CN110200973A - Purposes of the DNA dependent protein kinase specific inhibitor in preparation prevention and treatment kidney fibrosis drug - Google Patents
Purposes of the DNA dependent protein kinase specific inhibitor in preparation prevention and treatment kidney fibrosis drug Download PDFInfo
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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
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- 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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Abstract
The invention belongs to field of medicaments, and in particular to a kind of purposes of DNA dependent protein kinase specific inhibitor in preparation prevention and treatment kidney fibrosis drug.Further, the active inhibitor of the DNA dependent protein kinase is NU7441.DNA-PK activity inhibitor of the invention is the selective depressant of DNA-PK catalytic subunit, can reduce the renal interstitial fibrosis of unilateral ureteral obstruction induction, improves renal function.NU7441 inhibits DNA-PK activation by specificity, and then inhibit the abnormal activation of mTOR, renal cells epithelial-mesenchymal cell is inhibited to convert, significantly inhibit the generation of renal cells and the Stromal fibroblasts collagen under the stimulation of TGF-β 1, improve Pathological damage and renal function, plays the role of improving renal interstitial fibrosis.The present invention provides effective clinical medicine for prevention and treatment renal fibrosis associated disease.
Description
Technical field
The invention belongs to field of medicaments, and in particular to a kind of DNA dependent protein kinase (DNA-dependent
Proteinkinase, DNA-PK) use of the specific inhibitor NU7441 in preparation prevention and treatment kidney fibrosis associated disease drug
On the way.
Background technique
With the development of society, chronic kidney disease (Chronic kidney disease, CKD) has become global concern
One public health problem.Investigation display in 2012, in China, the illness rate of CKD about 10.8%, total number of persons nearly 1.2
Hundred million.Due to the CKD course of disease be in more duration progress, be finally developed to end-stage renal disease (end-stage renal disease,
ESRD), surrogate therapeutic can only be carried out by dialysis or kidney transplant.The high medical expense of ESRD, statistical data, which is shown, only to exist
2000-2010 during the decade, the ratio that medical expense of the whole world for dialysis is as high as 1.1 trillion dollars, and dialyses be in by
Year ascendant trend, there are about 2,000,000 people to need dialysis treatment every year in China at present.It is heavy that ESRD not only gives society and family to increase
Burden, also bring huge challenge to medical and health care system.However, the pathogenesis of CKD is not fully aware of at present, face
Also lack effective specific intervention means on bed.
A large amount of Clinical and experimental study show no matter CKD, renal fibrosis and impaired renal function caused by which kind of reason
Degree is closely related.Renal fibrosis is renal tissue in all kinds of impairment factors, as bacterium, virus, immune inflammation, drug with
And the organ fibrosis lesion occurred under the effects of hypoxic-ischemic, there is fibroblast proliferation and cytoplasm increases, especially
It, which is that stromatin synthesis increases, substrate degradation is suppressed, leads to extracellular matrix (extracellular matrix, ECM)
Bulk deposition, and then lead to the fibrosis of glomerulosclerosis and tubulo-interstital.Compared to glomerulosclerosis, renal interstitial fibrosis
It is more close with the correlation of renal hypofunction, and determine the principal element of kidney trouble progress.Thus, delay and improve kidney
Dirty fibrosis is the key that prevention and treatment CKD.
