CN115944737B - Application of MAP-2 inhibitor in preparation of medicine for treating hypertension - Google Patents
Application of MAP-2 inhibitor in preparation of medicine for treating hypertension Download PDFInfo
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Abstract
The invention discloses application of a MAP-2 inhibitor in preparing a medicament for treating hypertension. The invention discovers that the AAV-retro-MAP-2 virus can regulate and control the hypertension of SHR rats and DOCA-Salt model rats and reverse the damage of kidneys and blood vessels. This effect can also be achieved by intraperitoneal injection of MAP-2 siRNA in SHR rats. At present, clinical hypertension is mostly treated by medicines, and patients need to take one or more hypertension medicines for a long time and high frequency to control blood pressure. Whereas the sustained pharmacological effect of MAP-2 knockdown treatment of hypertension employed in the present invention may support administration once every half year or possibly once every year to control blood pressure. Reducing the frequency of administration compared to current treatment regimens may help to improve drug compliance, an important part of maintaining blood pressure control.
Description
Technical Field
The invention relates to application of MAP-2 inhibitor in preparing a medicament for treating hypertension.
Background
Hypertension is an important risk factor for congestive heart failure, stroke, and end stage renal disease. It is counted that about one adult population worldwide has hypertension, and some people over the age can have hypertension incidence. It is expected that the number of people suffering from hypertension worldwide will be fooled into tens of millions of people. Unfortunately, only approximately one third of patients reach the standard of pressure reduction therapy. The main reason is that hypertension is a life-long disease, and the half-life period of all antihypertensive drugs is relatively short at present, and the effective acting time is not longer than hours, so that the antihypertensive drugs must be taken every day, and patients are not easy to adhere to the antihypertensive drugs. In addition, the non-specificity and side effects of the drugs also make the treatment of hypertension difficult to achieve the intended goal. Thus, it has been the goal and direction of efforts of medical practitioners to find a long-term effective method of controlling hypertension by modulating gene expression in vivo, i.e., gene therapy.
The small interfering RNA (smallinterferingRNA, siRNA) is an initiator of RNA interference and can excite the complementary target mRNA to be silenced, thus having important significance for gene regulation and disease treatment.
In the neuroscience field, marking or manipulating projection neurons is an essential research tool for studying neural circuits. At present, neurons can be marked anterogradely by using DiI red fluorescent dye, and a projection loop of the downlink of a high-order center can be studied; or using fluorogold (Fluoro-Gold) to reverse label neurons, study neuronal projections of peripheral muscles at spinal level, or spinal cord conducting bundle projection loops at the center, etc. However, these fluorescent dye labeling methods only label the conductive strand, but cannot study the function of the conductive strand by up-regulating or down-regulating the expression of the gene. In such a context, AAV2-retro has been developed. In 2016, an article published in journal of neuroscience field, describes a method of constructing such AAV 2-retroviruses and uses thereof.
Perirenal adipose tissue is an atypical visceral fat pad with an intact blood supply, lymphatic drainage and innervation system. Epidemiological studies have shown that perirenal fat is a risk predictor of hypertension. Our previous studies have also found that specific disruption of perirenal adipose tissue afferent nerve endings and fat removal can both reduce blood pressure, whereas injection of capsaicin or Complete Freund's Adjuvant (CFA) in perirenal adipose tissue can increase blood pressure. This suggests that perirenal adipose tissue may be one of the critical tissues involved in hypertension regulation.
Disclosure of Invention
The invention aims to provide application of MAP-2 inhibitor in preparing medicines for treating hypertension.
The technical scheme adopted by the invention is as follows: use of a MAP-2 inhibitor in the manufacture of a medicament for the treatment of a hypertensive disorder, wherein the GeneID of MAP-2 is 25595; the website is https:// www.ncbi.nlm.nih.gov/gene/25595.
Preferably, the MAP-2 inhibitor is an AAV-retro-MAP-2 virus.
Preferably, the MAP-2 inhibitor is an siRNA of MAP-2.
Preferably, the site of administration of the AAV-retro-MAP-2 virus is perirenal fat.
The invention also discloses application of the AAV-retro-MAP-2 virus in preparing medicaments for treating kidney or vascular injury diseases.
Preferably, the site of administration of the AAV-retro-MAP-2 virus is perirenal fat.
