CN106822865B - Application of small molecular polypeptide KP-6 in preparation of medicine for treating chronic kidney diseases - Google Patents
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Abstract
The invention belongs to the field of biological medicine, relates to application of a small molecule polypeptide KP-6, and particularly relates to application of the small molecule polypeptide KP-6 in preparation of a medicine for treating Chronic Kidney Disease (CKD), wherein an amino acid sequence of the polypeptide KP-6 is shown as SEQ ID NO. 1. The small molecular polypeptide KP-6 provided by the invention has the effects of obviously inhibiting the kidney tissue fibrosis and CKD progression, and has no obvious toxic or side effect, so that the small molecular polypeptide KP-6 can be used for preparing a medicament for effectively treating chronic kidney diseases.
Description
Technical Field
The invention belongs to the field of biological medicines, relates to application of a unique small molecular polypeptide in treating Chronic Kidney Disease (CKD), and particularly relates to application of a KP-6 polypeptide in preparing a medicine for treating CKD.
Background
Chronic Kidney Disease (CKD) eventually progresses to end-stage renal failure (ESRD), with patients relying lifelong on "kidney replacement therapy" to maintain life. Over the past few decades, CKD prevalence has shown an increasing trend year by year with the population of the human society becoming older (Nat Rev Nephrol,2011,7: 684-. There are data showing that CKD is becoming a "public health problem", seriously harming human health and consuming a large amount of sanitary resources. However, there is currently no clinically effective drug to delay CKD progression. Aiming at the pathogenesis of CKD, finding a medicine for effectively inhibiting or delaying the progression of CKD is undoubtedly the urgent priority of the current kidney disease academy and becomes one of the strategic points to be urgently overcome.
A large number of studies show that the continuous activation of Wnt/β -catenin signals is a key path (Kidney Intsupple2014,4:84-90) for the generation and development of Kidney fibrosis and CKD, so that the strategy for blocking the Wnt/β -catenin signal path is searched, and the strategy has important theoretical significance and clinical application value for inhibiting the generation and development of Kidney fibrosis.
The invention relates to a polypeptide library, and finds a specific small molecular polypeptide (KP-6), which can inhibit a key signal path of kidney fibrosis, KP-6 polypeptide has no previous report, and is homologous with a sequence of a klotho molecule of antisenilin in amino acid sequence structure, klotho can bind to Wnt ligand and block Wnt/β -catenin signaling (JAm SocNophrol.2013, 24: 771-.
KP-6 is a novel and effective small molecular polypeptide, which can inhibit kidney tissue damage and kidney fibrosis, and delay or/and reverse the course of chronic kidney disease.
Unilateral ureteral ligation (UUO) is a classic animal model of CKD and is characterized by rapidly and completely displaying different pathological stages and characteristics of obstruction renal interstitial fibrosis, including inflammatory cell infiltration, proliferation and apoptosis of tubule cells, activation of myofibroblasts, and deposition of Fibronectin (Fibronectin) and Collagen type I (Collagen I). The ischemia-reperfusion (IRI) model is a model of the progression of classical Acute Kidney Injury (AKI) to Chronic Kidney Disease (CKD). The unilateral kidney is subjected to ischemia-reperfusion (IRI) operation for 10 days, then the unilateral kidney is subjected to resection (UIRI) of the contralateral kidney in a combined manner, the pathological process of chronic renal fibrosis can be obviously shown, the modeling method is simple and easy to implement, the success rate is high, the model has the advantages of small surgical incision, short surgical time and few complications, and the established model is suitable for the research of the progress of acute renal injury to chronic renal fibrosis.
More specifically, tissue fibrosis is often characterized, quantitatively observed and evaluated qualitatively and quantitatively by immunostaining and immunoblotting (Western blotting) using myofibroblast markers α -smooth muscle actin (α -SMA), fibronectin, and type I collagen.
Disclosure of Invention
The invention aims to provide application of a small molecule polypeptide (named KP-6) in preparing a medicament for treating chronic kidney diseases. The amino acid sequence of the polypeptide KP-6 is shown in SEQ ID NO. 1.
