CN108309987A - Applications of the PCN in preparing the drug for treating acute kidney injury associated disease - Google Patents

Applications of the PCN in preparing the drug for treating acute kidney injury associated disease Download PDF

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CN108309987A
CN108309987A CN201810121267.4A CN201810121267A CN108309987A CN 108309987 A CN108309987 A CN 108309987A CN 201810121267 A CN201810121267 A CN 201810121267A CN 108309987 A CN108309987 A CN 108309987A
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pcn
acute kidney
reperfusion
associated disease
platinum
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CN108309987B (en
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张爱华
于晓文
贾占军
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Nanjing Childrens Hospital of Nanjing Medical University
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/56Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone

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  • Chemical & Material Sciences (AREA)
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  • Pharmacology & Pharmacy (AREA)
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  • General Health & Medical Sciences (AREA)
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  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
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Abstract

Applications of the PCN in preparing the drug for treating acute kidney injury associated disease.The invention discloses a kind of new indications of pregnenolone 16a carbonitrile (PCN).The present invention, which proposes PCN, can mitigate the acute kidney injury associated disease of cis-platinum and ischemia-reperfusion induction, including illnesss such as acute renal tubular injury, renal function, rat tubular cell apoptosis, the expression of inflammatory factor and secretions, mainly mitigate acute kidney injury by inhibiting the apoptosis of renal tubular cell.