The invention discovers that the AAV-retro-MAP-2 virus can regulate and control the hypertension of SHR rats and DOCA-Salt model rats and reverse the damage of kidneys and blood vessels. This effect can also be achieved by intraperitoneal injection of MAP-2 siRNA in SHR rats. At present, clinical hypertension is mostly treated by medicines, and patients need to take one or more hypertension medicines for a long time and high frequency to control blood pressure. Whereas the sustained pharmacological effect of MAP-2 knockdown treatment of hypertension employed in the present invention may support administration once every half year or possibly once every year to control blood pressure. Reducing the frequency of administration compared to current treatment regimens may help to improve drug compliance, an important part of maintaining blood pressure control.
Drawings
FIG. 1, spontaneous Hypertensive Rats (SHR) were intraperitoneally injected with MAP-2RNAi once every 3 days and continuously arterial blood pressure monitored once a week for 38 days. Systemic knockdown of MAP-2 in SHR rats significantly reduced blood pressure levels. A statistical plot of Systolic Blood Pressure (SBP) changes. And B, a statistical graph of Diastolic Blood Pressure (DBP) change. C: mean Arterial Pressure (MAP) variation statistics. D: mRNA level differences of MAP-2 gene in dorsal root ganglion of two groups of rats were compared. (4 per group, P < 0.05)
FIG. 2 blood pressure and heart rate were monitored 16 weeks (1/week) after injection of AAV-retro-MAP-2 virus into the perirenal fat of SHR rats. Injection of AAV-retro-MAP-2 virus into perirenal fat in SHR rats knockdown the MAP-2 level of their Dorsal Root Ganglion (DRG) significantly reduces their blood pressure level. A statistical plot of Systolic Blood Pressure (SBP) changes. And B, a statistical graph of Diastolic Blood Pressure (DBP) change. C: mean Arterial Pressure (MAP) variation statistics. D: heart rate (heart rate) variation statistics. (10 per group, P < 0.05)
FIG. 3A renal hypertension model was established 5 weeks after unilateral nephrectomy+DOCA-Salt (DOCA Salt) induction in SD (SpragueDawley) rats. After molding, DOCA-Salt rats had significantly increased blood pressure and significantly decreased renal function compared to the control group. A: creatinine (CREA) content in both groups of blood. B: statistical map of Systolic Blood Pressure (SBP). C: urea Nitrogen (BUN) content in both groups of blood. D: mean Arterial Pressure (MAP) variation statistics. (10 per group, P < 0.05)
Fig. 4, a: MAP-2 antibodies were stained by immunofluorescent staining in dorsal root ganglion (L1 segment) of DOCA-Salt rats. MAP-2 expression level was significantly enhanced in dorsal root ganglion (L1 segment) of DOCA-Salt rats. B: according to the statistical graph of MAP-2 positive rate in panel A. (n=3 per group, p < 0.05)
FIG. 5 blood pressure was monitored for 6 weeks (1/week) following injection of AAV-retro-MAP-2 virus into perirenal fat in DOCA-Salt rats. Injection of AAV-retro-MAP-2 virus in perirenal fat in DOCA-Salt rats significantly reduced renal hypertension caused by DOCA-Salt. A: statistical map of Systolic Blood Pressure (SBP). B: four groups of 6 th week Systolic Blood Pressure (SBP) levels. C: mean Arterial Pressure (MAP) variation statistics. D: mean Arterial Pressure (MAP) levels at week 6 of four groups. ( Control (Sham) 8; 10 DOCA-Salt groups; AAV-retro-MAP-2 group 9; DOCA-salt+AAV-retro-MAP-2 group 10, P <0.05 )
Fig. 6, a: immunofluorescent staining of MAP-2 was performed on 5 dorsal root ganglions (T11-L2) of these four groups of rats. B: and counting the dyeing result. AAV-retro-MAP-2 virus knockdown the dorsal root ganglion of the T12-L1 segment, suggesting that these three segments may be projection segments of perirenal fat. (3 per group, P < 0.05)
Fig. 7, a: urea Nitrogen (BUN) content in the four groups of blood. B: creatinine (CREA) content in four groups of blood. (control (Sham) 8, DOCA-Salt 10, AAV-retro-MAP-2 9, DOCA-salt+AAV-retro-MAP-2 10, P < 0.05). Injection of AAV-retro-MAP-2 virus in perirenal fat in DOCA-Salt rats significantly ameliorates the decline in renal function caused by DOCA-Salt. C: masson and HE staining of kidney tissue in four groups of rats. D: ma Songmian product statistics. (3 per group, P < 0.05). Injection of AAV-retro-MAP-2 virus into perirenal fat in rats can significantly improve kidney fibrosis caused by DOCA-Salt.