SEQ ID NO.1：QPVVTLYHWDLPQRLQDAYGGWANRALADH。
According to a further feature of the use of the present invention, the medicament prepared comprises: a small molecular polypeptide (named KP-6) which is effective in treatment and pharmaceutically acceptable auxiliary materials.
The invention also aims to provide application of the derivative of the small molecule polypeptide KP-6 in preparing a medicament for treating chronic kidney diseases.
According to a further feature of the use according to the invention, the derivative of KP-6 comprises: contains a shorter peptide segment of KP-6 amino acid sequence, KP-6 related polypeptide after amino acid substitution, and KP-6 and its shorter peptide segment after chemical modification.
The results show that compared with a UUO or UIRI model group, the kidney interstitial collagen deposition of KP-6 group is obviously reduced, α smooth muscle actin and fibronectin are obviously reduced, β catenin (β -catenin) and downstream target gene expression thereof are obviously reduced, and the KP-6 can antagonize Wnt/β -catenin signal paths, thereby effectively inhibiting kidney tissue fibrosis of UUO and UIRI.
In conclusion, KP-6 has the function of obviously inhibiting the kidney tissue fibrosis and CKD progress, and has no obvious toxic or side effect, so that KP-6 can be used for preparing the medicine for effectively treating chronic kidney diseases.
Drawings
FIG. 1 is a diagram of KP-6 screening and identification, human renal tubular epithelial cells (HKC-8) are transfected with Wnt1 plasmid and then treated with different small molecule polypeptides, in FIG. 1, A shows the antagonism of Wnt1 expression and fibrosis-related protein by the small molecule polypeptides from No.1 to No. 6, B shows the antagonism of TGF- β expression and C shows the amino acid sequence of KP-6.
FIG. 2 is Masson staining of kidney of mice in each group of UUO model. In fig. 2, left: a sham operation group; the method comprises the following steps: a UUO model group; and (3) right: UUO + KP-6.
FIG. 3 is an immunostaining map of kidney fibrosis indicators for groups of mice of the UUO model. In the figure, Sham: a sham operation group; and (4) UUO: a model control group; UUO + KP-6: a medicine group.
FIG. 4 is an immunoblot of the protein levels of mouse kidney tissue β -catenin and its downstream target gene in each group of UUO model, wherein FIG. 4A is a representative result of immunoblot detection, FIG. 4B is a statistical graph of all the results, Sham is a Sham group, UUO is a model control group, and UUO + KP-6 is a drug group.
FIG. 5 is a Masson staining map of kidney of various groups of mice of the UIRI model. In the figure, left: a sham operation group; the method comprises the following steps: a UIRI model group; and (3) right: UIRI + KP-6.
FIG. 6 is an immunostaining plot of indices of kidney fibrosis in various groups of mice of the UIRI model. In the figure, Sham: a sham operation group; UIRI: a model control group; UIRI + KP-6: a medicine group.
FIG. 7 shows the immunoblotting detection of β -catenin and its downstream target gene protein level in mouse kidney, wherein FIG. 7A is a representative result of the immunoblotting detection, and FIG. 7B is a statistical chart of all the results.
Detailed Description
The invention will now be further described, by way of example only, with reference to the accompanying drawings.
The first embodiment is as follows: screening of KP-6 small molecule polypeptide
1. Experimental materials:
cell: human renal tubular epithelial cells.
Culture solution: DMEM/F129(1:1) medium containing 10% FBS.
The culture conditions are as follows: 5% CO at 37 ℃2An incubator.
Small molecule polypeptide library: 18 polypeptide sequences are generated by computer design, each polypeptide sequence has an average length of 30 amino acids, and the polypeptide sequences are artificially synthesized by Nanjing Jinslei Biotech company to build a small molecule polypeptide library for the following experiments.