DNA dependent protein kinase (DNA-dependent protein kinase, DNA-PK) is phosphatidylinositols 3-
One of kinases associated kinase (PI3K) family member, is primarily targeted for nucleus, connects (non-by non-homogeneous end
Homologous end joining, NHEJ) mode carry out the reparation of DNA double chain fracture, maintaining genome stable and
It generates and is played an important role in V (D) the J recombination of antibody diversity, the regulation that activity is broken by DNA double chain.Nevertheless,
More and more research discovery DNA-PKcs also play many other important biomolecule functions in human cell, such as maintain
Chromosome telomere is stable, adjusts energetic supersession, participates in inflammatory reaction, promoting mitosis and play in cell cycle regulating
Important function etc., and wherein many functions and it is not directly dependent on the fracture of DNA double chain.Existing research shows a variety of swollen
Highly expressed DNA-PKcs is activated by way of autophosphorylation in tumor tissue, and then is activated by directly or indirectly mode
MTOR access leads to the generation of tumour drug resistance.Mammal rapamycin target protein (Mammalian Target of
Rapamycin, mTOR) it is a kind of highly conserved serine threonine protein kinase, it is widely present in mammalian cell,
Belong to phosphoinositide 3-kinase associated kinase (Phosphatidylinositol 3-kinase-related Kinase, PIKK)
Protein family.In mammalian cell, mTOR exists in the form of two species complex of mTORC1 and mTORC2, and regulating cell is raw
Long, proliferation, differentiation, autophagy and apoptosis etc. regulate and control status in core in cell growth.With to mTOR and its signal path
Research deepens continuously, and the effect in many diseases is got more and more attention, recent studies indicate that, the excessive of mTOR swashs
Work is closely related with the occurrence and development of tissue fibrosis, and existing research shows that the excessive activation of mTOR directly activates interstitial at fiber
Cell and renal cells EMT etc. cause extracellular matrix largely to synthesize secretion, significantly promote FSGS, film property kidney
Renal fibrosis process in sick and obstructive kidney trouble, and inhibit the excessive activation of mTOR that can significantly inhibit fibrosis.
Nevertheless, there is presently no direct specificity, and the active inhibitor of mTOR to be inhibited to be used for due to the importance of mTOR itself
The clinical prevention of renal fibrosis.Renal interstitial fibrosis still lacks effective treatment means at present.
Summary of the invention
For the technical problems in the prior art, the present invention provides a kind of suppressions of DNA dependent protein kinase activity
Purposes of the preparation in preparation prevention and treatment kidney fibrosis associated disease, this DNA dependent protein kinase activity inhibitor
Purposes in preparation prevention and treatment kidney fibrosis associated disease solves in the prior art without suitable drug for treating kidney fibre
The technical issues of kidney structure and function damages in dimensionization associated disease.
The present invention provides a kind of DNA dependent protein kinase (DNA-dependent proteinkinase, DNA-PK)
Purposes of the specific inhibitor in the drug of preparation prevention and treatment kidney fibrosis.It is preferred that above-mentioned kidney fibrosis is unilateral ureteral obstruction
The renal interstitial fibrosis of induction.
Further, the DNA dependent protein kinase activity specific inhibitor is NU7441.
We use on the mouse model of the renal interstitial fibrosis of unilateral ureteral obstruction (UUO) induction
NU7441, to inquire by inhibiting DNA dependent protein kinase activity to kidney fibrosis improvement result and its mechanism.As a result it sends out
It is existing, the mouse model of the renal interstitial fibrosis of UUO induction is carried out using DNA dependent protein kinase inhibitor NU7441
Therapeutic intervention can significantly mitigate UUO mouse kidney pathological lesion, inhibit the deposition of nephridial tissue extracellular matrix, improve renal interstitial
Fibrosis.NU7441 inhibits DNA-PK activation by specificity, and then inhibits the abnormal activation of mTOR, it is suppressed that on renal tubule
Chrotoplast epithelial-mesenchymal cell converts (EMT), significantly inhibits renal cells and Stromal fibroblasts and pierces in TGF-β 1
The generation for swashing lower collagen, improves Pathological damage and renal function, plays the role of improving renal interstitial fibrosis.
Detailed description of the invention
The cytotoxicity analysis figure of Fig. 1 CCK-8 detection DNA-PK specific inhibitor NU7441.
The NU7441 less than 1 μM does not have direct toxic side effect to cell as the result is shown.
Fig. 2 Western blot detects fibrosis and proliferation-associated protein expression after NU7441 processing rat fibroblast
Horizontal analysis figure.
NU7441 processing can significantly inhibit the rat fibroblast activation of the induction of TGF β 1 as the result is shown.
Fig. 3 immunofluorescence and Western blot detection DNA-PK activation and the horizontal analysis of fibrosis correlative protein expression
Figure.
NU7441 processing can significantly inhibit TGF β 1 and induce source of people renal cells (HK2) fibrosis as the result is shown
The expression of GAP-associated protein GAP.
Fig. 4 histopathology, Western blot and fluorescence quantitative PCR detection NU7441 are to mouse UUO model kidney fibrous
The impact analysis figure of change.
NU7441 processing as the result is shown can significantly improve UUO mouse renal interstitial fibrosis.
