CN105296488B - Applications of the ultrasound microbubble mediated siRNA interference GRK4 in targeting adjusts natruresis and blood pressure level - Google Patents
Applications of the ultrasound microbubble mediated siRNA interference GRK4 in targeting adjusts natruresis and blood pressure level Download PDFInfo
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- CN105296488B CN105296488B CN201510872228.4A CN201510872228A CN105296488B CN 105296488 B CN105296488 B CN 105296488B CN 201510872228 A CN201510872228 A CN 201510872228A CN 105296488 B CN105296488 B CN 105296488B
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Abstract
The invention discloses a kind of applications of ultrasound microbubble mediated siRNA interference GRK4 in targeting adjusts natruresis and blood pressure level, the siRNA molecule sequence is 5 ' ccuguauucuuagaccaaadtdt 3 '.The present invention carries siRNA using ultrasound microbubble technique and is ruptured to kidney specific, effectively suppresses kidney GRK4 expression, increase urine sodium and urine volume excretion, realizes the purpose of targeting prevention and treatment hypertension.
Description
Technical field
The invention belongs to biomedicine technical field, ultrasound microbubble mediated siRNA disturbs GRK4 to adjust urine sodium in targeting
Application in excretion and blood pressure level.
Background technology
The main reason for hypertension and its complication are just becoming influence people's health.Kidney is responsible for the important of natruresis
Organ, most attention is obtained in hypertension research.In many factors of regulating blood pressure, 4 (G of g protein coupled receptor kinases
Protein-coupled receptor kinases 4, GRK4) gain a special interest in recent years.First, GRK4 is positioned at dye
The 4pl6.3 of colour solid, the morbidity that this region is considered with human essential hypertension have substantial connection；And known to GRK4
Multiple SNPs sites also have with the morbidity of hypertension to be directly linked.Secondly, different from other members of GRK families, as GRK2,
The extensive tissue expression of GRK3, GRK5 and GRK6, the tissue expression of GRK4 have specificity, and early-stage study finds GRK4 specificity
Expressed in the restricted groups such as kidney, testis, mesometrium and blood vessel.What is more important, GRK4 can pass through phosphorylation phase
G protein coupled receptor is answered, changes the function of corresponding acceptor, such as：Increase causes the blood angiotonin II receptor I of water-sodium retention
(AT1R) increase, and cause the phosphorylation level of these acceptors to change, and then receptor-mediated kidney natriuretic diuretic is damaged/water
Sodium retention effect strengthens, so as to cause elevation of the blood pressure.It is the reason for numerous function of receptors are abnormal that GRK4 activity, which increases, therefore,
GRK4 has become the novel targets of hypertension therapeutic concern.How effectively to suppress the activity of GRK4 and effect is ground as hypertension
Study carefully the new hot spot with therapy field.
It is a large amount of with treatment-related gene, acceptor, ligand etc. with the development of human activities environment and molecular biology
It was found that gene therapy hypertension is increasingly becoming the hot spot studied both at home and abroad at present.How by target gene safely, effectively, target
Internal certain organs, tissue are imported to tropism, and it is one of main bugbear urgently to be resolved hurrily at present to stablize expression in target cell.
Gene transfection method can be divided into three classes at present：(1) bioanalysis：Refer mainly to the gene transfection of viral vector mediation；(2) chemical method：
Including calcium phosphate precipitation, liposome embedded etc.；(3) Physical：Including electroporation, naked DNA direct injection etc..Wherein, it is viral
Carrier has compared with high gene transfection efficiency, but the potential danger there are immunogenicity and with host cell integral, its security and
Adverse consequences caused by immunogenicity is troubling.The methods of liposome embedded, has the advantages that less toxic, low immunogene reaction, but
There is the deficiencies of efficiency gene transfection is low, gene cannot express steadily in the long term.The physical methods such as electroporation are big to tissue damage, and pacify
Population parameter is difficult to determine.Comparatively speaking, ultrasonic mediation microbubble ruptures technology is not only safe but also efficient, application prospect desirable.