Description

Applications of the PCN in preparing the drug for treating acute kidney injury associated disease
Technical field
The present invention relates to the new opplications of PCN, are being prepared more particularly to PCN for mitigating ischemia-reperfusion and cisplatin induction Acute kidney injury associated disease drug in application.
Background technology
Acute kidney injury (acute kidney injury, AKI) refers to the decreased renal function occurred suddenly, can with or not With oliguresis or anuria, be the renal function caused by the lesions such as glomerulus, renal tubule, renal interstitial or blood vessel in a short time drastically under Drop or the clinical syndrome lost, show as that normal water-electrolyte balance cannot be kept suddenly, and interior metabolism product accumulation goes out Existing azotemia, water and the symptoms such as electrolyte disturbance and metabolic acidosis.Acute kidney injury is that one kind can be secondary to a variety of diseases The clinical syndrome of disease, it is more common in intensive care unit, have the characteristics that morbidity is anxious, progress is fast, case fatality rate is high, is chronic One of Important cause of disease of kidney trouble.It is one group of serious Comprehensive Clinical syndrome, and the death rate is high, delays the diagnosis and treatment or malpractice can It is in irreversible change to lead to renal function, so that patient is entered maintenance dialysis, very big negative effect is brought to social economy.
The illness rate community of AKI is 1%, is 7.1% in hospital.Incidence is the case fatality rate of the AKI of annual infection from hospital It is 10%~80%, merges the case fatality rate of multiple organ failure>50%, it is 80% to need the case fatality rate of renal replacement therapy, because This AKI has high incidence and lethality.Its Etiological is ischemic, caused by kidney noxious material or primary renal diseases, kidney Tubular epithelial cell (Renal tubular epithelial cells, RTEC) damage is the main pathological basis of AKI.In disease Under diseased state, the active RTEC of function is easier that acute tubular necrosis (Acute is occurred by damaging caused by nephrotoxin etc. Tubular Necrosis, ATN), cause AKI and renal failure.
Ischemia-reperfusion (ischemia reperfusion, IR) damage is the common disease factor of clinical AKI.Ischemia-reperfusion Damage is related to a variety of damage mechanisms, includes effect, intracellular calcium overload and the leukocyte activation of free radical.And kidney tubular epithelial Cellular damage is the target cell of various damage factors again.Although current therapy has an improvement, ischemia-reperfusion it is dead It dies rate still to remain high, so it is extremely urgent to find new therapy.
Cis-platinum (Cisplatin, CP) is that clinical treatment entity tumor includes that head, neck, ovary and testis are the most frequently used And one of most effective chemotherapeutics, because its antitumaous effect is strong, with other tumour medicines without in crossing drug resistant and combined chemotherapy One of most common antitumor drug.Clinical investigation shows since it is with dose dependent acute renal toxic effect, greatly Ground limits its clinical application, and the AKI incidences of cisplatin induction are 25%~35%, and it includes induction to cause the main mechanism of damage The oxidative stress of renal cells causes Apoptosis, and can trigger inflammatory reaction and participate in kidney injury.How to cut Real effectively to prevent and mitigate AKI caused by cis-platinum, preferably performance cis-platinum antitumor action has become current urgently to be resolved hurrily Problem.
In patient and animal model mesonephric tubule cell loss --- including tubular apoptosis and necrosis it is considered as AKI Main participation cell in development.In addition, the renal tubular cell to fall off forms cast with albumen in tube chamber blocks uroflow, damage Tubule may further promote renal interstitial fibrosis, interstitial inflammation, capillary lose.So how to prevent renal tubule Cell loss is the key that treatment AKI.
Mitochondria is cell " energy plants ", is the main place for synthesizing ATP, electron transmission and oxidative phosphorylation.Line Effect of the mitochondria function obstacle in injury of kidney has obtained extensive concern.It is proved that the acute kidney damage caused by nephrotoxic drugs In wound model, there is Mitochondrial Shape exception, Mitochondrial DNA Mutation, mitochondria DNA copy number decline and Apoptosis. Mitochondria has core status and effect in Apoptosis, is the main path that Apoptosis occurs.After cis-platinum enters cell The pro apoptotic protein such as Bax in Bcl-2 families can be activated, opening of mitochondria permeability transition pore, cromoci is promoted to wither It dies the rush antiapoptotic factors such as inducible factor and is discharged into endochylema from mitochondria, generate caspase cascade reactions, eventually lead to the hair of apoptosis It is raw.