2. Experimental treatment:
(I) culturing human renal tubular epithelial cells at 1.5 × 106The cells were seeded in 6-well cell culture plates, cultured for 1 day, starved for 24 hours, and given 18 different small molecule polypeptides (10. mu.g/ml) 1 hour in advance. Then, Wnt1 plasmid is transfected, and protein is collected after 24 hours, Western blot experiment is carried out, and peptide fragments which have the strongest inhibition on Wnt1 induced fibronectin are screened.
(II) culturing the cultured human renal tubular epithelial cells at 1.5X 106Planting in 6-well cell culture plate, culturing for 1 day, and advancingPeptide fragment No. 6 (KP-6) (10. mu.g/ml) was administered for 1 hour, then, TGF- β (2ng/ml) was added for stimulation, and the protein was collected 24 hours later and subjected to Western blot experiment.
3. Results of the experiment
(I) The experimental result is shown in figure 1A, and a part of the small molecular peptide fragments can inhibit the expression of Fibronectin (Fibronectin) and α -smooth muscle actin (α -SMA) mediated by Wnt1, wherein the 6 th peptide fragment (named as KP-6) has the strongest inhibition effect.
(II) KP-6 can inhibit the expression of fibrosis-associated genes caused by TGF- β, so KP-6, as a novel small molecule polypeptide, can antagonize Wnt and TGF- β activities, block key in vivo profibrosis signaling pathways, and thus inhibit the expression of fibrosis-associated proteins.
(III) amino acid sequence of KP-6
The amino acid sequence of the polypeptide KP-6 is QPVVTLYHWDLPQRLQDAYGGWANRALADH (SEQ ID NO. 1).
Example two: inhibition effect of small molecular polypeptide KP-6 on kidney fibrosis of mouse UUO model
1. Experimental animals: c57 mice, male and female matched, weight 20-22g, SPF grade.
Animals were weighed and numbered, 12 healthy mice weighing 20-22g were selected and randomly divided into 3 groups of 4 animals each. Comprises a pseudo-operation group, a model control group and a medicine group.
2. Experiment grouping
1) The sham operation group: at room temperature, after the mice are anesthetized with 3% sodium pentobarbital at 1 ml/kg body weight, the left flank of the mice is selected to be 2-3cm as an incision; after local disinfection, the skin, subcutaneous, muscular and peritoneal membranes are incised layer by layer, and the left ureter is discovered and then sutured layer by layer. After partial sterilization, the markers were verified and placed in the corresponding cages.
2) Model control group: the anesthesia and disinfection are performed as above. The skin, subcutaneous layer, muscular layer and peritoneum are incised layer by layer, and after finding the left ureter, the left ureter is ligated with section 1/3 of ureter, and the left ureter is sutured layer by layer. After partial sterilization, the markers were verified and placed in the corresponding cages.
3) The medicine group is as follows: the anesthesia and disinfection are performed as above. The skin, subcutaneous layer, muscular layer and peritoneum are incised layer by layer, and after finding the left ureter, the left ureter is ligated with section 1/3 of ureter, and the left ureter is sutured layer by layer. After partial sterilization, the markers were verified and placed in the corresponding cages.
3. Procedure of experiment
KP-6 water soluble powder is diluted with sterile physiological saline to 25mg/ml storage concentration, each experimental component is raised in cages, only observation of a sham operation group is carried out, only physiological saline tail vein injection is given to a model control group, 1ml of physiological saline tail vein injection containing 0.5mg/kg body weight of KP-6 is carried out for 6 days after UUO begins by a drug group, mice are killed after 7 days of raising, left side kidneys are taken, 10% neutral buffer formaldehyde fixing and liquid nitrogen freezing tissues are respectively carried out, after dehydration, embedding, slicing and flaking are carried out on the formaldehyde fixing tissues, Masson staining and smooth muscle actin α and fibronectin immunostaining are respectively carried out, after freezing tissue homogenization, protein is extracted, and the expression level of β -catenin and target genes thereof is detected by an immunoblotting method (Western Blot).
4. Results of the experiment
1) Masson staining for detecting degree of kidney tissue fibrosis
(I) KP-6 reduces the deposition of UUO mouse renal interstitial collagen
The experimental results are shown in fig. 2, and the renal interstitial collagen deposition of the mice in the drug group is obviously lower than that of the model control group.