Specifically, ultrasonic mediation microbubble ruptures (ultrasound-targeted microbubble destruction, UTMD) technology
It is after being loaded with the microbubble contrast agent intravenous administration of target gene, to give the ultrasonic irradiation of certain condition in target tissue, cause
Microvascular lesions, make endovascular microbubble ruptures and discharge gene, while produce " cavitation effect " and " acoustic horn effect ", make capillary
Penetrability of vessels and permeability of cell membrane increase, so as to promote release gene largely to enter target cell, make microvesicle or the base of release
Because can intravasation wall and tissue space, and then play targeted therapy effect.Research shows, ultrasonic irradiation and micro- is used in combination
Bubble can significantly improve the transfection efficiency of gene.Ultrasound microbubble technique has the characteristics that 3：(1) security：Acoustic contrast agent is a kind of high
The suspension of concentration microvesicle, has no toxic side effect human body；(2) targeting delivery：Carried out using therapeutic ultrasound or diagnostic ultrasound
Irradiation, after rupturing microvesicle avalanche, Targeting delivery goes out entrained gene；(3) Penetration enhancing effect：Microbubble ruptures can produce cavitation
Effect, causes the transient rise of membrane permeability, and the microjet of generation etc. can promote medicine or gene delivery.Exactly above-mentioned protrusion is excellent
Point so that ultrasound microbubble technique seems especially noticeable.
In ultrasound microbubble technique, microvesicle is the main component of ultrasonic targeted contrast agent, including shell and interior inflatable body.Newly
Inflatable body is based on the macromolecule inert gases such as sulfur hexafluoride, fluorine carbon, nitrogen in type microvesicle；The shell of parcel microbubble mainly has fat
Class, albumin class, polymer class and surfactant-based, can increase microvesicle stability, extend in blood circulation system and stop
Stay the time.In recent years, ultrasound microbubble mediated targeting is related in angiocardiopathy, diabetic nephropathy or kidney neoplasms to control
Treat, but in kidney urinates Natrium metabolism and hypertension research field, the application of the gene therapy of ultrasound microbubble technique mediation is still
Have no report.
RNA interference (RNA interfering, RNAi) can efficiently suppress specific gene, because its toxicity is relatively low, in base
Because having critical role in Therapy study, technology also reaches its maturity.SiRNA (small interfering RNA, siRNA) is
The key link and effector molecule of RNAi effects.The effect of siRNA is using the mRNA of homologous complementary sequence as target, is promoted
MRNA degrades, and the internal specific gene of blocking that can be efficient, special is expressed, induced gene silence effect.According to this principle, for
The mRNA of target gene, designs and synthesizes specific siRNA, can close the expression of specific gene.With other genes one
Sample, siRNA will be transported successfully, need to undergo 3 stages：Extracellular transport, cellular uptake and intracellular transport.Up to the present,
There is not yet being disturbed using siRNA technologies for GRK4 in kidney, and then change the report of kidney natruresis level.
The content of the invention
In view of this, it is an object of the invention to provide a kind of ultrasound microbubble mediated siRNA interference GRK4 to adjust in targeting
The application in natruresis and blood pressure level is saved, the expression for effectively suppressing kidney GRK4 is disturbed by siRNA, and then change kidney
Natruresis is horizontal, reduces blood pressure.
The present invention takes following technical scheme：
1st, a kind of siRNA molecule, sequence 5 '-ccuguauucuuagaccaaadtdt-3 ', 5 '-
Ggcugucugauauaugaaadtdt-3 ' or 5 '-ggagagagcuccugaaguudtdt-3 '.
Preferably, sequence 5 '-ccuguauucuuagaccaaadtdt-3 '.
It should be noted that in sequence, a, u, c, g are ribonucleic acid, and t is DNA, and d represents the nucleic acid
For DNA.
2nd, application of the above-mentioned siRNA molecule in the medicine for preparing prevention or treatment hypertension.
Preferably, the siRNA targetings interference g protein coupled receptor kinases 4.
Preferably, siRNA is carried by ultrasonic microbubble.
Preferably, the ultrasonic microbubble is lipid microbubble.
Preferably, the ultrasonic microbubble is lipid microbubble " fat fluorine is shown ", and core gas is perfluoropropane, microvesicle average grain diameter
2 μm, microbubble concentration is 4 × 109~9 × 109/ml。
Preferably, the ultrasonic microbubble first adsorbs one layer of poly-D-lysine, then adsorbs siRNA.
3rd, application of the siRNA molecule in the medicine for adjusting urine sodium and/or urine volume excretion is prepared.