PCN is the agonist of Pregnane X Receptor (pregnane X receptor, PXR).PXR swashs as endogenous and allogene Receptor living plays important biological regulation effect and " removing toxic substances " functions in the defense mechanism of body.In addition, numerous studies also table Bright the PXR substance of wide participation body and energetic supersession by adjusting the expression of downstream target gene, and in the hair of certain diseases It plays a significant role in hair tonic exhibition.At present about the research of PXR it is more concentrate on Liver Lipid Metabolism, angiocarpy, obesity etc. side Face.And in terms of AKI not yet studies have reported that.Currently, caused by also ischemia-reperfusion and cis-platinum can be fought there has been no PCN The report of AKI.
Invention content
The purpose of the present invention is to provide a kind of PCN to prepare the AKI phases for mitigating ischemia-reperfusion and cisplatin induction Application in the drug of related disorders.
The present invention has found PCN for mitigating ischemia-reperfusion or suitable by zoopery and the aspect of In vitro cell experiment two Application in the drug of the AKI associated diseases of platinum induction.
Specifically, the present invention proposes PCN and is preparing the AKI renal functions for mitigating ischemia-reperfusion and cisplatin induction Application in drug.
The invention also provides PCN in the medicine of the expression and the secretion that prepare the renal inflammation molecule for mitigating cisplatin induction Application in object.
Further, present invention finds PCN in the drug for preparing the rat tubular cell apoptosis for mitigating cisplatin induction In application.
Meanwhile it has also been found that PCN prepare for cisplatin induction kidney tubule cells injury of mitochondria drug in Application.
Description of the drawings
Fig. 1 is the renal function and staining for glycogen (PAS) knot after treating with modeling after cis-platinum and ischemia-reperfusion and with PCN Fruit;
Fig. 2 is the shadow of QPCR methods and ELISA method research PCN to expression and the secretion of the renal inflammation molecule of cisplatin induction It rings;
Fig. 3 is QPCR method research PCN to the tubule cells apoptosis of cisplatin induction and the influence of kidney injury relevant molecule;
Fig. 4 is that fluidic cell and QPCR methods detect PCN in vitro to tubule cells apoptosis, active oxygen and the line of cisplatin induction The influence of mitochondrial DNA copy number;
Fig. 5 is the Western blot method researchs PCN influences to the kidney tubule cells apoptosis of cisplatin induction in vitro.
Specific implementation mode
The concrete operation step of Western blot, real-time fluorescence quantitative PCR, PAS dyeing, flow cytometry in the present invention It is as follows:
Western blot:
Tissue lysates extract renal tissue total protein, measure protein concentration using BCA methods, take 30 μ g albumen loadings, 10% or 12% polyacrylamide gel electrophoresis (SDS.PAGE), 300mA × 1.5h is wet to walk around to pvdf membrane, confining liquid room temperature 1h is closed, primary antibody, Bax (Cell Signaling Technology), Bcl-2 (Cell is added after TBST elutions SignalingTechnology), cleaved caspase3 (Cell SignalingTechnology), PXR (Abcam), GAPDH (Cell SignalingTechnology), 4 DEG C of overnight incubations.TBST washes film 5 times, each 5min, with corresponding secondary antibody room Temperature is incubated 1h, and TBST washes film 5 times.Antigen antibody complexes show that darkroom X-ray film is exposed with Enhanced chemiluminescence (ECL) And scan, quantification of protein is used carries out gray value analysis to purpose band, with purpose band gray value/GAPDH gray value tables Show the relative expression quantity of destination protein.
Real-time fluorescence quantitative PCR (QPCR):
Renal tissue total serum IgE is extracted, RNA solution concentration and purity are measured with spectrophotometry.Utilize Reverse Transcriptase kit 1 μ gRNA reverse transcriptions at cDNA, the situation of change of different genes are detected according to following reaction system by (Takara, DaLian).
A. reaction system
B.PCR thermal circulation parameters
55℃-95℃,snap every 0.5℃,repeat 81circles.
PAS is dyed:
4% paraformaldehyde fixing organization 48h, specimens paraffin embedding slices, dewaxing to water, distilled water flushing, 70% alcohol rinse 3 It is secondary.Periodic acid alcoholic solution 10min (this solution temperature is preferably 17-20 degree) is immersed, after 70% alcohol is washed, is entered in reducing solution 1min (this solution temperature is preferably 17-20 degree) after 70% alcohol is washed, enters colourless slag fuchsin solution 1-1.5h, winter room When temperature is relatively low, 37 degree of incubators can be put into.Flowing water rinses 10min, with Mayer ' s haematoxylins redye liquid and redye nucleus 3-5min, Broken up again with 1% hydrochloride alcohol, after flowing water rinses, is dehydrated transparent, last mounting.
The double dye experiments of Annexin V/PI apoptosis:
