CN111122873A - Application of retinoic acid receptor response protein 1 as biomarker in chronic kidney disease - Google Patents
Application of retinoic acid receptor response protein 1 as biomarker in chronic kidney disease Download PDFInfo
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- CN111122873A CN111122873A CN201911389676.3A CN201911389676A CN111122873A CN 111122873 A CN111122873 A CN 111122873A CN 201911389676 A CN201911389676 A CN 201911389676A CN 111122873 A CN111122873 A CN 111122873A
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- Prior art keywords
- kidney disease
- chronic kidney
- rares
- retinoic acid
- acid receptor
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Abstract
The invention discloses an application of retinoic acid receptor-reactive protein 1 as a biomarker in chronic nephropathy, belongs to the technical field of biology and medicine, and predicts the prognosis of nephropathy by detecting the change of the expression level of retinoic acid receptor-reactive protein 1 in body fluid of patients with chronic nephropathy.
Description
Technical Field
The invention relates to the technical field of biology and medicine, in particular to application of retinoic acid receptor-reactive protein 1 as a biomarker in chronic nephropathy.
Background
The incidence of diabetic nephropathy (DN, also known as DKD) is increasing worldwide, and DKD patients have a higher risk of end-stage renal disease (ESRD), which is a major cause of dialysis in chronic renal disease (CKD) patients.
Therefore, it is important to identify early high risk groups that may progress to ESRD. Current prognostic studies are primarily concerned with changes in urine protein and creatinine or glomerular filtration rate, butChanges in urinary protein lack sensitivity and specificity to risk stratification for DKD progression, while changes in creatinine or glomerular filtration rate are susceptible to diabetes over-diuresis, nephrotoxic drug use, infection, and the like, sometimes reflecting only transient changes in renal perfusion. For this purpose, the art has carried out successively blood uric acid, cystatin C, inflammatory markers, cytokines (e.g. CTGF, FGF-23, sCD)28) And miRNA and other markers, but at present, the markers still have the defects of poor specificity and the like;
therefore, further studies on markers for chronic kidney disease, especially diabetic nephropathy, are highly desirable.
Disclosure of Invention
The invention aims to provide an application of retinoic acid receptor response protein 1 as a biomarker in chronic kidney disease so as to solve the problem.
In order to achieve the purpose, the technical scheme adopted by the invention is as follows:
the application of retinoic acid receptor-reactive protein 1 as a biomarker in chronic kidney disease.
As a preferable technical scheme, the prognosis of chronic kidney disease is predicted by detecting the change of the expression level of the retinoic acid receptor-reactive protein 1 in the body fluid of a patient with chronic kidney disease.
Human retinoic acid receptor-responsive protein 1 (RARES 1), the amino acid sequence of which is shown in SEQ ID NO:1 (MQPRRQRLPA PWSGPRGPRP TAPLLALLLL LAPVAAPAGS GDPDDPGQPQ DAGVPRRLLQQAARAALHFFNFRSGSPSAL RVLAEVQEGR AWINPKEGCK VHVVFSTERY NPESLLQEGE GRLGKCSARV FFKNQKPRPTINVTCTRLIE KKKRQQEDYL LYKQMKQLKN PLEIVSIPDN HGHIDPSLRL IWDLAFLGSS YVMWEMTTQVSHYYLAQLTS VRQWKTNDDT IDFDYTVLLH ELSTQEIIPC RIHLVWYPGK PLKVKYHCQE LQTPEEASGTEEGSAVVPTE LSNF), also called as a retinoic acid receptor response element or a retinoic acid receptor response gene, is not reported to be applied to chronic kidney disease markers at present, and the inventor of the present application proves that the expression level of human RAR RES1 in body fluid of chronic kidney disease patients is obviously higher than that of healthy people through a large number of experiments, and if the expression of RAR RES1 in body fluid of chronic kidney disease patients, especially diabetic kidney disease patients, is continuously reduced, the prognosis is good.