The beneficial effects of the present invention are：The present invention is ruptured using ultrasound microbubble technique carrying siRNA to kidney specific,
Effectively suppress kidney GRK4 expression, increase urine sodium and urine volume excretion, realize the purpose of targeting prevention and treatment hypertension.Relative to
For the other materials such as albumen, lipid microbubble will not be denatured because of high fever, echogenicity stronger and easy preparation, its molecular layer it is variable
Property is conducive to the coupling of ligands specific.Ultrasound microbubble contrast agent is a kind of good genophore, is held compared with viral vector
Bigger is measured, few GEM 132, even DNA fragmentation, whole chromosome can be carried, therefore, specific target is connected on microvesicle
To ligand or antibody construction ultrasound targeted microbubble, make to combine more closely between microvesicle and target organ, can further improve gene
Transfection efficiency, while the infringement to normal cell, tissue or blood vessel can be reduced, and it is more stable in circulation in vivo.
SiRNA technologies can overcome the absorption that Antisense OligodeoxynucleotideTechnique Technique stability is poor, transfer system is to antisensenucleic acids
Rate is relatively low, the defects of easily causing toxicity, with specific depletion or can reduce the expression of specific gene, have high specific (siRNA
With stringent sequence-specific, its identification can be accurate to a nucleotide), high efficiency (only need an a small amount of siRNA to make effect
Encoding gene product (be remarkably decreased), (effect of siRNA inhibition of gene expression can cross over cell boundary to high Cell permeable
Transmitted in different iuntercellulars) the features such as, it has also become the powerful of target gene therapy.
Brief description of the drawings
In order to make the purpose of the present invention, technical solution and beneficial effect clearer, the present invention provides drawings described below：
Fig. 1 fluorescence microplate readers verification microvesicle parcel siRNA, the "+" of abscissa, which represents, adds microvesicle, and "-", which represents, not to be had
Add microvesicle；The fluorescent value for the microvesicle that ordinate represents to be suspended in liquid level accounts for the proportion of total fluorescent liquid value.
Fig. 23 expresses the mRNA of GRK4 in spontaneous hypertensive rat renal proximal tubules cell different siRNA
Interference results contrast, 1,2,3 represent 1-3 primers respectively, effect most preferably No. 1 primer.
After the ultrasound microbubble mediated GRK4siRNA of Fig. 3 (No. 3 primers) intervene spontaneous hypertensive rat, its kidney GRK4 tables
Up to result.
After the ultrasound microbubble mediated siRNA of Fig. 4 intervene spontaneous hypertensive rat kidney GRK4 expression, twenty-four-hour urine amount is at any time
Between result of variations.
After the ultrasound microbubble mediated siRNA of Fig. 5 intervene spontaneous hypertensive rat kidney GRK4 expression, natruresis rate is at any time
Between result of variations.
After the ultrasound microbubble mediated siRNA of Fig. 6 intervene spontaneous hypertensive rat kidney GRK4 expression, mean arterial pressure is at any time
Between result of variations.
Embodiment
The preferred embodiment of the present invention is described in detail below.The experiment side of actual conditions is not specified in embodiment
Method, usually according to normal condition or according to the condition proposed by manufacturer.
Embodiment 1.
Using lipid microbubble " fat fluorine is shown ", (lipid microbubble " fat fluorine is shown " has detailed Jie in ZL02133720.9 patents for experiment
Continue), its core gas is perfluoropropane, 2 μm of microvesicle average grain diameter when developing for substantial viscera, wherein 98% be less than 8 μm, it is micro-
It is about 4 × 10 to steep concentration9~9 × 109/ ml, after being shaken using faster speed mechanical, microvesicle particle diameter is significantly reduced.
3 pairs of siRNA primers are designed, its sequence difference is as follows：
No. 1 primer：5 '-ccuguauucuuagaccaaadtdt-3 ', SEQ ID NO.1；
No. 2 primers：5 '-ggcugucugauauaugaaadtdt-3 ', SEQ ID NO.2；
No. 3 primers：5 '-ggagagagcuccugaaguudtdt-3 ', SEQ ID NO.3.
