CN113209294B - Application of DOR agonist in preparation of medicines for resisting kidney fibrosis - Google Patents
Application of DOR agonist in preparation of medicines for resisting kidney fibrosis Download PDFInfo
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- CN113209294B CN113209294B CN202010080755.2A CN202010080755A CN113209294B CN 113209294 B CN113209294 B CN 113209294B CN 202010080755 A CN202010080755 A CN 202010080755A CN 113209294 B CN113209294 B CN 113209294B
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/472—Non-condensed isoquinolines, e.g. papaverine
- A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
The invention belongs to the technical field of medicines, and mainly relates to application of a DOR agonist in preparation of medicines for resisting kidney fibrosis. The DOR agonist is applied as the following a1, a2, a3 or a4; a1: preparing a medicament for preventing and/or treating kidney fibrosis; a2: preventing and/or treating kidney fibrosis; a3: activating and/or inhibiting DOR-related cellular and molecular signaling pathways; a4: an ex vivo model is established to activate DOR and thereby prevent and/or treat kidney fibrosis. The invention discovers for the first time that the DOR can be activated by adopting a specific DOR agonist (such as UFP-512) to regulate Smad, p38, akt and other signal paths, and can act on a transcription factor Snail to regulate and control the renal tubular interstitial transformation (EMT), thereby relieving the progress of renal fibrosis. The invention firstly expounds the relation between DOR and kidney fibrosis, reveals that activating DOR on kidney cells effectively relieves fibrosis lesions of kidney cells, provides a new way for preventing and treating pathological changes of kidney fibrosis, and has important scientific value and clinical significance.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to application of a DOR agonist in preparation of medicines for resisting kidney fibrosis.
Background
Renal fibrosis is a common feature of all chronic kidney diseases (chronic kidney disease, CKD) and is also a common pathological process that progresses to end stage renal disease (end stage renal disease, ESRD). Chronic kidney disease refers to a general term for a class of kidney disease with or without a decrease in glomerular filtration rate that is associated with a loss of kidney structure or function for more than 3 months, and includes various types of kidney disease such as chronic glomerulonephritis/nephrotic syndrome, diabetic nephropathy, and hereditary kidney disease (e.g., polycystic kidney, alport syndrome). Normal tissue is replaced by fibrotic tissue during the progression of renal fibrosis, progressive decline in renal function, and eventually chronic renal failure (chronic renal failure, CRF) occurs, requiring life-long dialysis or kidney transplant therapy by the patient.
Currently, about more than 5 hundred million people worldwide suffer from chronic kidney diseases, and the prevalence rate in China is as high as 10% -13%, and the prevalence rate is increasing. Chronic kidney disease has become a serious disease which seriously threatens human health after cardiovascular and cerebrovascular diseases, tumors and diabetes, has high incidence rate and poor prognosis, and finally will develop into end-stage renal failure, thus not only having high medical cost, but also seriously affecting the life quality of patients. End-stage patients can only receive dialysis or kidney transplant therapy, which creates a huge economic burden on society, and despite the significant progress that has been made in a number of studies on kidney fibrosis, methods for effectively alleviating and treating kidney fibrosis remain essentially at the limit. Therefore, the research on the occurrence mechanism of kidney fibrosis and the prevention and treatment way thereof is a research hotspot, and the research on new kidney protective medicaments is a necessary way for reducing the occurrence rate of end-stage renal disease and the mortality of patients, and has important social significance and economic benefit.
Endogenous delta-opioid receptors (DOR) belong to the superfamily of G protein-coupled receptors (G-protein coupled receptors, GPCRs), which are widely distributed in mammals and are densely distributed in the cerebral cortex and striatum. The existing experimental evidence suggests that DOR plays a role in analgesia, motor integration, gastrointestinal motility, smell, respiration, cognition, emotional behavior and other functions. DOR can stabilize the ion imbalance of the anoxic membrane, enhance the activity of antioxidant enzymes, reduce the generation of oxygen free radicals, reduce the expression of apoptotic proteins, and regulate MAPKs signal pathways, thereby generating cytoprotective effects. RT-PCR technique detection showed that the kidney was actually an enriched region of DOR. Applicant's preliminary experiments verify that DOR is expressed in higher levels in rat tubular epithelial cells at the protein and mRNA levels.
