CN103948940A - MicroRNA-23b, and application of analogue thereof in preparation of medicament for preventing and treating nephropathy - Google Patents
MicroRNA-23b, and application of analogue thereof in preparation of medicament for preventing and treating nephropathy Download PDFInfo
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- CN103948940A CN103948940A CN201410095609.1A CN201410095609A CN103948940A CN 103948940 A CN103948940 A CN 103948940A CN 201410095609 A CN201410095609 A CN 201410095609A CN 103948940 A CN103948940 A CN 103948940A
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Abstract
The invention discloses microRNA-23b, and application of an analogue thereof in preparation of a medicament for preventing and treating nephropathy. The microRNA-23b has a nucleotide sequence shown as SEQ ID NO.1, and the nucleotide sequence of the analogue of the microRNA-23b is obtained by combination of one or more of ribose modification, base modification and phosphate skeleton modification of other nucleotides except UCACAUU bases or increase, decrease and replacement of nucleotides on the basis of the nucleotide sequence of the microRNA-23b. The medicament prepared from the microRNA-23b can be a single ingredient of the microRNA-23b and the analogue of the microRNA-23b, and also can be a pharmaceutical composition. According to the invention, the medicament is prepared by interlinkage of the microRNA-23b and/or the analogue of the microRNA-23b and an acceptable carrier, and the medicament can be used for treating the nephropathy by intravenous, intramuscular or intraperitoneal injection and the like, and particularly aims to diabetic nephropathy.
Description
Technical field
The present invention relates to microRNA-23b and intend preventing and treating the application in the medicine of nephropathy like thing in preparation, be specifically related to microRNA-23b and intend the application in the medicine of the nephropathy such as preparation control diabetic nephropathy, glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephropathy like thing, belong to biomedicine field.
Background technology
Diabetes (Diabetes mellitus, DM) are a kind of worldwide diseases, are the high a kind of metabolism syndromes of current sickness rate, and according to WHO report, the current whole world exceedes 346million people and suffers from diabetes.In China, nearly 4,300 ten thousand diabeticss, occupy global second at present.Diabetes can concurrent multiple complications, and diabetic nephropathy (Diabetic nephropathy, DN) is one of its complication, accounts for the 20-30% of chronic complicating diseases of diabetes, is to cause end stage renal failure, the one of the main reasons of DM patient death.The diabetics of 10-20% is died from renal failure according to estimates.
DN is similar as the nephropathy such as glomerulonephritis, nephrotic syndrome, hypertensive nephropathy with other nephritic diseases, and main clinic symptoms all shows as the clinical symptoms such as albuminuria, edema, hypertension, renal dysfunction.The early stage same glomerulonephritis of main pathological characters, nephrotic syndrome, the same main manifestations of hypertensive nephropathy are glomerule hypertrophy; glomerule and renal tubular basement membrane thicken and the carrying out property of mesangial region extracellular matrix (Extracellular matrix, ECM) is gathered; Later stage is the fibrosis of glomerule, renal tubular interstitium, finally causes albuminuria and renal failure.Diabetes hyperglycemia is the key factor that causes DN, the activation pathway of Sorbitol-aldose reductase that in cell, high glucose concentration causes, aminohexose biosynthesis pathway, Protein kinase C, mitogen activated protein kinase (MAPK), participates in the morbidity of diabetic nephropathy
At present, unsatisfactory for the prevention effect of diabetic nephropathy, very easily cause the generation of multiple complications, be therefore badly in need of setting up a kind of active drug with new treatment target spot research and development.MicroRNA(miRNA) originating from endogenous expression transcript, is the double stranded rna molecule that is about 21-25nt.Ripe microRNA can be in conjunction with gene silencing complex (RNA-Induced Silencing Complex, RISC) complementary side by side with target mRNA; The complementary degree of microRNA and target sequence has determined that target gene mRNA is partly suppressed or fracture completely in translation skill.In plant, seemingly main working method of fracture, in mammal taking the inhibition of translation skill as major way.Research shows, the regulation and control of the processes such as microRNA wide participation growth, apoptosis, differentiation, propagation, metabolism play an important role in the various vital movements of life entity.In recent years, the medicine that is target spot based on microRNA constantly obtains Success in Experiment, thereby for the treatment of various diseases brings new hope, therefore, novel targets fat as treatment with microRNA and dyslipidemia has very great breakthrough and application.
