Application of alkannic acid in preparation of medicine for treating lupus nephritis

Abstract

The invention provides an application of alkannic acid in preparation of a medicine for treating lupus nephritis, the structural formula of the alkannic acid is as shown in the specification, and the invention also provides an application of the alkannic acid in preparation of a medicine for reducing kidney macrophage infiltration caused by lupus nephritis. Experiments find that alkannic acid can reduce expression of lupus autoantibodies and cytokines, reduce macrophage infiltration and deposition of immune globulin and the like, a new method is provided for treating lupus nephritis, and the problem of innate immune cell infiltration of lupus nephritis, which is a therapeutic drug participating in an important process of renal lesion, is effectively solved.

Description

Technical Field

[0001] The invention belongs to the field of biomedicine and relates to a medicine for treating lupus nephritis, specifically to the use of lithospermic acid in preparing a medicine for treating lupus nephritis. Background Art

[0002] Lupus nephritis (LN) is one of the most common severe complications of systemic lupus erythematosus (SLE). Its pathogenesis is complex, involving multiple links such as the formation of immune complexes, complement activation, and inflammatory cell infiltration. Although the use of glucocorticoids and immunosuppressants has made some progress in controlling LN disease activity and delaying disease progression, some patients still cannot achieve remission after treatment, or relapse after remission, and eventually progress to end-stage renal disease. At the same time, complications such as glucose and lipid metabolism disorders, gastrointestinal ulcers, osteoporosis, and secondary infections caused by treatment also seriously affect the quality of life and prognosis of patients.

[0003] As an important source of clinical drugs, Chinese medicine monomers have been widely recognized for their safety and effectiveness. Studies have shown that some Chinese medicine monomers have the characteristics of antioxidant, anti-inflammatory, and anti-fibrosis, and have a certain protective effect on kidney damage. These characteristics make Chinese medicine monomers a potential candidate for the treatment of LN. However, the molecular targets and mechanisms of action of many Chinese medicine monomers in the treatment of kidney disease are still unclear, which not only limits their clinical application, but also is the main difficulty in developing drugs for the treatment of kidney disease based on Chinese medicine monomers. Therefore, exploring the molecular targets and mechanisms of action of Chinese medicine monomers in the treatment of LN is of great significance for the development of new treatment strategies. This can not only improve the treatment effect and reduce adverse reactions, but also provide patients with individualized treatment plans and improve prognosis. Summary of the invention

[0004] In view of the above technical problems in the prior art, the present invention provides the use of lithospermic acid in the preparation of a drug for treating lupus nephritis, and the use is intended to solve the technical problem that the drugs in the prior art are not effective in treating lupus nephritis.

[0005] The present invention provides the use of lithospermic acid in preparing a medicine for treating lupus nephritis. The structural formula of lithospermic acid is shown below:

[0006]

[0007] The present invention also provides the use of lithospermic acid in preparing a drug for reducing renal macrophage infiltration caused by lupus nephritis. The structural formula of the lithospermic acid is shown below:

[0008]

[0009] The present invention provides a Chinese medicine monomer lithospermic acid for inhibiting lupus nephritis macrophage infiltration. Experiments have found that lithospermic acid can reduce the expression of lupus autoantibodies and cytokines, reduce macrophage infiltration and deposition of immunoglobulins, etc., providing a new method for treating lupus nephritis and effectively improving the problem of therapeutic drugs for lupus nephritis innate immune cell infiltration, which is an important process involved in kidney disease.

[0010] Compared with the prior art, the present invention has positive and obvious technical effects. The present invention improves the renal macrophage infiltration of lupus nephritis. Compared with compound Chinese medicine, Chinese medicine monomer has better controllability of efficacy and efficacy evaluation. Moreover, the use of Chinese medicine monomer lithospermic acid to treat lupus nephritis has a wide source, low cost, good efficacy, no kidney toxicity and side effects, and is conducive to long-term treatment. BRIEF DESCRIPTION OF THE DRAWINGS

[0011] Figure 1 The figure shows that lithospermic acid improves the levels of serum autoantibodies and chemokines in mice with lupus nephritis: serum anti-double-stranded DNA (dsDNA) antibody levels (upper figure) and monocyte / macrophage chemokine levels (lower figure) in mice in the control group (Mpj), model group (Lpr), and lithospermic acid treatment group (LSA).

[0012] Figure 2 The figure shows that lithospermic acid improves renal function and urine protein levels in mice with lupus nephritis: serum creatinine levels (upper figure), urea nitrogen (middle figure) and urine protein / urine creatinine levels (lower figure) of mice in the control group (Mpj), model group (Lpr) and lithospermic acid treatment group (LSA).

[0013] Figure 3 The results showed that lithospermic acid improved the renal pathology and vascular changes in mice with lupus nephritis: kidney tissue of mice in the control group (Mpj), model group (Lpr) and lithospermic acid treatment group (LSA) were stained with hematoxylin and eosin (HE), periodic acid-Schiff (PAS), Sirius red (PSR), type I collagen (CollagenI), type IV collagen (CollagenIV) and α-smooth muscle actin (α-SMA).

[0014] Figure 4 The results show that lithospermic acid improves the renal immunoglobulin and complement deposition in mice with lupus nephritis: immunofluorescence staining of immunoglobulins IgG (red fluorescence), IgM (green fluorescence) and complement C3 (red fluorescence) in the renal tissues of mice in the control group (Mpj), model group (Lpr) and lithospermic acid treatment group (LSA).