Although DOR is enriched in the kidney, its specific function in the kidney has been rarely reported, and only the literature report in 2013 that the agonist dalargin of DOR can reduce tubular cell death by promoting phosphorylation of kidney glycogen synthase kinase 3 beta, thereby alleviating gentamicin-induced kidney injury.
Disclosure of Invention
Previous studies in the applicant's panel have found that DOR activation in the kidney can act on related miRNAs under hypoxic conditions, thereby providing more favorable conditions for kidney survival and function. Meanwhile, applicant's recent research data show that DOR can be involved in the protection of kidney hypoxic injury by modulating MAPKs signaling pathways.
Furthermore, for the first time, the applicant has found that activation of DOR with a specific agonist (such as UFP-512) modulates Smad, p38, akt and other signaling pathways and acts on the transcription factor Snail to regulate tubular interstitial transformation (EMT) and thereby alleviate the renal fibrosis process. The important research results firstly illustrate the relation between DOR and kidney fibrosis, and reveal that activating DOR on kidney cells effectively relieves fibrosis lesions of kidney cells, which provides a new way for preventing and treating pathological changes of kidney fibrosis and has important scientific value and clinical significance.
Specifically, the technical scheme of the invention is as follows:
it is an object of the present invention to provide the use of a DOR agonist as follows a1, a2, a3 or a4:
a1: preparing a medicament for preventing and/or treating kidney fibrosis;
a2: preventing and/or treating kidney fibrosis;
a3: activating and/or inhibiting DOR-related cellular and molecular signaling pathways;
a4: an ex vivo model is established to activate DOR and thereby prevent and/or treat kidney fibrosis.
Preferably, the active ingredient of the medicament comprises a DOR agonist and an active ingredient capable of affecting DOR-related cells and molecular signaling pathways.
Preferably, the DOR agonist is a natural or synthetic molecule capable of activating DOR; more preferably, the DOR agonist is UFP-512.
Preferably, the medicament for preventing and/or treating the anti-renal fibrosis is a medicament for treating chronic kidney disease.
Preferably, in a4, the isolated kidney fibrosis model is established by kidney cells NRK-52E.
In a second aspect, the invention discloses a medicament for the prevention and/or treatment of renal fibrosis, the active ingredient of the medicament comprising a DOR agonist.
Preferably, the DOR agonist is UFP-512 and other molecules that produce a similar effect.
The structural formula of the UFP-512 is shown as follows:
this structure, although published prior to the present application, is currently unknown for its role in the prevention and/or treatment of kidney fibrosis.
Preferably, the medicament further comprises a pharmaceutically acceptable excipient selected from one or any combination of binders, fillers, plasticizers, glidants, disintegrants and lubricants.
More preferably, the medicament is in a liquid or solid form.
In some preferred embodiments of the invention, the concentration of DOR agonist in the drug is 0.1-10. Mu.M; preferably, the DOR agonist is UFP-512.
Preferably, the medicament is for use in renal fibrosis. In some embodiments of the invention, the medicament is applied to TGF-beta 1 induced kidney fibrosis.
On the basis of the common general knowledge in the field, the above preferred conditions can be arbitrarily combined without exceeding the conception and the protection scope of the invention.
Compared with the prior art, the invention has at least the following beneficial effects:
for the first time, DOR activation with specific agonists (such as UFP-512) was found to modulate Smad, p38 and Akt signaling pathways and act on the transcription factor Snail to modulate tubular interstitial transformation (EMT) and thereby alleviate the progression of renal fibrosis.
The relationship between DOR and kidney fibrosis is explained for the first time, and the DOR on the kidney cells is activated to effectively relieve fibrosis lesions of the kidney cells, so that a new way is provided for preventing and treating pathological changes of the kidney fibrosis, and the DOR has important scientific value and clinical significance.
Drawings
FIG. 1 is a schematic representation of the effect of TGF-. Beta.1 and DOR activation on NRK-52E cells.
FIG. 2 is a schematic representation of the effect of DOR activation on TGF- β1 induced morphological changes.
FIG. 3 is a schematic representation of the effect of DOR activation on TGF- β1 induced cell migration.
FIG. 4 is a schematic representation of the effect of DOR activation on TGF-beta 1 induced Fibronectin, E-cadherin (Ecadherin), and alpha-SMA expression.