Summary of the invention
In order to address the above problem, the present invention adopts multiple technologies means to prove microRNA-23b(miR-23b) and intend preventing and treating the application in the medicine of nephropathy like thing in preparation, be specifically related to microRNA-23b and intend the application in the medicine of the nephropathy such as preparation control diabetic nephropathy, glomerulonephritis, nephrotic syndrome, hypertensive nephropathy like thing.Wherein, the nucleotide sequence of described microRNA-23b is as shown in SEQ ID NO.1; Described microRNA-23b intends classifying as on the basis into the nucleotide sequence at microRNA-23b like the nucleotides sequence of thing, the combination of one or more in ribose modification, base modification and the phosphoric acid backbone modification that other nucleotide except UCACAUU base is carried out or increase and decrease, the replacement of nucleotide.Preferably, described microRNA-23b intends classifying as on the basis of the nucleotide sequence of microRNA-23b base having been carried out to modifications that methylate like the nucleotides sequence of thing, and holds and utilize cholesterol to carry out labelling 5 '.
Those skilled in the art can and intend microRNA-23b of the present invention suitably modifying like the nucleotide sequence of thing; described modification comprises one or more combination or increase and decrease, the replacement of nucleotide arbitrarily in ribose modification, base modification and the phosphoric acid backbone modification of any nucleotide, as long as the nucleotide sequence after modifying still has within the activity identical with microRNA-23b just should belong to invention which is intended to be protected.
Further, the present invention also comprises the serum biomarker(mark of microRNA-23b as the diagnostic detection of kidney disease), preferably, described kidney disease comprise that diabetic nephropathy, glomerulonephritis, glomerular sclerosis are levied, nephrotic syndrome or hypertensive nephropathy etc.
Further, it is a kind of for prevention or treatment kidney disease pharmaceutical composition that the present invention also provides, and the plan that described compositions contains microRNA-23b or microRNA-23b is like thing and the carrier of pharmaceutically accepting.Preferably, described kidney disease be selected from that diabetic nephropathy, glomerulonephritis, glomerular sclerosis are levied, nephrotic syndrome or hypertensive nephropathy etc.Preferred, described carrier is virus, cholesterol, nano-particle, chitosan or liposome.
In the present invention, the conventional method that above-mentioned composition can be prepared according to medicine is made ejection preparation, oral formulations, spray agent, ointment formulation or patch etc.
Brief description of the drawings
Fig. 1 is the expression situation of change of microRNA-23b in diabetics and diabetic nephropathy and other inflammatories nephrotic serum; And Diabetic Nephropathy Patients clear in the dependency of urine protein content in the expression of microRNA-23b and urine; In I type Diabetic nephropathy and II type Diabetic nephropathy mouse kidney tissue, microRNA-23b expresses and changes; Wherein, in Figure 1A, Con is normal human serum, and 2Di is type 2 diabetes mellitus patients serum, and 1Di is type 1 diabetes patients serum, and DN is patients with diabetic nephropathy, and CI is other inflammatories nephropathy patient's serum; In Figure 1B, Con is normal C57 mice, and Db/Db is 2 type transgenic diabetic mices; In Fig. 1 C, Con is normal C57 mice, and Dia is type 1 diabetes mice; The dependency of protein content in the expression of the clear middle microRNA-23b of Diabetic Nephropathy Patients and urine in Fig. 1 D, result is shown as R2=0.3336, and p value is less than 0.01;
Fig. 2 is the expression variation diagram of microRNA-23b in 1 month to 6 months renal tissue of type Ⅰ diabetes mellitus;
Fig. 3 is that microRNA-23b rising can suppress Proliferation of Renal Tubular Epithelial Cells, and reduction can promote Proliferation of Renal Tubular Epithelial Cells figure; Wherein, A:microRNA-23b intends suppressing like thing the HK-2(renal cells that high sugar is induced) cell proliferation; B:microRNA-23b inhibitor promotes HK-2 cell proliferation;