Fig. 5 Western blot detects NU7441 processing to the impact analysis figure of mTOR Pathway Activation and cell EMT.
NU7441 processing as the result is shown can significantly inhibit the abnormal activation of mTOR and the EMT of renal tubular cell.
Specific embodiment
Below by way of specific embodiment, invention is further explained:
Embodiment 1
Material and method
1) material and reagent
Inhibitor NU7441 is purchased from Selleck company, and mTOR, p-mTOR, a-SMA and PCNA antibody are purchased from Cell
Signaling Technology company.FN, DNA-PK and p-DNA-PK antibody are purchased from ABCAM company.β-actin is purchased from south
Jing Baao get company.Fluorescence secondary antibody is purchased from Invitrogen company.TGF β 1 is purchased from R&D company.Secondary antibody needed for Western Blot
And other reagents are purchased from Sigma company.
2) cell culture and processing
Source of people renal cells (HK2) and rat fibroblast (NRK49F), which are used, contains 10% fetal calf serum,
The DMEM/F12 culture medium culture of 0.5% penicillin and streptomysin, condition of culture are 37 DEG C, 5% carbon dioxide and 95% air.
It is research NU7441 for renal fibrosis protective effect and mechanism caused by TGF β 1, we change culture medium into serum-free
The NU7441 of suitable concentration is added in culture medium, while the TGF β 1 that final concentration of 5ng/ml is added simulates renal fibrosis, finally receives
Collect cell and carries out the analysis such as Western Blot detection and progress immunofluorescence.
3) unilateral ureteral obstruction (unilateral ureteral obstruction, UUO) nephropathy model and experiment
Grouping
Eight weeks C57/B6J male mices are randomly divided into three groups, every group 8.UUO modeling, mouse is with penta bar of ratio of 45mg/kg
After appropriate intraperitoneal injection of anesthesia, the open abdominal cavity under aseptic condition, blunt separation left side ureter, on ureter 1/3 under
Ureter is ligatured at 1/3 respectively, then successively closes abdominal cavity, 7 days execution mouse of Yu Shuhou, and leaves and takes sham group left side and UU0
Group operation side nephridial tissue sample.The daily stomach-filling physiological saline of sham control group, that is, sham-operation group；UUO group is equally given isodose
Physiological saline stomach-filling, UUO+NU7441 group, UUO is postoperative to be given once daily the NU7441 stomach-filling that dosage is 40mg/kg and instructs UUO model
Terminate, NU7441 is configured to suspension with physiological saline and carries out stomach-filling, and stomach-filling is carried out using intragastric administration on mice needle.All zooperies are equal
In accordance with Chinese experimental the care of animal and use regulations.
4) histology, immunohistochemistry and immunofluorescence dyeing
Renal tissue fixes through paraformaldehyde, paraffin Bao Li, and histology and immunohistochemical staining are carried out after histotomy.
The normal process of Masson and glycogen PAS dyeing according to the literature carries out.When carrying out immunohistochemistry and immunofluorescence, α-
The primary antibodies concentration such as SMA, DNA-PK is 1:100, and immunofluorescence primary antibody carries out DAPI and contaminates nucleus after overnight, immunofluorescence and
Immunohistochemical staining illustrates to carry out according to standard operation.
5) protein immunoblotting
Renal tissue extracts albumen, operates according to literature method.Protein immunoblotting (Western blot) result is used
ImageJ software carries out gray analysis.
6) real-time fluorescence quantitative PCR
Tissue and cell total rna are extracted using Trizol one-step method.Testing consumptive material used is rnase-free consumptive material, matches reagent
Water is the DEPC water after high pressure.Tissue RNA is extracted: being weighed nephridial tissue 10-15mg on ice, is set in 2mlEP pipe, be first added
500u1Trizol adds 500u1 after homogenate, is stored at room temperature 5min after mixing of turning upside down；Chloroform 200u1 is added, mixes,
It is stored at room temperature 5min, will appear layering at this time: 4 DEG C, 12,000g are centrifuged 15min；Upper strata aqueous phase is transferred to new 1.5mlEP pipe
Isometric isopropanol is added in (generally taking 450u1 or so), mixing of turning upside down, and is then stored at room temperature 10min, and 4 DEG C, 12,
000g is centrifuged 10min；It discards supernatant, is added 75% ethyl alcohol of 1ml pre-cooling in precipitating, 4 DEG C, 7,500g centrifugation 5min, in abandoning
Clearly, precipitating is dried, and rnase-free ddh2o 100ul, instant reverse transcription is added.For cell sample, the thin of 12 orifice plate cultures is utilized
Born of the same parents after collecting cell, are first washed one time with pre-cooling PBS, and 1ml Trizol is added in every hole later, remaining step is identical as tissue.It is inverse
The cDNA that transcription obtains is template, carries out quantitative fluorescent PCR using SYBR green PCR method, detailed process is glimmering according to standard
Fluorescent Quantitative PCR step carries out.