In addition, the present inventors confirmed that the above-described principle as a marker is: RARRES1 can be cleaved with soluble cleavants and the cleavage site of RARRES is well defined; the soluble shear body can promote the apoptosis of glomerular podocyte, and the expression of RARES 1 in the blood and urine of patients with chronic nephropathy, especially diabetic nephropathy, is obviously increased, so that RARES 1 and the soluble shear body thereof can be used as novel biomarkers of chronic nephropathy, especially diabetic nephropathy, and the prognosis of diabetic nephropathy is predicted.
As a further preferred solution, the body fluid is blood and/or urine.
In a more preferred embodiment, the detection method is an Elisa method.
In a further preferred embodiment, the chronic kidney disease is focal segmental glomerulosclerosis or diabetic nephropathy.
In a further preferred embodiment, the chronic kidney disease is diabetic nephropathy. The specificity is higher.
The invention also aims to provide a product for predicting the prognosis of chronic kidney disease, which comprises a substance for detecting the expression level of the retinoic acid receptor-reactive protein 1 in body fluid of a patient with chronic kidney disease.
Preferably, the body fluid is blood and/or urine.
Preferably, the chronic kidney disease is focal segmental glomerulosclerosis or diabetic nephropathy.
In a further preferred embodiment, the chronic kidney disease is diabetic nephropathy.
Compared with the prior art, the invention has the beneficial effects that: the invention takes the retinoic acid receptor-reactive protein 1 as a marker of chronic nephropathy, particularly diabetic nephropathy, for the first time, has higher specificity, can also provide a theoretical basis for making a new standard for DN pathological typing, has more important guiding significance for clinical prognosis of chronic nephropathy, particularly diabetic nephropathy, is beneficial to further understanding the pathogenesis of DN, and can better guide clinical treatment and judge prognosis.
Drawings
FIG. 1 is a graph showing the immunohistochemical staining results of early stage renal biopsy specimens, wherein the health control group, FSGS (focal segmental glomerulosclerosis) group, DKD (diabetic nephropathy) group and MCD (minimal change nephropathy) group are healthy control group, FSGS (focal segmental glomerulosclerosis) group, DKD (diabetic nephropathy) group and MCD (minimal change renal disease) group;
FIG. 2 is a western-blot diagram of membrane proteins of extracted cells after transfection of 293T cells with an RARES 1 subtype eukaryotic expression plasmid (pN 1-RARES 1-v 5);
FIG. 3 is a western-blot of cell culture supernatants of 293T cells transfected with an eukaryotic expression plasmid of RARES 1 subtype (pN 1-RARES 1-v 5); in the figure, 1 is a control plasmid transfection group, and 2 is a pN 1-RARES 1-v5 plasmid transfection group;
FIG. 4 is a graph of a deglycosylated soluble RARES 1 western-blot, wherein 1 is the negative control, 2 is untreated soluble RARES 1, 3 is deglycosylated soluble RARES 1, and 4 is the cell lysate;
FIG. 5 is a western-blot of cell lysates ("Iysate" in FIG. 5) and supernatants ("suprant" in FIG. 5) of pN 1-RARES 1-v 5;
FIG. 6 is a western-blot of cell lysates ("Iysate" in FIG. 6) and supernatants ("super" in FIG. 6) of pCDNA 4-Flag-RARES 1;
FIG. 7 is a diagram showing the amino acid sequence modification to find the cleavage site of pN1-hRARRES1-v 5;
FIG. 8 is a western-blot of pN1- △ 34 aa-hRARRES 1-v5 and pN1- △ 13 aa-hRARRES 1-v 5;
FIG. 9 is a western-blot diagram of the collection of supernatants after the construction of different amino acid mutation sequences of the suspected mutation site "FFNF" respectively, corresponding plasmids transfected 293T cells;
FIG. 10 is a graph showing the results of flow cytometry for detecting Annexin V positive podocytes;
FIG. 11 is a Western blot detecting caspase-3 splice expression. A result graph;
figure 12 is a graph of blood RARRES1 expression levels for diabetic kidney patients and healthy controls;
figure 13 is a graph of urine RARRES1 expression levels for diabetic kidney patients and healthy controls.