[0015] Figure 5The results show that lithospermic acid improves macrophage infiltration in mice with lupus nephritis: CD86 (green fluorescence) and CD206 (red fluorescence) in kidney tissues of mice in the control group (Mpj), model group (Lpr), and lithospermic acid treatment group (LSA). DETAILED DESCRIPTION

[0016] Example 1

[0017] 1. Animal model of lupus nephritis and experimental groups

[0018] MRL / Lpr lupus model mice with spontaneous disease (purchased from Shanghai Slake Experimental Animal Co., Ltd.) were selected. At the 8th week, Lpr mice were divided into a model group and a lithospermic acid (purchased from Targetmol) treatment group, and MRL / Mpj mice with the same background (purchased from Shanghai Slake Experimental Animal Co., Ltd.) were used as controls. Lithospermic acid was dissolved in DMSO + sterile saline with a mass percentage concentration of 2%, and intraperitoneally injected at a dose of 40 mg / kg, once every other day, for 12 weeks. The control group and the model group were given an equal amount of DMSO + sterile saline with a mass percentage concentration of 2%. At the end of the administration, the mice were anesthetized with sodium pentobarbital with a mass percentage concentration of 0.1%, and blood and kidney tissue were collected.

[0019] 2. Experimental Methods

[0020] The levels of mouse serum autoantibodies and chemokines were detected by ELISA. The urine protein and urine creatinine levels of each group of animals were detected using kits, and the urine protein to creatinine ratio (UPCR), blood creatinine (Cr), and blood urea nitrogen (BUN) levels were calculated. The pathological changes of mouse renal tissue were observed by HE staining and PAS staining, the changes of mouse renal fibrosis were observed by immunohistochemistry, and the deposition of mouse kidney immunoglobulins and the distribution of macrophages were observed by immunofluorescence.

[0021] 3. Experimental Results

[0022] 1. Lithospermic acid improves the levels of autoantibodies and chemokines in mice with lupus nephritis.

[0023] The level of anti-double-stranded DNA antibodies in lupus nephritis mice was significantly higher than that in the control group, while the level of anti-double-stranded DNA antibodies in the lithospermic acid (LSA) treatment group was significantly lower than that in the model group, indicating that lithospermic acid can effectively reduce the overall disease activity of SLE (see Figure 1). The detection of mouse serum chemokines revealed that the levels of monocyte chemoattractant protein 1 (MCP-1), macrophage inflammatory protein 1α (MIP-1α), macrophage inflammatory protein 1β (MIP-1β) and regulated normal T cell expressed and secreted factor (RANTES) in the monocyte / macrophage chemokines were statistically different between the groups, all of which were significantly higher in the lupus nephritis model group than in the control group, while the levels of these four chemokines in the lithospermic acid (LSA) treatment group were significantly lower than those in the model group, indicating that lithospermic acid can effectively reduce the levels of monocyte / macrophage chemokines.

[0024] 2. Lithospermic acid improves renal function and urine protein levels in mice with lupus nephritis.

[0025] The serum creatinine, serum urea nitrogen, and urine protein / urine creatinine levels of lupus nephritis mice were significantly higher than those of the control group, but they were significantly reduced after treatment with lithospermic acid (LSA), indicating that lithospermic acid can effectively improve the renal function and urine protein of lupus nephritis mice (see Figure 2 ).

[0026] 3. Lithospermic acid reduces renal pathology and fibrosis changes in mice with lupus nephritis.

[0027] The renal pathology of lupus nephritis mice showed active lesions such as endothelial cell proliferation, lymphocyte infiltration, and cellular crescents, as well as chronic lesions such as glomerular sclerosis and fibrous crescents. After treatment with lithospermic acid (LSA), the area of ​​renal structural lesions in lupus nephritis mice was reduced. Sirius red staining (PSR), type I collagen (CollagenI), type IV collagen (CollagenIV) and α-smooth muscle actin (α-SMA) immunohistochemical staining of the kidneys showed that the glomeruli and interstitium of lupus nephritis mice had increased collagen fiber deposition and increased fibroblasts, which were reduced after treatment with lithospermic acid (LSA), indicating that lithospermic acid can effectively improve the fibrotic lesions in the kidneys of lupus nephritis mice (see Figure 3 ).

[0028] 4. Lithospermic acid reduces the deposition of immunoglobulin and complement in the kidneys of mice with lupus nephritis.

[0029] Immunofluorescence staining of IgG (red fluorescence), IgM (green fluorescence) and complement C3 (red fluorescence) in the kidneys showed that the deposition of immunoglobulins and complement in the glomeruli of mice with lupus nephritis increased and concentrated in multiple locations such as the mesangial area in the form of granules or clumps, while these were significantly reduced after treatment with lithospermic acid (LSA), indicating that lithospermic acid can effectively improve the deposition of immunoglobulins and complement in mice with lupus nephritis (see Figure 4 ).

[0030] 5. Lithospermic acid reduces renal macrophage infiltration in mice with lupus nephritis

[0031] Immunofluorescence staining of CD86 (green fluorescence) and CD206 (red fluorescence) in the kidneys showed that the number of CD86+M1 macrophages and CD206+M2 macrophages in the kidneys of mice with lupus nephritis increased, mainly distributed in the interstitial area outside the glomerulus and around the tubules, while they were significantly reduced after treatment with lithospermic acid (LSA), indicating that lithospermic acid can effectively improve the infiltration of macrophages in the kidneys of mice with lupus nephritis (see Figure 5 ), which is consistent with the trend of decreased monocyte / macrophage chemotactic factors in serum.

Claims

1. Use of lithospermic acid in the preparation of a drug for treating lupus nephritis. The structural formula of lithospermic acid is shown below:

2. Use of lithospermic acid in the preparation of a drug for reducing renal macrophage infiltration caused by lupus nephritis. The structural formula of the lithospermic acid is shown below:

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