Fig. 8, a: TUNEL staining of four groups of kidney tissue. B: TUNEL staining positive cell statistics. C: western blot of fibrosis index (COL-1, TGF-beta, alpha-SMA) and apoptosis index (Caspase-3, bax, BCL-2). D: westernBlot statistical graphs. (3 per group, P < 0.05). Injection of AAV-retro-MAP-2 virus in perirenal fat in DOCA-Salt rats significantly improved apoptosis and fibrosis in kidney cells caused by DOCA-Salt.
Fig. 9, a: kidney weight ratio of four groups of rats. (6 per group, P < 0.05) B: kidney blood flow speckle experiments in four groups of rats. C: statistical map of a blood flow graph. D: four sets of electron microscopy images of renal cortex. (white arrow: basement membrane; black arrow: podophy; red star: apoptotic cells.) (3 per group, P < 0.05.) injection of AAV-retro-MAP-2 virus into perirenal fat in DOCA-Salt rats significantly improved renal hypertrophy, glomerular basement membrane thickening, podophy fusion and apoptosis and blood supply insufficiency caused by DOCA-Salt.
Fig. 10: the mesenteric artery of four groups of rats was subjected to an ex vivo vascular ring systolic-diastolic experiment. A, endothelial dependent vasoconstriction experiment. B: non-endothelial dependent vasoconstriction assay. Endothelial dependent vasodilation assay. And D, performing an endothelial-independent vasodilation experiment. (3 per group, P < 0.05).
Fig. 11: a, performing a blood flow speckle experiment on mesenteric arteries of four groups of rats. And B, a statistical diagram of a blood flow diagram. Western blot of mesenteric arterial fibrosis index (COL-1, TGF-beta, alpha-SMA). D, a WesternBlot statistical graph. (3 per group, P < 0.05)
Detailed Description
In order to further describe the technical means and effects adopted by the present invention for achieving the intended purpose, the following detailed description will refer to the specific implementation, structure, characteristics and effects according to the present invention with reference to the accompanying drawings and preferred embodiments. The experimental methods used in the following examples are conventional methods unless otherwise specified. Materials, reagents and the like used in the examples described below are commercially available unless otherwise specified.
Example 1
As shown in fig. 1, we injected MAP-2RNAi (acubo organism, south kyo, jiangsu) once every 3 days into the abdominal cavity of 8-week-old male spontaneous hypertensive rats (SHR, veloci) and performed continuous tail artery blood pressure monitoring once a week for 38 days. Through statistics of blood pressure, we found that systemic knockdown of MAP-2 in SHR rats significantly reduced their blood pressure levels (fig. 1a, b and C). Subsequently we euthanized rats, sampled dorsal root ganglia, extracted tissue RNAs, and examined the mRNA levels of MAP-2 gene in dorsal root ganglia with fluorescent real-time quantitative PCR (RT-PCR), found that the mRNA levels of MAP-2 in SHR rat dorsal root ganglia injected with MAP-2RNAi were significantly reduced compared to control group (fig. 1D).
This suggests that knockdown of MAP-2 may reduce spontaneous hypertension.
Example 2
The construction method of the nerve retrograde virus AAV-retro-MAP-2 comprises the following steps: firstly, an empty vector H12663pAAV-U6-spgRNAv2.0[ shRNA ] -CMV-EGFP-WPRE-spolyA (Hantao, shanghai) is established, then a target gene MAP2 (target point: GCATAACAGTACCTAGCAT) is inserted, and upstream and downstream cloning restriction enzyme sites are BsmBI and NheI respectively, so that an original is generated after construction: pAAV-U6-shRNA (Map 2) -CMV-EGFP-WPRE-spolyA. As shown in fig. 2, the neuroretroviruses AAV-retro-MAP-2 were injected and injected at perirenal fat in SHR rats. The aim was to knock down the expression of the MAP-2 gene in the dorsal root ganglion projected by perirenal fat. We monitored blood pressure and heart rate for 16 weeks (1/week) and found that both the hypertension level (fig. 2a, b and C) and heart rate (fig. 2D) were significantly reduced in SHR rats. Blood pressure and heart rate remained stable after 16 weeks of duration.
This suggests that knockdown of MAP-2 in dorsal root ganglions projected by perirenal fat may reduce spontaneous hypertension.
Example 3
As shown in fig. 3, to further investigate whether knockdown of the MAP-2 gene in DRG projected by perirenal fat has the same effect on other types of hypertension, we constructed a model of renal hypertension in SD rats (8 weeks old, velocin). We performed a total of five weeks after unilateral kidney resection of SD rats, 1% saline feeding and subcutaneous injection of deoxycorticosterone acetate (DOCA, 10mg/2 times/week, sigma, usa). Creatinine and urea nitrogen levels in the blood were examined to detect renal function (fig. 3A and C) and weekly blood pressure (fig. 3B and D). We found that blood pressure, serum creatinine, and urea nitrogen levels were significantly higher in model rats than in control.
