CN108042791B - Application of small molecular polypeptide KP-1 in preparation of medicine for treating chronic kidney diseases - Google Patents
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Abstract
The invention relates to a new application of a small molecule polypeptide KP-1, in particular to an application of the small molecule polypeptide KP-1 in preparing a medicine for treating Chronic Kidney Disease (CKD). The invention provides the application of KP-1 in treating CKD, and the curative effect is obvious, and no obvious toxic or side effect is seen. Therefore, KP-1 described in the present invention can be prepared into pharmaceutical preparations for treating CKD.
Description
Technical Field
The invention relates to application of a unique small molecule polypeptide in treating Chronic Kidney Disease (CKD), in particular to application of a KP-1 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 great deal of research shows that the activation of TGF- β/Smad signal pathway is a key pathway of the occurrence and development of kidney fibrosis and CKD (Nat Rev Nephrol, 2016, 12: 325-38). therefore, the search of a strategy for blocking the TGF- β/Smad signal pathway has important theoretical significance and clinical application value for inhibiting the occurrence and development of kidney fibrosis.
TGF- β binds to TGF- β receptor II in vivo, recruits and activates TGF- β receptor I TGF- β receptor I signals to the cell, phosphorylates Smad2/3, and the activated Smad2/3 forms a complex with Smad4 to enter the nucleus, thereby regulating the expression of target genes. protein interactions are generally accomplished through domains composed of specific amino acid sequences. the present invention relates to screening of polypeptide libraries to find a specific small molecule polypeptide (KP-1) that inhibits the critical signaling pathway of kidney fibrosis.KP-1 polypeptide has no previous report that is homologous in amino acid sequence structure to a sequence of the anti-aging protein Klotho molecule.
KP-1 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 diseases.
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). Renal ischemia-reperfusion (IRI) is a model of the progression of 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 KP-1, namely application of the small molecule polypeptide KP-1 in preparing a medicament for treating chronic kidney diseases. The amino acid sequence of the polypeptide KP-1 is shown in SEQ ID NO. 1.
KP-1 sequence: FQGTFPDGFLWAVGSAAYQTEGGWQQHGK (SEQ ID NO. 1).
According to a further feature of the use of the present invention, the medicament prepared comprises: therapeutically effective small molecular polypeptide KP-1, and pharmaceutically acceptable adjuvants.
The invention also aims to provide application of the derivative of the small molecule polypeptide KP-1 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-1 comprises: contains a shorter peptide segment of KP-1 amino acid sequence, KP-1 related polypeptide after amino acid substitution, and KP-1 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-1 group is obviously reduced, α smooth muscle actin and fibronectin are obviously reduced, and the expression of key factors p-Smad2 and p-Smad3 of a TGF- β signal channel is obviously reduced, so that KP-1 can antagonize the TGF- β/Smad signal channel and effectively inhibit the fibrosis of kidney tissues of UUO and UIRI.
In conclusion, KP-1 has the effect of obviously inhibiting kidney tissue fibrosis and CKD progression, and has no obvious toxic or side effect, so that KP-1 can be used for preparing a medicament for effectively inhibiting CKD progression.
Drawings
FIGS. 1A and 1B are graphs showing the results of screening and identification of the small molecule polypeptide KP-1, which is stimulated by TGF- β recombinant protein after rat kidney fibroblasts (NRK-49F) are treated with different small molecule polypeptides, wherein, FIG. 1A shows the antagonism of TGF- β induced fibrosis-related proteins by the small molecule polypeptides No.1 to No. 3, and FIG. 1B shows immunofluorescence staining of fibronectin (a fibrosis-related protein) induced by KP-1 antagonizing TGF- β.
Figure 2 is a small animal in vivo imaging plot. UUO model mouse tail vein is injected with FITC-labeled KP-1 (FITC-KP-1), and small animal living body imaging system is used for detecting fluorescence intensity of organs such as heart, liver, spleen, lung, kidney, etc. Arrows indicate UUO kidney.
Figure 3 is a Masson staining of kidney of each group of mice in UUO model. In the figure, left: sham (Sham); the method comprises the following steps: UUO (model control); and (3) right: UUO + KP-1 (KP-1 medicinal group).
FIG. 4 is a graph of immunostaining of renal fibronectin 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-1: KP-1 medicinal group.
FIGS. 5A and 5B are immunoblots of the levels of p-Smad3 and its downstream fibrosis marker protein in mouse kidney tissues from groups of UUO models. Wherein, fig. 5A is a representative result of an immunoblot assay; FIG. 5B is a statistical chart of all results. And Sham: a sham operation group; and (4) UUO: a model control group; UUO + KP-1: KP-1 medicinal group.
FIG. 6 is a photograph of immunostaining of renal fibronectin in various groups of mice of the UIRI model. In the figure, Sham: a sham operation group; UIRI: a model control group; UIRI + KP-1: KP-1 medicinal group.
