by those skilled in the art. It is obvious that those skilled in the art can easily make various modifications to these embodiments and apply the general principles described herein to other embodiments without creative work. Therefore, the present invention is not limited to the above embodiments, and improvements and modifications made by those skilled in the art based on the disclosure of the present invention without departing from the scope of the present invention should be within the scope of protection of the present invention.

Claims

1. Application of sphingosine-1-phosphate as a potential biomarker for mesangial proliferative glomerulonephritis.

2. A potential biomarker combination for mesangial proliferative glomerulonephritis, characterized in that: The potential biomarker combination includes sphingosine-1-phosphate as described in claim 1; The potential biomarker combination also includes any one or more of the renal function damage indexes Scr, BUN, eGFR, cell proliferation factors VEGF, PDFG, and cell inflammatory factor levels IL-6, TNF-α, IL-17.

3. Use of sphingosine-1-phosphate according to claim 1 in the preparation of a kit for predicting and / or evaluating mesangial proliferative glomerulonephritis.

4. The use according to claim 3, characterized in that The kit predicts and / or evaluates the risk of mesangial proliferative glomerulonephritis based on the sphingosine-1-phosphate content level in the peripheral blood serum of the detected human subject.

5. Use of sphingosine-1-phosphate according to claim 1 in the preparation of a medicament for preventing and / or treating and / or managing the prognosis of mesangial proliferative glomerulonephritis.

6. The use according to claim 5, characterized in that: The drug is a drug that degrades sphingosine-1-phosphate and / or blocks the synthesis of sphingosine-1-phosphate and / or converts sphingosine-1-phosphate.

7. Use of the sphingosine-1-phosphate antagonist FTY720 or its analogs as claimed in claim 1 in the preparation of a medicament for preventing and / or treating and / or managing the prognosis of mesangial proliferative glomerulonephritis.

8. Use of the sphingosine-1-phosphate receptor modulator according to claim 1 in the preparation of a medicament for preventing and / or treating and / or managing the prognosis of mesangial proliferative glomerulonephritis.

9. Use of sphingosine-1-phosphate or its analogues or metabolic regulators as claimed in claim 1 in the preparation of a pharmaceutical combination for preventing and / or treating and / or prognostic management of mesangial proliferative glomerulonephritis, wherein the metabolic regulator has the effect of degrading sphingosine-1-phosphate and / or blocking the synthesis of sphingosine-1-phosphate and / or converting sphingosine-1-phosphate.

10. The use according to claim 9, characterized in that: The pharmaceutical composition comprises a drug which degrades sphingosine-1-phosphate and / or blocks the synthesis of sphingosine-1-phosphate and / or converts sphingosine-1-phosphate.

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