Logarithmic growth phase renal cells (RTEC) are inoculated in 6 orifice plates, give cis-platinum and PCN, drug respectively After effect for 24 hours, with no EDTA trypsin digestion cells, 5min is centrifuged with 1000rpm rotating speeds, cell is collected, discards culture medium.With pre- Twice, 400 μ L1 × Binding Buffer suspension cells are added, cell density is big in the PBS solution washing cell of cold mistake wherein About 1 × 106cells/mL.Every group of cell suspension is separately added into 5 μ LAnnexin V and 5 μ L PI, and gently room temperature is kept away after mixing 15min is incubated under the conditions of light.Flow cytomery is used in 1h.
Mitochondrial membrane potential (JC-1) detects:
The decline of mitochondrial membrane potential is the hallmark events of Apoptosis early stage.By JC-1 from red fluorescence to The transformation of green fluorescence can reliably detect the decline of cell membrane potential, at the same can also use JC-1 from red fluorescence to A Testing index of the transformation of green fluorescence as Apoptosis early stage.Select the cell inoculation of exponential phase in 6 orifice plates In, give cis-platinum and PCN respectively, drug effect for 24 hours after, with no EDTA trypsin digestion cells, centrifuged with 1000rpm rotating speeds 5min collects cell, discards culture medium.Cell is washed with precooled PBS solution twice, and 1mL JC-1 are added and dye work Liquid mixes well.37 DEG C of incubation 20min in cell incubator.In incubation period, according to every 1mL JC-1 dye solutions (5 ×) ratio of 4mL ultra-pure waters is added, suitable JC-1 dye solutions (1X) are prepared, and be positioned over ice bath.37 DEG C of incubations terminate Afterwards, supernatant is absorbed, is washed 2 times with JC-1 dye solutions (1X).2mL cell culture fluids are added, flow cytometer is used in 1h Detection.
Active oxygen (ROS) detects:
Select the cell inoculation of exponential phase in 6 orifice plates, give cis-platinum and PCN respectively, drug effect for 24 hours after, use Without EDTA trypsin digestion cells, 5min is centrifuged with 1000rpm rotating speeds, cell is collected, discards culture medium.It is molten with precooled PBS Liquid washing cell is primary, and 500 μ LmitoSOX dyeing working solutions (1X) are added, mix well.37 DEG C of incubations in cell incubator 20min.After 37 DEG C are incubated, supernatant is absorbed in centrifugation, and PBS solution washs cell twice, 500 μ L cell culture fluids is added, 1 Flow cytomery is used in hour.
Below by specific embodiment, the present invention will be described in detail.
The influence for the acute kidney injury renal function that embodiment 1PCN induces cis-platinum and ischemia-reperfusion.
The male C57BL/6 mouse for taking 18~22g of weight are divided into 3 groups, i.e. control group, cis-platinum model group and PCN treatments Group (n=8).
Control group:Isometric medium is injected intraperitoneally one time a day, totally 5 days;
Cis-platinum model group:Intraperitoneal injection, 20mg/kg, single-dose;
PCN treatment groups:2 days (intraperitoneal injection, 100mg/kgPCN, 200 μ L/ times) is administered in PCN in advance, one time a day, then Single-dose cis-platinum (is injected intraperitoneally, 20mg/kg), PCN re-treatments 3 days, takes blood after cis-platinum injections 72h, leaves and takes nephridial tissue.
Blood specimen is centrifuged into (20min, 3000r/min), with creatinine reagent box (Creatinine Assay Kit (cat: K625-100, biomars)), urea nitrogen kit (QuantiChrom Urea Assay kit (cat:DIUR-500, Hayward, CA)) serum creatinine, urea nitrogen are measured, experimental result is shown in Figure 1A.
We use whether ischemia-reperfusion injury model, PCN have therapeutic effect to ischemical reperfusion injury simultaneously.Take weight 18~ The male C57BL/6 mouse of 22g are divided into 3 groups, i.e. control group, ischemia-reperfusion injury model group and PCN treatment groups (n=8).
Control group:Isometric medium is injected intraperitoneally one time a day, totally 3 days;
Ischemia-reperfusion group:Give simple medium one time a day, totally 3 days;
PCN treatment groups:2 days (intraperitoneal injection, 100mg/kgPCN, 200 μ L/ times) is administered in PCN in advance, one time a day, then To mouse kidney ischemia-reperfusion, PCN re-treatments 1 day, ischemia-reperfusion takes blood afterwards for 24 hours, leaves and takes nephridial tissue.Utilize method above Each group serum creatinine, urea nitrogen are measured respectively, and experimental result is shown in Figure 1A.
Figure 1B is the PAS coloration results after treating with cis-platinum and ischemia-reperfusion modeling and with PCN, can be with from result Find out, is significantly increased using modeling success, serum creatinine, urea nitrogen after cis-platinum and ischemia-reperfusion, kidney is prompted to be damaged. And after using PCN treatments, it can be obviously improved renal function, creatinine, the urea nitrogen levels model compared with model group reduce, p< 0.05.According to PAS coloration results, cis-platinum group and ischemia-reperfusion group renal tubule structure are destroyed, and protein cast is formed, and PCN can Significantly improve the kidney injury of cis-platinum and ischemia-reperfusion induction.