(II), KP-6 reduction of UUO mouse renal interstitial fibrosis
The experimental results are shown in fig. 3, and compared with the model control group, the mouse kidney fibroblast specific protein 1(Fsp1) and smooth muscle actin α (α -SMA) levels of the drug group are obviously reduced.
(III), KP-6 inhibits the β -catenin signal channel of UUO mouse abnormal activation
The experimental result is shown in FIG. 4, compared with the model control group, the β -catenin protein of the kidney of the mice in the drug group and the downstream target gene proteins PAI-1 and MMP-7 are obviously reduced.
Example three: inhibitory effect of small molecular polypeptide KP-6 on mouse UIRI model kidney fibrosis
1. Experimental animals: BABL/c mice, males, body weight 20-22g, SPF grade.
Animals were weighed and numbered, 18 healthy mice weighing 20-22g were selected and randomly divided into 3 groups of 6 animals each. Comprises a normal saline group, a model control group and a medication group.
2. Experiment of each group
1) The sham operation group: at room temperature, after the mice are anesthetized with 3% sodium pentobarbital at 1 ml/kg body weight, the left flank of the mice is selected to be 2-3cm as an incision; after topical sterilization, the skin, subcutaneous, muscular and peritoneal membranes were dissected layer by layer and the left renal pedicle was found and then sutured layer by layer. After partial sterilization, the markers were verified and placed in the corresponding cages.
2) Model control group: the anesthesia and disinfection are performed as above. The skin, subcutaneous layer, muscular layer and peritoneum were incised layer by layer, the left renal pedicle was rapidly blocked with a non-invasive arteriole clamp after finding the left renal pedicle, it was seen that the kidney became reddish purple, indicating successful clamping, the mouse was placed on a 37 degree metal hot plate, timed for 35 minutes, and sutured layer by layer after the surgery was finished. After partial sterilization, the markers were verified and placed in the corresponding cages. On day 10 after surgery, the right kidney was excised, anesthetized and disinfected as above. Performing 1-2cm incision on the right back, ligating the right renal pedicle, then cutting off the right kidney, and suturing layer by layer after the operation is finished. After partial sterilization, the markers were verified and placed in the corresponding cages.
3) The medicine group is as follows: the anesthesia and disinfection are performed as above. The skin, subcutaneous layer, muscular layer and peritoneum were incised layer by layer, the left renal pedicle was rapidly blocked with a non-invasive arteriole clamp after finding the left renal pedicle, it was seen that the kidney became reddish purple, indicating successful clamping, the mouse was placed on a 37 degree metal hot plate, timed for 35 minutes, and sutured layer by layer after the surgery was finished. After partial sterilization, the markers were verified and placed in the corresponding cages. On day 10 after surgery, the right kidney was excised, anesthetized and disinfected as above. Performing 1-2cm incision on the right back, ligating the right renal pedicle, then cutting off the right kidney, and suturing layer by layer after the operation is finished. After partial sterilization, the markers were verified and placed in the corresponding cages.
3. Procedure of experiment
KP-6 water soluble powder is diluted with sterile physiological saline to 25mg/ml storage concentration, each component is raised in cages, only observation of a sham operation group is carried out, only physiological saline tail vein injection is given to a model control group, 1ml of physiological saline tail vein injection containing KP-6 with 0.5mg/kg body weight is continuously carried out for 10 days after ischemia reperfusion injury of a drug group is started, mice of each group are killed by 11 days of raising, blood samples are collected, left side kidneys are taken, 10% neutral buffer formaldehyde fixing and liquid nitrogen freezing tissues are respectively carried out, after dehydration, embedding, slicing and sectioning of the formaldehyde fixing tissues, Masson staining and smooth muscle actin α, fibronectin immunostaining are respectively carried out, proteins are extracted after freezing and homogenizing tissues, and β -catenin and target gene expression level thereof are detected by an immunoblotting method (Western Blot).