FIG. 5 is a schematic representation of the effect of DOR activation on TGF-. Beta.1 induction of Smad3 expression.
FIG. 6 is a schematic representation of the role of p38 and Akt in TGF- β1 induced renal fibrosis.
Detailed Description
The technical solution of the present invention will be described in detail below with reference to the drawings and examples, but the present invention is not limited to the scope of the examples.
The experimental methods, in which specific conditions are not noted in the following examples, were selected according to conventional methods and conditions, or according to the commercial specifications. The reagents and materials used in the present invention are commercially available.
It should be noted that the reagents used, if specific conditions are not noted, are carried out according to conventional conditions or conditions suggested by the manufacturer, and the reagents used are conventional products available on the market.
The technical scheme of the invention mainly comprises the following contents:
1. establishing an in-vitro kidney cell fibrosis model
After 24 hours of passage of isolated rat kidney epithelial cells NRK-52E, the new culture solution added with 10ng/ml TGF-beta 1 is replaced and then placed into a normal incubator again for culture.
2. Cell grouping
(1) The control group was cultured in DMEM medium;
(2) TGF-. Beta.1 groups were treated with recombinant TGF-. Beta.1 (10 ng/ml).
(3) The TGF- β1+UFP-512 group was treated with recombinant TGF- β1 (10 ng/ml) while using different concentrations of UFP-512 (1. Mu.M, 5. Mu.M and 10. Mu.M) as specific and potent DOR agonists.
(4) UFP-512 treatment was used alone (1. Mu.M, 5. Mu.M and 10. Mu.M).
(5) The DOR antagonist Naltrindole was used alone.
(6) Naltrindole is used simultaneously with UFP-512.
3. Extraction of Total protein and Total RNA
The total proteins and total RNAs of the different groups were extracted according to the experimental group.
4. Effect of DOR activation on cell activity and morphology
(1) The effect of DOR activation in isolated kidney fibrotic cells was judged by measuring changes in cellular activity in different groups using CCK 8.
(2) The morphological changes of the cells of different groups were examined by optical microscopy techniques to examine the effect of UFP-512 on cell morphology.
5. DOR activation effects on fibrotic marker proteins and associated signaling pathways in cells
(1) Effect of DOR activation on TGF- β1 induced Fibronectin (fibrinectin), E-cadherin (E-cadherin), and α -SMA expression.
(2) Effect of DOR activation on TGF- β1 induction of Smad3 expression.
(3) Effect of DOR activation on TGF- β1 induction of Snail expression.
(4) DOR activation plays a role in TGF- β1 induced renal fibrosis for p38 and Akt.
Example 1
This example investigated the effect of TGF-. Beta.1 and DOR activation on NRK-52E cells. The specific experimental results are shown in fig. 1, in which (a): DOR expression in NRK-52E cells. Western blotting detects DOR expression in these cells (24-72 h). (B): mRNA levels of NRK-52E cell DOR. (C): effects of TGF- β1, UFP-512 and Naltrindole on cell viability. Specific DOR agonist UFP-512 was added to the medium at different concentrations (0, 1, 5, 10. Mu.M) of 10ng/ml for 24-48h and cell viability was determined using the cell count kit (CCK 8). Wherein, C: control group. T:10ng/ml TGF-. Beta.1. U: UFP-512.N: naltrindole (inhibitor of DOR). T+u1:10ng/ml TGF-. Beta.1+1. Mu.M UFP-512.T+u5:10ng/ml TGF-. Beta.1+5. Mu.M UFP-512.T+u10:10ng/ml TGF-. Beta.1+10. Mu.M UFP-512. N1: 1. Mu.M Naltrindole. N5: 5. Mu.M Naltrindole. N5+u1: 5. Mu.M Naltrindoole+ 1. Mu.M UFP-512. N5+u5: 5. Mu.M Naltrindoole+5. Mu.M UFP-512. N5+u10: 5. Mu.M Naltrindoole+10. Mu.M UFP-512.
Fig. 1C: the bar graphs of left figures 24h and 48h represent, from left to right, the OD values of group C, TGF- β1, t+u1, t+u5, t+u10, U1, U5, and U10 in that order; the bar graphs of the right figures 24h and 48h represent the OD values of group C, group N1, group N5, group n5+u1, group n5+u5, group n5+u10, in that order from left to right.