Influences of the embodiment 2PCN to expression and the secretion of the renal inflammation molecule of cisplatin induction.
Influence using QPCR methods and ELISA method research PCN to expression and the secretion of the renal inflammation molecule of cisplatin induction.
As shown in Figure 2 A, using ELISA method research PCN to the shadow of expression and the secretion of the renal inflammation molecule of cisplatin induction It rings.In the AKI models of cisplatin induction, inflammatory factor IL-6, the TNF-α expression of cis-platinum model group are bright compared with the control group It is aobvious to increase, p<0.001.And PCN treatment groups can significantly reduce IL-6, TNF-α expression, p<0.05.
As shown in Figure 2 B, using QPCR method research PCN to the shadow of expression and the secretion of the renal inflammation molecule of cisplatin induction It rings.In the AKI models of cisplatin induction, inflammatory factor IL-6, the TNF-α expression of cis-platinum model group are bright compared with the control group It is aobvious to increase, p<0.05.And PCN treatment groups can significantly reduce IL-6, TNF-α expression, p<0.01.
The result shows that PCN can be substantially reduced IL-6, TNF-α expression in the AKI models of cisplatin induction.
Embodiment 3PCN is to the tubule cells apoptosis of cisplatin induction and the influence of kidney injury relevant molecule.
PCN is measured to cisplatin induction using the expression that QPCR methods detect kidney apoptosis and lose relevant molecule The improvement situation of AKI, the results are shown in Figure 3, and the apoptosis relevant molecule Bax expression of cis-platinum model group is significantly raised, Bcl-2 expression It is substantially reduced;It is significantly raised to damage the expression of relevant molecule Kim-1, NGAL, p<0.05.And PCN treatment groups can significantly reduce The expression of Bax, Kim-1, NGAL increase the expression of Bcl-2, p<0.05.
The result shows that PCN can be substantially reduced the kidney apoptosis of cisplatin induction and lose the expression of relevant molecule.
Embodiment 4PCN is in vitro to the shadow of the tubule cells apoptosis of cisplatin induction, active oxygen and mitochondria DNA copy number It rings.
External application RTEC cells (Mouse Renal Tubular Epithelial Cells system), select the cell inoculation of exponential phase in 6 holes In plate, give cis-platinum (5 μ g/mL) and PCN (5 μM) respectively, drug effect for 24 hours after, utilize flow cytomery tubule cells Apoptosis incidence and reactive oxygen species, QPCR methods detect tubule cells mitochondria DNA copy number variation.As a result such as Fig. 4 A institutes Show, the ratio of cis-platinum model group apoptosis is significantly raised, it is observed that about 30% apoptosis rate, PCN treatment groups with Cis-platinum model group is compared, and the ratio that apoptosis occurs is substantially reduced, and observes about 20% apoptosis rate.As shown in Figure 4 B, cis-platinum mould The intracellular reactive oxygen species of type group are significantly raised compared with the control group, P<0.001.PCN treatment groups are compared with cis-platinum model group Intracellular reactive oxygen species, P can be substantially reduced<0.05.As shown in Figure 4 C, cis-platinum model group cell mitochondrial DNA copy Number is substantially reduced compared with the control group, P<0.05.PCN treatment groups being capable of significantly raised cell mitochondrial compared with cis-platinum model group DNA copy number, P<0.01.
The result shows that cis-platinum stimulation RTEC cells are for 24 hours, can apparent inducing cell apoptosis generation, and cell can be led to Interior ROS levels raising, the reduction of mitochondria DNA copy number.After giving PCN treatments, the cell of cisplatin induction can be significantly reduced The generation of apoptosis, and intracellular ROS level can be reduced, increase mitochondria DNA copy number, it prompts PCN to be possible to improvement cis-platinum and lures The mitochondrial function damage led.
The embodiment 5PCN influences to the tubule cells apoptosis of cisplatin induction in vitro.
External application RTEC cells (Mouse Renal Tubular Epithelial Cells system), select the cell inoculation of exponential phase in 6 holes In plate, give cis-platinum (5 μ g/mL) and PCN (5 μM) respectively, drug effect for 24 hours after, using western blot detections Bax, The expression of Bcl-2, cleaved-caspase 3, while detecting the protein expression situation of PXR.The results are shown in Figure 5, cis-platinum mould The expression of type group, PXR is lowered, while 3 expression of apoptosis-related protein Bax and cleaved-caspase raises, Bcl-2 tables Up to downward.PCN treatment groups can obviously raise the expression of PXR, Bcl-2 compared with cis-platinum model group, lower Bax and Cleaved-caspase3 expressions.
The result shows that cis-platinum stimulation RTEC cells are for 24 hours, the expression of intracellular PXR can be lowered.Give PXR agonists PCN Processing can raise the expression of PXR, while inhibit the tubule cells apoptosis induced by cis-platinum.