Above-mentioned 3 pairs of primers are wrapped up with above-mentioned ultrasonic microbubble respectively, parcel step is as follows：
Since siRNA is negatively charged, the surface potential of lipid ultrasonic microbubble contrast agent is also negative, two kinds of negatively charged things
Matter is with the help of no positive charge, it is difficult to combine.Poly-D-lysine is cationic polymer, is surpassed to improve lipid
Sound microbubble contrast agent carries the ability of gene, by siRNA and poly-D-lysine layered adsorption on lipid ultrasonic microbubble contrast agent, system
Into the polymer for carrying siRNA and poly-D-lysine.Experimental procedure is as follows：Lipid microbubble is taken, PBS buffer is rinsed 3 times, added
Amount poly-D-lysine, jog blending incubation 30min, then unnecessary poly-D-lysine is rinsed with PBS buffer at room temperature, then
The siRNA of 5 μ g/kg siRNA (50 μM) fluorescent markers, jog blending incubation are added in the microvesicle of poly-D-lysine
30min, low-speed centrifugal 5min, upper strata lotion are to carry the siRNA- microvesicle complexs of gene, and lower floor is free siRNA, is used
Fluorescence microplate reader detects the content of RNA in respective solution (see attached drawing 1).From attached drawing 1, lipid microbubble successfully wraps up
siRNA。
3 pairs of siRNA primers are added respectively in the renal proximal tubules cell of spontaneous hypertensive rat (SHR) to mix and trained
Support, after 2 days, by fluorescence quantitative PCR detection GRK4 expressions, it is concretely comprised the following steps：1) after extraction interference GRK4 expression
Cell RNA；2) reverse transcription RNA：The reaction condition of reverse transcription is：37 DEG C, 15 minutes, circulate 3 times；85 DEG C, 5 seconds；4 DEG C, 15 points
Clock, is put in -20 DEG C of preservations after the completion of reaction；3) quantitative fluorescent PCR：The primer of GRK4 and GAPDH is designed, sequence is as follows：
GRK4 sense primers：5 '-tgtcctgatcctgaggc-3 ', (SEQ ID NO.4)；
GRK4 anti-sense primers：5 '-acacaccctgtcgcaaat-3 ', (SEQ ID NO.5)；
GAPDH sense primers：5 '-gacatgccgcctggagaaac-3 ', (SEQ ID NO.6)；
GAPDH anti-sense primers：5 '-agcccaggatgccctttagt-3 ', (SEQ ID NO.7)；
Quantitative fluorescent PCR reaction condition：95 DEG C (3 minutes)；95 DEG C (10 seconds)+55 DEG C (30 seconds), totally 39 circulations；65℃
To 95 DEG C totally 5 seconds.After reaction, data are read and make data analysis, the result is shown in Fig. 2.As shown in Figure 2, design is utilized
SiRNA specific can play specificity interference work in the renal proximal tubules cell of spontaneous hypertensive rat for GRK4
With the mRNA expressions of effective GRK4 for reducing spontaneous hypertensive rat renal proximal tubules cell, wherein No. 1 primer effect
Fruit is optimal.
Further, GRK4 expression is intervened by ultrasound microbubble mediated GRK4siRNA in SHR rats.By the 1 of microvesicle parcel
After number siRNA primers are by being injected intravenously spontaneous hypertensive rat, ultrasonic irradiation (mechanical index 0.9, frequency are utilized
7.0MHz, irradiation time 5min, depth 3cm), ruptured microbubbles, make endovascular microbubble ruptures and discharge in kidney specific
SiRNA, and make capillary penetrability and permeability of cell membrane increase, so that promote release siRNA largely to enter kidney cell,
Enable microvesicle or the siRNA intravasations wall and tissue space of release, so as to play targeting.Weigh interference GRK4 expression
Renal tissue 1mg afterwards, then extracts kidney total serum IgE, same by fluorescence quantitative PCR detection GRK4 expressions, experimental procedure
On.After reaction, data are read and make data analysis, the result is shown in Fig. 3, it turns out that the primer equally can be reduced effectively certainly
The GRK4 expression of Essential hypertension rat kidney.
Embodiment 2.