The results show that DOR is highly expressed in NRK-52E cells, and the cell viability is not changed significantly after drug treatment.
Example 2
This example investigated the effect of DOR activation on TGF- β1 induced morphological changes. The results are shown in FIG. 2, where: (A): effects of TGF- β1 and UFP-512 on cell morphology changes under light. NRK-52E cells were incubated with 10ng/ml TGF-. Beta.1 for 24-48h, UFP-512 at various concentrations (0, 1, 5, 10. Mu.M), and cell morphology was observed under light-microscope. (B): immunofluorescent staining of NRK-52E cells. Cells were treated with the drug for 24 hours and the cell morphology was visualized by immunofluorescent staining with beta-tubulin. Wherein, C: control group. T: TGF-. Beta.1. U: UFP-512.N: naltrindole. T+u1:10ng/ml TGF-. Beta.1+1. Mu.M UFP-512.T+u5:10ng/ml TGF-. Beta.1+5. Mu.M UFP-512.T+u10:10ng/ml TGF-. Beta.1+10. Mu.M UFP-512. N5+u1: 5. Mu.M Naltrindoole+ 1. Mu.M UFP-512. N5+u5: 5. Mu.M Naltrindoole+5. Mu.M UFP-512. N5+U10 5. Mu.M Naltrindoole+10mu.M UFP-512.
The results show that control NRK-52E cells (untreated) were pebble, the TGF- β1 treated cell morphology was more elongated, while UFP-512 reversed the TGF- β1 induced morphological changes. However, UFP-512 or/and Naltrindole has no obvious effect on cell morphology.
Example 3
This example investigated the effect of DOR activation on TGF- β1 induced cell migration. The results are shown in FIG. 3, (A): effects of TGF- β1 and UFP-512 on cell migration. (B): effect of DOR activation or inactivation on cell migration. (C): effects of Naltrindole and UFP-512 on cell migration. The NRK-52E cell layer on the petri dish was scraped with a micropipette and observed microscopically before and after 24 hours of drug treatment. Wherein, C: control group. T: TGF-. Beta.1. U: UFP-512.N: naltrindole. T+u1:10ng/ml TGF-. Beta.1+1. Mu.M UFP-512.T+u5:10ng/ml TGF-. Beta.1+5. Mu.M UFP-512.T+u10:10ng/ml TGF-. Beta.1+10. Mu.M UFP-512. N5+u1: 5. Mu.M Naltrindoole+ 1. Mu.M UFP-512. N5+u5: 5. Mu.M Naltrindoole+5. Mu.M UFP-512. N5+u10: 5. Mu.M Naltrindoole+10. Mu.M UFP-512.
The results show that TGF- β1 treatment increases cell migration, while UFP-512 reverses the effects of TGF- β1. On the other hand, UFP-512 or/and Naltrindole had no significant effect on cell migration in the absence of TGF- β1.
Example 4
This example was designed to investigate the effect of DOR activation on TGF-beta 1 induced Fibronectin, E-cadherin (Ecadherin) and alpha-SMA expression. The results are shown in FIG. 4, (A): expression of fibronectin, E-cadherin and alpha-SMA after TGF-beta 1 and UFP-512 treatments. (B): expression of fibronectin, E-cadherin and alpha-SMA after TGF-beta 1 or UFP-512 treatment. Cells were incubated with 10ng/ml TGF- β1 or UFP-512, respectively. Wherein, C: control group. T: TGF-. Beta.1. U: UFP-512.T+u1:10ng/ml TGF-. Beta.1+1. Mu.M UFP-512.T+u5:10ng/ml TGF-. Beta.1+5. Mu.M UFP-512.T+u10:10ng/ml TGF-. Beta.1+10. Mu.M UFP-512.
The bar graphs of 24h and 48h in FIG. 4 (A) represent, in order from left to right, group C, TGF-. Beta.1, T+U1, T+U5, and T+U10; (B) The 24h and 48h histograms in the figure represent, from left to right, group C, TGF-. Beta.1, group U1, group U5, and group U10 in that order.