Fig. 4 is that microRNA-23b suppresses fibrinous generation figure in diabetic nephropathy cell model and animal model; Wherein, A:microRNA-23b suppresses the HK-2(renal cells of high sugar induction) generation of fibrin (FN) in cell; The fibrin (FN) that B:miR-23b suppresses in diabetic nephropathy Mouse Kidney bead generates;
Fig. 5 is the expression figure that microRNA-23b suppresses fibrosis related gene in diabetic nephropathy renal tissue;
Fig. 6 is that microRNA-23b suppresses albuminuria figure in diabetic nephropathy; Wherein, Con is normal C57 mice urine microdose urine protein content; Db/Db is microdose urine protein content in type 2 diabetes mellitus transgenic mice urine; MicroRNA-23b is that type 2 diabetes mellitus transgenic mice injection microRNA-23b intends like microdose urine protein content in urine after thing; MiNEG is that type 2 diabetes mellitus transgenic mice injection microRNA-23b intends like microdose urine protein content in urine after thing negative control;
Fig. 7 is that microRNA-23b suppresses podocytic process fusion figure in Sorbitol Withinglomeruli In Diabetic Nephropathy; Wherein, A is podocytic process in normal C57 mouse kidney mesonephric glomerulus; B is podocytic process in type 2 diabetes mellitus transgenic mice kidney mesonephric glomerulus; C is that type 2 diabetes mellitus transgenic mice injection microRNA-23b intends like thing podocytic process in glomerule after month; D is that type 2 diabetes mellitus transgenic mice injection microRNA-23b intends like thing negative control podocytic process in glomerule after month.
Detailed description of the invention
Further describe the present invention below in conjunction with specific embodiment, advantage and disadvantage of the present invention will be more clear along with description.But embodiment is only exemplary, scope of the present invention is not formed to any restriction.It will be understood by those skilled in the art that lower without departing from the spirit and scope of the present invention and can the details of technical solution of the present invention and form be modified or be replaced, but these amendments and replacement all fall within the scope of protection of the present invention.
Embodiment 1 microRNA-23b and plan thereof are like the therapeutical effect of thing to diabetic nephropathy
Selecting body weight is 45-50g adult healthy db/db transgenic type Ⅱdiabetes mellitus obesity mice, is divided into 4 groups: (1) Normal group; (2) db/db transgenic type Ⅱdiabetes mellitus obesity mice; (3) db/db transgenic type Ⅱdiabetes mellitus obesity mice is injected the reagent that contains microRNA-23b sequence (shown in SEQ ID NO.1), and injected dose is 0.2ml/10nM; (4) db/db transgenic type Ⅱdiabetes mellitus obesity mice injection negative control reagent, negative control reagent main component is the reagent that contains sequence shown in SEQ ID NO.2, injected dose is 0.2ml/10nM.
This microRNA and anyone, rat, mice microRNA, almost without homology, are widely used in microRNA related experiment, and injection injection dosage is 0.2ml/10nM.3, serum is drawn materials, got to the injection in every 3 days of 4,5 groups of Db/Db mices once, after one month.
Result of the test:
As shown in Figure 1, the visible microRNA-23b of result significantly reduces (P<0.05 in type Ⅰ diabetes mellitus, type Ⅱdiabetes mellitus, diabetic nephropathy and other glomerulonephritis nephropathy, P<0.001), in microRNA-23b and diabetic nephropathy patient urine, protein content is negative correlation significant difference, in type Ⅰ diabetes mellitus and type Ⅱdiabetes mellitus nephropathy mouse tissue, significantly reduce, microRNA-23b can be used as the biomarker of diabetic nephropathy and inflammatory nephropathy simultaneously.MicroRNA-23b shown in Fig. 2 is persistence in type 1 diabetes animal model 1-6 month kidney to be reduced.MicroRNA-23b shown in Fig. 3 expresses to raise and can suppress cell proliferation, expresses to reduce to promote cell proliferation.MicroRNA-23b shown in Fig. 4 significantly suppresses fibrinous generation in cell model and animal model, has anti-fibrosis effect.MicroRNA-23b shown in Fig. 5 also other fibrous ring factor genes of antagonism expresses.MicroRNA-23b shown in Fig. 6 can suppress the generation of microdose urine protein in diabetic nephropathy mice urine.MicroRNA-23b shown in Fig. 7 can suppress podocytic process in diabetic nephropathy mouse kidney glomerule and merge.