7) cytotoxicity of drug is measured using CCK8 kit.
8) it statisticallys analyze
Data are indicated using mean value scholar SD.More comparison among groups are with one-way analysis of variance (ANOVA), and data compare between two groups
It is examined with T.It is with statistical significance with P < 0.05.
The cell toxicological experiment of 2 NU7441 of embodiment
It using source of people kidney proximal tubular cell line (HK2), is taped against in 96 orifice plates, is cultivated in 100 μ L culture mediums.Cell is set
It is cultivated 24 hours in CO2 incubator in 37 DEG C.By it is final concentration of (100nM, 500nM, 1000nM, 5000nM, 10000nM with
And 20000nM) NU7441 (complete medium preparation) be added plate in, culture plate continue in the incubator be incubated for 24 hours.Make
10 μ L CCK-8 solution are added into each hole of 96 orifice plates with pipettor.It is careful not to introduce bubble in hole, by culture plate
It is incubated for 2 hours in the incubator.Use the absorbance at microplate reader measurement 450nm.As a result as shown in Figure 1.The results show that being lower than
The NU7441 of 1000nM (1 μM) will not cause direct toxic side effect to renal cells.
3 NU7441 of embodiment influences the activation of the rat long fibre cell of transforming growth factor (TGF β 1) induction
In Cultured Rat fibroblast (NRK49F) after cell is pre-processed 1 hour using NU7441, then gives TGF β
1 (5ng/ml) handles sample preparation in 24 hours, and Western blot detects the expression of fibrosis GAP-associated protein GAP in NRK49F, as a result sends out
Existing NU7441 processing can significantly inhibit the synthesis (figure of the fibrosis albumen such as the α-SMA and Fibronectin of the induction of TGF β 1
2)；Further, in NRK49F cell, NU7441 processing can significantly inhibit the synthesis of cell multiplication related protein PCNA
(Fig. 2)；Western blot is the results show that NU7441 can inhibit DNA- by inhibiting the phosphorylation of DNA-PKcs to play
PKcs kinase activity (Fig. 2).In conclusion DNA-PKcs specific inhibitor NU7441 can pass through the phosphorus of inhibition DNA-PKcs
Acidification, and then inhibit activation of the NRK49F cell under the stimulation of TGF β 1.
4 NU7441 of embodiment influences the table that TGF β 1 induces source of people renal cells (HK2) fibrosis GAP-associated protein GAP
It reaches.
In vitro culture source of people renal cells (HK2), after cell is pre-processed 1 hour using (0.5 μM) of NU7441, then
It giving TGF β 1 (5ng/ml) and handles sample preparation in 24 hours, Western blot detects the expression of fibrosis GAP-associated protein GAP in HK2,
As a result, it has been found that NU7441 processing can significantly inhibit the synthesis (Fig. 3) of the Fibronectin fibrosis albumen of the induction of TGF β 1；Into
One step, immunofluorescence the results show that NU7441 can pass through inhibit DNA-PKcs phosphorylation play inhibition DNA-
PKcs kinase activity (Fig. 3).In conclusion DNA-PKcs specific inhibitor NU7441 can pass through the phosphorus of inhibition DNA-PKcs
Acidification, and then inhibit the synthesis of HK2 cell fibrosis albumen under the stimulation of TGF β 1.