4. Results of the experiment
1) Masson staining for detecting degree of kidney tissue fibrosis
(I) KP-6 reduces kidney interstitial collagen deposition in UIRI mice
The experimental results are shown in fig. 5, and the renal interstitial collagen deposition of the mice in the drug group is obviously lower than that of the model control group.
(II), KP-6 reduction of renal interstitial fibrosis in UIRI mice
The experimental results are shown in fig. 6, and compared with the model control group, the renal tissue of the mice in the drug group is obviously reduced in the levels of fibroblast specific protein 1, smooth muscle actin α and fibronectin.
(III), KP-6 inhibits the abnormally activated β -catenin signaling pathway in UIRI mice
The experimental results are shown in FIG. 7, and compared with the model control group, the β -catenin protein and the downstream target gene proteins PAI-1 and Snail of the kidney of the mice in the drug group are obviously reduced.
In conclusion, KP-6 can obviously reduce the deposition of kidney interstitial collagen of UUO and UIRI mice, obviously reduce the expression levels of UUO, UIRI mouse kidney tissue fibronectin and I-type collagen α -SMA, and obviously inhibit the β -catenin signal channel which is abnormally activated in a CKD model, so KP-6 can be a new drug for effectively inhibiting the progress of CKD.
SEQUENCE LISTING
<110> southern hospital of southern medical university
Application of <120> small molecular polypeptide KP-6 in preparation of medicine for treating chronic kidney diseases
<130>
<160>1
<170>PatentIn version 3.4
<210>1
<211>30
<212>PRT
<213> Artificial Synthesis
<400>1
Gln Pro Val Val Thr Leu Tyr His Trp Asp Leu Pro Gln Arg Leu Gln
1 5 10 15
Asp Ala Tyr Gly Gly Trp Ala Asn Arg Ala Leu Ala Asp His
20 25 30
Claims (2)
1. The application of the small molecular polypeptide KP-6 in the preparation of medicines for treating chronic kidney diseases is disclosed, wherein the amino acid sequence of the polypeptide KP-6 is shown in SEQ ID NO. 1.
2. The use of claim 1, wherein the medicament comprises: small molecular polypeptide KP-6 with effective therapeutic dose, and pharmaceutically acceptable adjuvants.
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| CN108042791B (en) * | 2017-11-30 | 2020-03-06 | 南方医科大学南方医院 | Application of small molecular polypeptide KP-1 in preparation of medicine for treating chronic kidney diseases |
| CN110511266B (en) * | 2019-08-07 | 2022-08-30 | 南方医科大学南方医院 | Small molecule polypeptide and application thereof |
| CN111184856B (en) * | 2020-02-26 | 2023-12-01 | 南方医科大学南方医院 | Application of small molecule polypeptide TP-7 in preparation of medicine for treating chronic kidney disease |
| CN112915193B (en) * | 2021-03-05 | 2022-09-13 | 南方医科大学南方医院 | Application of KP-1 in preparation of medicine for treating chronic lung diseases |
| CN112915192B (en) * | 2021-03-05 | 2022-10-25 | 南方医科大学南方医院 | Application of KP-1 in preparation of medicine for treating chronic liver diseases |
Citations (2)
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| CN102861343A (en) * | 2012-10-17 | 2013-01-09 | 南方医科大学 | Application of secretory type Klotho in preparing medicine for treating chronic renal failure |
| CN104740604A (en) * | 2013-12-25 | 2015-07-01 | 胡卓伟 | Application of polypeptide and derivatives thereof in preparation of anti-pulmonary fibrosis medicine |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102861343A (en) * | 2012-10-17 | 2013-01-09 | 南方医科大学 | Application of secretory type Klotho in preparing medicine for treating chronic renal failure |
| CN104740604A (en) * | 2013-12-25 | 2015-07-01 | 胡卓伟 | Application of polypeptide and derivatives thereof in preparation of anti-pulmonary fibrosis medicine |
Non-Patent Citations (2)
| Title |
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| Klotho的研究进展;常晋瑞等;《生理科学进展》;20150831;第46卷(第4期);245-249 * |
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