Originally experimental results show that in microRNA-23b body, injection can significantly improve diabetic nephropathy, illustrate that microRNA-23b can be used as the biomarker of diabetic nephropathy and glomerulonephritis nephropathy, microRNA-23b can be used as the novel drugs of prevention and treatment diabetic nephropathy and glomerulonephritis disease.
Claims (8)
1.microRNA-23b and intend preventing and treating the application in the medicine of nephropathy like thing in preparation, is characterized in that, the nucleotide sequence of described microRNA-23b is as shown in SEQ ID NO.1; Described microRNA-23b intends classifying as on the basis of the nucleotide sequence of microRNA-23b like the nucleotides sequence of thing, the combination of one or more in ribose modification, base modification and the phosphoric acid backbone modification that other nucleotide except UCACAUU base is carried out or increase and decrease, the replacement of nucleotide.
2. application according to claim 1, it is characterized in that, described microRNA-23b intends classifying as on the basis of the nucleotide sequence of microRNA-23b base having been carried out to modifications that methylate like the nucleotides sequence of thing, and holds and utilize cholesterol to carry out labelling 5 '.
3. application according to claim 1 and 2, is characterized in that, described nephropathy comprises that diabetic nephropathy, glomerulonephritis, glomerular sclerosis are levied, nephrotic syndrome or hypertensive nephropathy.
4. application according to claim 1 and 2, is characterized in that, the blood serum designated object that the nucleotide sequence of described microRNA-23b detects as Diagnosis of Renal Disorders.
5. application according to claim 4, is characterized in that, described kidney disease comprises that diabetic nephropathy, glomerulonephritis, glomerular sclerosis are levied, nephrotic syndrome or hypertensive nephropathy etc.
6. for prevention or a treatment kidney disease pharmaceutical composition, it is characterized in that, the plan that contains microRNA-23b or microRNA-23b in described compositions is like thing and the carrier of pharmaceutically accepting.
7. pharmaceutical composition according to claim 6, is characterized in that, described carrier is virus, cholesterol, nano-particle, chitosan or liposome.
8. pharmaceutical composition according to claim 7, is characterized in that, the conventional method that described compositions is prepared according to medicine is made ejection preparation, oral formulations, spray agent, ointment formulation or patch etc.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103372218A (en) * | 2012-04-19 | 2013-10-30 | 中国科学院上海生命科学研究院 | microRNA related to autoimmune disease and application thereof |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103372218A (en) * | 2012-04-19 | 2013-10-30 | 中国科学院上海生命科学研究院 | microRNA related to autoimmune disease and application thereof |
Non-Patent Citations (5)
| Title |
|---|
| KARTHIKEYAN ET AL: "Role of microRNAs in kidney homeosatasis and disease", 《NATURE》 * |
| MAJID ER AL: "MicroRNA-23b functions as a tumor suppressor by regulating Zeb1 in bladder cancer", 《PLOS ONE》 * |
| QINGQING WEI ET AL: "The regulation and function of MicroRNAs in Kidney Diseases", 《IUBMB LIFE》 * |
| SHINJI HAGIWARA等: "MicroRNA in diabetic nephropathy:Renin angiotensin,AGE/RAGE,and oxidative stress pathway", 《JOURNAL OF DIABETES RESEARCH》 * |
| 王超男 等: "miR-23b通过靶定TAB2/3抑制糖尿病肾病纤维化", 《中国生物化学与分子生物学报》 * |
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Application publication date: 20140730 |