Meanwhile, we detected the mRNA level of MAP-2 gene in dorsal root ganglion of two groups of rats by fluorescence real-time quantitative PCR (RT-PCR), and found that the model was significantly increased compared with the control group (FIGS. 4A and B).
We randomly picked half of the rats in both groups and injected their perirenal fat with AAV-retro-MAP-2 and monitored blood pressure for 6 weeks. We found that simple injection of AAV-retro-MAP-2 virus did not affect blood pressure in rats, whereas if rats with renal hypertension were injected with virus, a significant decrease in blood pressure was seen in the first week and was stable for six weeks (fig. 5).
To verify the level of knockout of the DRG segment of perirenal fat projection and MAP-2 at each segment, we taken T11 to L2 segments from four groups of rats and performed immunofluorescent staining of the MAP-2 gene on them. We found that the DRG of perirenal fat projection was mainly three segments T12, T13 and L1. Whereas the knockdown of MAP-2 was most pronounced with T13 and L1 (fig. 6).
We examined serum creatinine and urea nitrogen levels in four groups of rats and found that perirenal fat injection of AAV-retro-MAP-2 significantly reduced serum creatinine and urea nitrogen levels in renally hypertensive rats (fig. 7A and B). Marathon and HE staining also demonstrated that perirenal fat injection of AAV-retro-MAP-2 can significantly reduce kidney fibrosis in renally hypertensive rats (FIGS. 7C and D).
TUNEL staining of kidney tissue (bi-cloudy, shanghai) indicated that perirenal fat injection of AAV-retro-MAP-2 could significantly reduce apoptosis of kidney cells in renally hypertensive rats (fig. 8A and B). The results of WesternBlot on some protein indicators of fibrosis and apoptosis also validated the results (FIGS. 8C and D).
We measured and calculated the kidney weight to weight ratio of the four groups of rats, and knockdown of MAP-2 at DRG could also significantly improve kidney hypertrophy in renally hypertensive rats (fig. 9A). Blood flow speckle experiments showed that knockdown of MAP-2 at DRG can significantly increase kidney blood flow in renally hypertensive rats (fig. 9B and C). By electron microscopy, we observed that knockdown of MAP-2 at DRG improved glomerular basement membrane thickening, podocyte fusion and apoptosis in kidney hypertensive rats (FIG. 9D).
In figure 10, we performed an ex vivo vascular ring experiment on mesenteric arteries of four groups of rats to examine their systolic and diastolic capabilities. We used endothelin (ET-1) (fig. 10A) and Norepinephrine (NA) (fig. 10B) to verify endothelial and non-endothelial dependent vasoconstrictor potency, respectively, and Sodium Nitroprusside (SNP) (fig. 10C) and acetylcholine (Ach) (fig. 10D) to verify non-endothelial and endothelial dependent vasoconstrictor potency, respectively. We found that renal hypertension impaired the endothelial dependent diastolic capacity of the mesenteric artery, whereas knockdown of MAP-2 at DRG improved its function (fig. 10D).
Blood flow speckle experiments on mesenteric arteries showed that knockdown of MAP-2 at DRG can significantly increase blood flow in mesenteric arteries in renal hypertensive rats (fig. 11A and B). The results of WesternBlot on some protein indicators of fibrosis also demonstrate that knockdown of MAP-2 at DRG can significantly improve fibrosis in mesenteric arteries in renal hypertensive rats (fig. 11C and D).
In conclusion, the knocking-down of MAP-2 in DRG can obviously reduce the blood pressure of the rat with renal hypertension and improve the damage of the renal function and vascular function of the rat with renal hypertension.
The present invention is not limited to the above embodiments, but is capable of modification and variation in detail, and other modifications and variations can be made by those skilled in the art without departing from the scope of the present invention.
Claims (2)
- Use of a MAP-2 inhibitor in the manufacture of a medicament for the treatment of a hypertensive disorder, said MAP-2 inhibitor being the vector AAV-retro-MAP-2 virus loaded with shRNA of MAP-2; or the MAP-2 inhibitor is siRNA of MAP-2, and the sequence of the MAP-2 inhibitor is GCACAGAGACTCCGGATAT.
- 2. The use according to claim 1, characterized in that: the administration site of the AAV-retro-MAP-2 virus is perirenal fat.
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