Claims (5)

1.PCN answering in the drug for preparing the acute kidney injury associated disease for mitigating ischemia-reperfusion and cisplatin induction With.
2. application according to claim 1, which is characterized in that the acute kidney for mitigating ischemia-reperfusion and cisplatin induction Damage associated disease is to mitigate the acute kidney injury renal function of cisplatin induction.
3. application according to claim 1, which is characterized in that the acute kidney for mitigating ischemia-reperfusion and cisplatin induction Damage associated disease is to mitigate the rat tubular cell apoptosis of cisplatin induction.
4. application according to claim 1, it is characterised in that the acute kidney for mitigating ischemia-reperfusion and cisplatin induction Damage associated disease is the expression and secretion for the renal inflammation factor for mitigating cisplatin induction.
5. application according to claim 1, which is characterized in that the acute kidney for mitigating ischemia-reperfusion and cisplatin induction Damage associated disease is to improve the kidney tubule cells mitochondrial function of cisplatin induction.
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Cited By (3)

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CN109908139A (en) * 2018-12-28 2019-06-21 南京市儿童医院 Cilomilast is preparing the purposes in the drug for treating acute kidney injury associated disease
CN113730416A (en) * 2021-09-18 2021-12-03 南京市儿童医院 Application of BIX-01294 in preparation of medicine for treating acute kidney injury related diseases
CN117122603A (en) * 2023-09-07 2023-11-28 南方医科大学顺德医院(佛山市顺德区第一人民医院) Pharmaceutical preparation and application thereof

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Publication number Priority date Publication date Assignee Title
CN109908139A (en) * 2018-12-28 2019-06-21 南京市儿童医院 Cilomilast is preparing the purposes in the drug for treating acute kidney injury associated disease
CN109908139B (en) * 2018-12-28 2022-02-22 南京市儿童医院 Use of cilomilast for the preparation of a medicament for the treatment of a disorder associated with acute kidney injury
CN113730416A (en) * 2021-09-18 2021-12-03 南京市儿童医院 Application of BIX-01294 in preparation of medicine for treating acute kidney injury related diseases
CN117122603A (en) * 2023-09-07 2023-11-28 南方医科大学顺德医院(佛山市顺德区第一人民医院) Pharmaceutical preparation and application thereof
CN117122603B (en) * 2023-09-07 2024-03-19 南方医科大学顺德医院(佛山市顺德区第一人民医院) Pharmaceutical preparation and application thereof

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