12 SHR rats are randomly divided into microvesicle group and " microvesicle+GRK4siRNA (No. 1 primer) " group, are loaded with above-mentioned
The microvesicle of GRK4siRNA through in rat tail vein injection rat body, starting ultrasound when injecting microvesicle, ultrasound condition with embodiment 1,
And intervene once every three days ultrasounds, continue 6 times, the time is 20 days.The SHR rats of ultrasonic mediation microbubble ruptures technical role
In, its kidney natruresis level changes there occurs obvious.First, with the extension of action time, its twenty-four-hour urine amount with
Control group is compared, and there occurs substantially increase (see attached drawing 4)；Secondly, (the urine sodium measured through blomelicalbloodgasandelectrolrteanalyzers is dense for natruresis rate
Degree is multiplied by twenty-four-hour urine amount) substantially increase (see attached drawing 5) also with continuous extend of action time.
Embodiment 3.
12 SHR rats are randomly divided into microvesicle group and " microvesicle+GRK4siRNA (No. 1 primer) " group, are loaded with above-mentioned
The microvesicle of GRK4siRNA through in rat tail vein injection rat body, starting ultrasound when injecting microvesicle, ultrasound condition with embodiment 1,
And intervene once every three days ultrasounds, continue 6 times, the time is 20 days.In the SHR using ultrasonic mediation microbubble ruptures technical role
In rat, its mean arterial pressure substantially reduces (see attached drawing 6) relative to control group.
Experiment shows above, and the present invention carries siRNA to kidney specific rupture using ultrasound microbubble technique, can be effective
Suppress kidney GRK4 expression, increase urine sodium and urine volume excretion, realize the purpose of targeting prevention and treatment hypertension.
Finally illustrate, preferred embodiment above is merely illustrative of the technical solution of the present invention and unrestricted, although logical
Cross above preferred embodiment the present invention is described in detail, however, those skilled in the art should understand that, can be
Various changes are made to it in form and in details, without departing from claims of the present invention limited range.
Claims (7)
1. the application in preventing or treating the medicine of hypertension, its feature are being prepared by the siRNA molecule that ultrasonic microbubble carries
It is：The siRNA molecule sequence for 5 '-ccuguauucuuagaccaaadtdt-3 ', 5 '-
Ggcugucugauauaugaaadtdt-3 ' or 5 '-ggagagagcuccugaaguudtdt-3 '；In sequence, a, u, c, g are core
Ribosomal ribonucleic acid, dt are DNA.
2. the medicine for preventing or treating hypertension is being prepared by the siRNA molecule that ultrasonic microbubble carries according to claim 1
Application in thing, it is characterised in that：The siRNA molecule sequence is 5 '-ccuguauucuuagaccaaadtdt-3 '.
3. the medicine for preventing or treating hypertension is being prepared by the siRNA molecule that ultrasonic microbubble carries according to claim 1
Application in thing, it is characterised in that the siRNA targetings interference g protein coupled receptor kinases 4.
4. the medicine for preventing or treating hypertension is being prepared by the siRNA molecule that ultrasonic microbubble carries according to claim 1
Application in thing, it is characterised in that the ultrasonic microbubble is lipid microbubble.
5. the medicine for preventing or treating hypertension is being prepared by the siRNA molecule that ultrasonic microbubble carries according to claim 1
Application in thing, it is characterised in that the ultrasonic microbubble is lipid microbubble " fat fluorine is shown ", and core gas is perfluoropropane, microvesicle
2 μm of average grain diameter, microbubble concentration are 4 × 109~9×109/ml。
6. the medicine for preventing or treating hypertension is being prepared by the siRNA molecule that ultrasonic microbubble carries according to claim 5
Application in thing, it is characterised in that the ultrasonic microbubble first adsorbs one layer of poly-D-lysine, then adsorbs siRNA.
7. the application in adjusting the medicine for urinating sodium and/or urine volume excretion is being prepared by the siRNA molecule that ultrasonic microbubble carries, its
It is characterized in that：The siRNA molecule sequence for 5 '-ccuguauucuuagaccaaadtdt-3 ', 5 '-
Ggcugucugauauaugaaadtdt-3 ' or 5 '-ggagagagcuccugaaguudtdt-3 '；In sequence, a, u, c, g are core
Ribosomal ribonucleic acid, dt are DNA.
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| CN104189918A (en) * | 2014-07-21 | 2014-12-10 | 香港中文大学深圳研究院 | Application of dynein light chain roadblock-type 2 in preparation of medicine treating kidney failure and the medicine thereof |
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