5 NU7441 of embodiment influences UUO mouse renal interstitial fibrosis.
UUO model is prepared using C57BL/6J mouse, mouse is divided into three groups by Yu Zaomo second day, and every group eight, UUO+
NU7441 group is daily according to 40mg/kg dosage stomach-filling DNA-PKcs specific inhibitor NU7441, UUO+Vehicle group and vacation
Operation group (sham) same amount of normal saline of stomach-filling daily, the 7th day execution mouse of modeling simultaneously take renal tissue, Western blot
And the expression of fluorescence quantifying PCR method detection fibrosis GAP-associated protein GAP, as the result is shown NU7441 processing can significantly inhibit fibre
The expression (Fig. 4) of dimensionization GAP-associated protein GAP α-SMA and Fibronectin；Immunohistochemistry the results show that NU7441 processing is significant
DNA-PKcs phosphorylation level is inhibited, the pathological stainings such as PAS, Masson and α-SMA immunohistochemistry are the results show that DNA-
PKcs specific inhibitor NU7741 can significantly improve kidney injury and fibrosis progression (Fig. 4).
6 NU7441 of embodiment influences the abnormal activation for the mTOR that TGF β 1 is induced and the EMT of renal tubular cell
In vitro culture source of people renal cells (HK2), 5ng/ml TGF β 1, which is added, to be stimulated different time and receives sample, benefit
MTOR and its phosphorylation level are detected with Western blot, discovery TGF β 1 stimulates the phosphorylation water that can significantly raise mTOR
It is flat, time gradient is presented and raises trend, stimulation 6 hours are the most significant, gradually lower (Fig. 5 A and 5B) later；HK2 is cultivated, is utilized
After 0.5 μM of DNA-PKcs specific inhibitor NU7441 is handled 1 hour, examined after the stimulation of TGF β 16 hours of various concentration are added
MTOR and its phosphorylation level are surveyed, the results show that NU7441 processing can significantly inhibit in mPTCs mTOR under the stimulation of TGF β 1
Phosphorylation (Fig. 5 C)；Western blot is the results show that NU7441 is handled while being inhibited cell EMT GAP-associated protein GAP
The up-regulation (Fig. 5 C and 5D) of vimentin.Further, the above experiment is carried out using NRK49F, discovery NU7441 processing is also significant
Inhibit the phosphorylation (Fig. 5 E and 5F) of mTOR；Can we further analyze NU7441 processing using Western blot significant
The phosphorylation for inhibiting mTOR in UUO kidney of mouse, the results show that compared to sham-operation group, in UUO model mice nephridial tissue
MTOR phosphorylation significantly raises, and give UUO mouse NU7441 processing after, the phosphorylation of mTOR significantly be suppressed (Fig. 5 G and
5H).It may be by regulation mTOR access the above results show that reconciling and activating during renal fibrosis, on DNA-PKcs
Activate and then participate in the progress of fibrosis.
It is prevented and treated in conclusion the present invention provides a kind of DNA dependent protein kinase activity inhibitor NU7441 in preparation
Purposes in renal fibrosis drug, the inhibitor are administered by way of stomach-filling, by inhibiting DNA dependent protein kinase living
Property so inhibit the activation of mTOR, and then inhibit renal cells EMT and fibroblastic activation, to play anti-
Control the purpose of renal interstitial fibrosis.
Particular embodiments described above has carried out further in detail the purpose of the present invention, technical scheme and beneficial effects
It describes in detail bright, it should be understood that the above is only a specific embodiment of the present invention, is not intended to restrict the invention, it is all
Within the spirit and principles in the present invention, any modification, equivalent substitution, improvement and etc. done should be included in guarantor of the invention
Within the scope of shield.
Claims (4)
- Purposes of the 1.DNA deopendent protein kinase specific inhibitor in the drug of preparation prevention and treatment kidney fibrosis.
- 2. purposes according to claim 1, it is characterised in that the kidney fibrosis is unilateral ureteral obstruction induction Renal interstitial fibrosis.
- 3.DNA deopendent protein kinase specific inhibitor inhibits the abnormal activation of mTOR in preparation, inhibits renal tubular epithelial thin The conversion of born of the same parents' epithelial-mesenchymal cell inhibits renal cells and the Stromal fibroblasts collagen under the stimulation of TGF-β 1 Generation drug in purposes.
- 4. purposes according to claim 1,2 or 3, it is characterised in that: the DNA dependent protein kinase specificity suppression Preparation is NU7441.
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