The results show that TGF-. Beta.1 enhances fibronectin and alpha-SMA expression, but reduces E-cadherin expression. The effect of TGF- β1 on fibronectin was reversed by 10. Mu.M UFP-512, while 5. Mu.M or 10. Mu.M UFP-512 reversed TGF- β1-induced α -SMA expression.
Example 5
This example investigated the effect of DOR activation on TGF-. Beta.1 induction of Smad3 expression. The results are shown in FIG. 5, (A): changes in Smad3 after TGF- β1 and UFP-512 treatments. (B): changes in Smad3 following TGF- β1 or UFP-512 treatment. Wherein, C: control group. T: TGF-. Beta.1. U: UFP-512.T+U1 10ng/ml TGF-. Beta.1+1. Mu.M UFP-512.T+u5:10ng/ml TGF-. Beta.1+5. Mu.M UFP-512.T+U10:10ng/ml TGF-. Beta.1+10. Mu.M UFP-512.
The bar graphs of 24h and 48h in FIG. 5 (A) represent, in order from left to right, group C, TGF-. Beta.1, T+U1, T+U5, and T+U10; (B) The 24h and 48h histograms in the figure represent, from left to right, group C, TGF-. Beta.1, group U1, group U5, and group U10 in that order.
The results suggest that TGF- β1 significantly increases the level of phosphorylated Smad3, while UFP-512 completely reverses the effect of TGF- β1. TGF-beta 1 and UFP-512 have no significant effect on the expression of total Smad 3.
Example 6
This example investigated the role of p38 and Akt in TGF- β1 induced renal fibrosis. The results are shown in FIG. 6, (A): effect of DOR activation on TGF- β1 induced p38 and Akt changes. (B): effects of TGF- β1 or UFP-512 on p38 and Akt. Wherein, C: control group. T: TGF-. Beta.1. U: UFP-512.T+U1 10ng/ml TGF-. Beta.1+1. Mu.M UFP-512.T+U5:10ng/ml TGF-. Beta.1+5. Mu.M UFP-512.T+U10:10ng/ml TGF-. Beta.1+10. Mu.M UFP-512.
The bar graphs of 24h and 48h in FIG. 6 (A) represent, in order from left to right, group C, TGF-. Beta.1, T+U1, T+U5, and T+U10; (B) The 24h and 48h histograms in the figure represent, from left to right, group C, TGF-. Beta.1, group U1, group U5, and group U10 in that order.
The results show that TGF- β1 treatment increases phosphorylation of Akt and p38 proteins, while UFP-512 activation of DOR completely reverses the effect of TGF- β1.
While embodiments of the present invention have been shown and described above, it will be understood that the above embodiments are illustrative and not to be construed as limiting the invention, and that variations, modifications, alternatives and variations may be made to the above embodiments by one of ordinary skill in the art within the scope of the invention.
Claims (4)
- Use of a dor agonist in the manufacture of a medicament for the prevention and/or treatment of renal fibrosis;the DOR agonist is UFP-512.
- 2. The use according to claim 1, characterized in that: the medicament further comprises a pharmaceutically acceptable excipient selected from one or any combination of binders, fillers, plasticizers, disintegrants and lubricants.
- 3. The use according to claim 1, characterized in that: the medicine is liquid or solid.
- 4. A use according to claim 3, characterized in that: the working concentration of DOR agonist in the liquid medicine is 0.1-10 mu M.
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| WO2009033751A2 (en) * | 2007-09-11 | 2009-03-19 | Mondobiotech Laboratories Ag | Use of a peptide as a therapeutic agent |
| CN109475626A (en) * | 2016-07-14 | 2019-03-15 | 儿童医院医疗中心 | The method for treating fibrosis |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN106975070A (en) * | 2008-02-26 | 2017-07-25 | 康奈尔大学 | Method for preventing and treating acute injury of kidney |
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| CN1568186A (en) * | 2001-10-15 | 2005-01-19 | 詹森药业有限公司 | Substituted 4-phenyl-4-[1h-imidazol-2-yl]-piperidine derivatives for reducing ischaemic damage |
| WO2009033751A2 (en) * | 2007-09-11 | 2009-03-19 | Mondobiotech Laboratories Ag | Use of a peptide as a therapeutic agent |
| CN109475626A (en) * | 2016-07-14 | 2019-03-15 | 儿童医院医疗中心 | The method for treating fibrosis |
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