FIGS. 7A and 7B are immunoblots of immunoblots measuring the levels of p-Smad3 and its downstream fibrosis marker proteins in the kidneys of various groups of mice. Wherein, fig. 7A is a representative result of an immunoblot assay; FIG. 7B is a statistical chart of all results. And Sham: a sham operation group; UIRI: a model control group; UIRI + KP-1: KP-1 medicinal group.
Detailed Description
The invention will now be further described, by way of example only, with reference to the accompanying drawings.
Establishing a small molecular polypeptide library, and screening the KP-1 peptide fragment. The KP-1 peptide fragment was artificially synthesized by Nanjing Kinsrui Biotechnology Ltd, and the following experiment was performed.
The first embodiment is as follows: screening of KP-1 small molecule polypeptide
1. Experimental materials:
cell: rat kidney fibroblasts (NRK-49F).
Culture solution: DMEM/F12 (1: 1) medium containing 10% FBS.
The culture conditions are as follows: 37oC contains 5% CO2An incubator.
Small molecule polypeptide library: 18 polypeptide sequences are generated by computer design, the average length of each polypeptide sequence is 30 amino acids, and the polypeptide sequences are handed to Nanjing Jinslei Biotech company for artificial synthesis to build a small molecule polypeptide library.
2. Experimental treatment:
(I) cultured rat kidney fibroblasts were cultured at 1.5X 106The polypeptide is planted in a 6-well cell culture plate, cultured for 1 day, starved for 24 hours, 18 different small molecule polypeptides (10 mug/ml) are given 1 hour in advance, then TGF- β recombinant protein (2 ng/ml) is given for stimulation, the protein is collected after 48 hours, a Western blot experiment is carried out, and peptide sections which have the strongest inhibition on TGF- β induced fibronectin are screened.
(II) culturing rat kidney fibroblast cells at 1.5X 1066-well cell culture plates which are planted on bottom surface cover glass are cultured for 1 day, starved for 24 hours, peptide fragment No.1 (KP-1) (10 mug/ml) is given 1 hour in advance, then TGF- β (2 ng/ml) is added for stimulation, cells are fixed after 48 hours, and an immunofluorescence experiment is carried out.
3. Results of the experiment
(I) As shown in FIG. 1A, some small molecular peptide fragments can inhibit the expression of Fibronectin (Fibronectin) and α -smooth muscle actin (α -SMA) mediated by TGF- β, wherein the 1 st peptide fragment (named as KP-1) has the strongest inhibition effect.
(II) As shown in FIG. 1B, immunofluorescence intuitively reveals that KP-1 can inhibit the expression of fibronectin caused by TGF- β therefore, KP-1, as a novel small molecule polypeptide, can antagonize TGF- β activity, block the key in vivo pro-fibrotic signaling pathway, and thereby inhibit the expression of fibrosis-associated proteins.
(III) amino acid sequence of KP-1
Through sequencing, the amino acid sequence of the small molecule polypeptide KP-1 is as follows:
FQGTFPDGFLWAVGSAAYQTEGGWQQHGK。
example two: FITC-labeled KP-1 distributed in organs of UUO mice
1. Experimental animals: c57 mouse, male, body weight 20-22g, SPF grade.
Weighing and numbering animals, selecting 2 healthy mice with the weight of 20-22g, and dividing the mice into UUO and UUO + KP-1.
2. Experiment grouping
1) UUO mice: at room temperature, after the mice are anesthetized with 1% sodium pentobarbital at the weight of 5 ml/kg, the left flank of the mice is selected to be 2-3cm as an incision; after local sterilization, the skin, subcutaneous tissue, muscular layer and peritoneum were incised layer by layer, and after finding the left ureter, the left ureter was ligated to section 1/3 of ureter, and sutured layer by layer. After partial sterilization, the markers were verified and placed in the corresponding cages.
2) UUO + KP-1 mice: 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
The water-soluble powder of FITC-KP-1 was diluted with sterile 0.01mol/L glacial acetic acid to a stock concentration of 25 mg/ml. UUO mice were given tail vein injections of 0.01mol/L glacial acetic acid solution only. A glacial acetic acid solution containing FITC-KP-1 was injected into the tail vein of UUO + KP-1 mice at a concentration of 5 mg/kg. Mice were sacrificed 5 minutes after injection and organs such as hearts, liver, spleen, lung, kidneys, etc. were placed in a clean glass vessel. The fluorescence intensity of each organ is detected by a small animal living body imaging system. The experiment was protected from light throughout the course.
4. Results of the experiment
The experimental results are shown in fig. 2: the fluorescence signals of organs of the UUO + KP-1 mouse are obviously stronger than those of the UUO mouse. The fluorescence signals of organs of the UUO + KP-1 mouse are respectively from strong to weak: left kidney, right kidney, lung, liver, heart and spleen.
Example three: inhibition effect of small molecular polypeptide KP-1 on kidney fibrosis of mouse UUO model
1. Experimental animals: BALB/C mice, male, body 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 6 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 1% sodium pentobarbital at the weight of 5 ml/kg, 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-1 water soluble powder is diluted to 25mg/ml storage concentration by sterile 0.01mol/L glacial acetic acid solution, experimental components are raised in cages, a sham operation group only observes, a model control group only gives 0.01mol/L glacial acetic acid solution for tail vein injection, a drug group is injected with the glacial acetic acid solution containing KP-1 for 6 continuous days after UUO starts, mice are killed after raising for 7 days with the concentration of 1 mg/kg., the left side kidney is taken, 10% neutral buffer formaldehyde fixing and liquid nitrogen freezing tissues are respectively applied to the left side kidney, the formaldehyde fixing tissues are respectively applied with Masson staining and smooth muscle actin α and fibronectin immunostaining after dehydration, proteins are extracted after homogenizing the frozen tissues, and the protein levels of p-Smad3, p-Smad2 and downstream fibrosis index protein levels are detected by an immunoblotting method (Western Blot).
4. Results of the experiment
(I) KP-1 reduces UUO mouse renal interstitial collagen deposition
The experimental results are shown in fig. 3, and the degree of kidney tissue fibrosis is detected by Masson staining, which shows that the kidney interstitial collagen deposition of the mice in the drug group is obviously lower than that of the model control group.
(II), KP-1 reduction of UUO mouse renal interstitial fibrosis
The results are shown in FIG. 4, and the level of fibronectin (fibronectin) in the mouse kidney was significantly decreased compared to the model control group.
(III), KP-1 inhibits the abnormally activated TGF- β signaling pathway in UUO mice
The results of the Wester-blot experiment are shown in FIG. 5A and FIG. 5B, and compared with the model control group, the fibrosis indexes of the kidney of the mice in the drug group, namely fibrinectin, α -SMA and p-Smad3 protein, are obviously reduced.
Example four: inhibitory effect of small molecular polypeptide KP-1 on mouse UIRI model kidney fibrosis
1. Experimental animals: c57 mouse, male, 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 1% sodium pentobarbital at the weight of 5 ml/kg, 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 1-2 cm 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 1-2 cm 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-1 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 is given to a model control group for tail vein injection, a drug group is used for continuous 10 days after ischemia reperfusion injury begins, glacial acetic acid solution containing KP-1 is injected into tail vein, the concentration is 1 mg/kg., mice of each group are killed on 11 days, blood samples are collected, left kidneys are taken, 10% neutral buffer formaldehyde fixing and liquid nitrogen freezing tissues are respectively carried out, the formaldehyde fixing tissues are respectively dehydrated, embedded, sliced and sliced, after dehydration, Masson staining and smooth muscle actin α and fibronectin immunostaining are respectively carried out, proteins are extracted after the freezing tissues are homogenized, and the expression levels of p-Smad3, p-Smad2 and target genes thereof are detected by an immunoblotting method (Western Blot).
4. Results of the experiment
(I) KP-1 reduces renal interstitial fibrosis in UIRI mice
The results are shown in FIG. 6, and the level of fibronectin in kidney tissue of mice in the drug group is significantly reduced compared with the model control group.
(II), KP-1 inhibits abnormally activated TGF- β signaling pathway in UIRI mice
The experimental results are shown in FIG. 7A and FIG. 7B, and compared with the model control group, the fibrosis indexes of the kidney of the mice in the drug group, namely fibrinectin and α -SMA, and p-Smad3 protein are obviously reduced.
In conclusion, KP-1 can obviously reduce the deposition of UUO and UIRI mouse renal interstitial collagen, obviously reduce the expression levels of UUO, UIRI mouse renal tissue fibronectin and α -SMA, and obviously inhibit abnormally activated TGF- β signal channels in a CKD model, so KP-1 can be a new drug for effectively inhibiting the progression of CKD.
Sequence listing
<110> southern hospital of southern medical university
Application of <120> small molecular polypeptide KP-1 in preparation of medicine for treating chronic kidney diseases
<141>2017-11-30
<160>1
<170>SIPOSequenceListing 1.0
<210>1
<211>29
<212>PRT
<213> Artificial Sequence (Artificial Sequence)
<400>1
Phe Gln Gly Thr Phe Pro Asp Gly Phe Leu Trp Ala Val Gly Ser Ala
1 5 10 15
Ala Tyr Gln Thr Glu Gly Gly Trp Gln Gln His Gly Lys
20 25
Claims (2)
1. The application of the small molecular polypeptide KP-1 in preparing the medicine for treating chronic kidney diseases is disclosed, wherein the amino acid sequence of the polypeptide KP-1 is shown in SEQ ID NO. 1.
2. The use of claim 1, wherein the medicament comprises: small molecular polypeptide KP-1 with effective therapeutic dose and pharmaceutically acceptable auxiliary materials.
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| 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 |
| 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 |
| 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 |
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| AU2015237176A1 (en) * | 2014-03-28 | 2016-10-20 | New York University | FGF23 fusion proteins |
| CN105838661B (en) * | 2014-12-30 | 2020-11-10 | 深圳市第二人民医院 | Application of Klotho gene editing in xenogenic kidney transplantation |
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