Detailed Description
The present invention will be further described with reference to the following examples.
Example 1:
expression of retinoic acid receptor-responsive protein 1 in chronic kidney disease
Immunohistochemical staining of early stage kidney biopsy specimens of CKD (chronic kidney disease),
kidney puncture specimens of different types of CKD early diseases (GFR >60 ml/min) (FSGS, DKD, MCD and the like) with complete clinical data (including etiology, ACR, GFR, CRP and the like) are collected, relative normal tissues around a kidney cancer resection tumor are used as a control, a paraffin section is subjected to antigen retrieval and then immunohistochemical staining according to a conventional method, a TIG1 antibody (sc-98965, 1:50 dilution) of Santa Cruz is used as a primary antibody, and a goat-anti-rabbit secondary antibody marked by horseradish peroxidase is used for detecting the expression amount of RARES 1. The results are shown in FIG. 1, which reveals in FIG. 1: the expression of RARRES1 was significantly upregulated in the FSGS and DKD groups compared to the healthy control group, while the MCD group was not significantly upregulated.
Example 2:
transmembrane protein RARES 1 can be cut to have soluble cutter
It is currently generally accepted that RARRES1 is a type I transmembrane protein. In this example, 293T cells were transfected with a eukaryotic expression plasmid of human RARES 1 subtype (pN 1-RARES 1-V5), cell membrane proteins were extracted using the procedures described in the Biovision's cell membrane protein extraction kit (Catalog # K268), 30. mu.l of cytoplasmic protein, total cell membrane protein, and total cell protein were loaded to western-blot, and RARES 1 and known membrane proteins were detected using V5 antibody and Pan-cadherin, indicating that: the membrane protein is enriched in RARRES1, which is consistent with the prediction of transmembrane proteins (as shown in figure 2). At the same time, after plasmid transfection for 24 hours, serum-free medium was used, cell culture supernatant was collected, 30ug of cell holoprotein and 30. mu.l of cell culture supernatant were loaded, and western-blot was performed, indicating that: a large amount of RARES 1 protein was found in the cell culture supernatant, suggesting that RARES 1 has a soluble protein form (as shown in FIG. 3). The supernatant Protein was treated with Protein deglycosylation mix II (P6044S) from NEB and found to undergo glycosylation modification (as shown in fig. 4).
Example 3
pTRE-Right-hRARES 1, pTRE-Right-Flag-hRARES 1 vector was constructed. Then EcoRI and NoTI are used for double digestion of pTRE-light-Flag-hRARES 1 vector, the Flag-hRARES 1 fragment after digestion is recovered and is connected to the pCDNA4 vector digested by the same digestion, and the pCDNA 4-Flag-hRARES 1 vector is constructed (figure 6); 293T cells were transfected with C-terminally linked V5-tagged overexpression plasmid (pN 1-RARES 1-V5) (FIG. 5) and N-terminally linked Flag-tagged overexpression plasmid (pCDNA 4-Flag-RARES 1) (FIG. 6), respectively, and lysates and supernatants were examined for RARES 1 protein, confirming that RARES 1 is cleaved near the N-terminus and thus has a soluble cutter.
Example 4
Based on pN 1-hRARES 1-V5 plasmid, expression plasmid with deletion of different amino acid fragments is constructed, Westernblot is used for detecting RARES 1 protein of cell lysate and culture supernatant, and a shearing site of RARES 1 is searched. Construction of AA Using SacII and BssH II cleavage sites43-76Deleted RARES 1 expression vector (pN1- △ 34 AA-hRARRES 1-v5) AA was constructed using SacII and PstI cleavage sites43-55The deleted RARES 1 expression vector (pN1- △ 13 aa-hRARRES 1-v5) (FIG. 7) WB results suggest that the cleavage site of RARES 1 is between 56-76 amino acids (FIG. 8). further, amino acids 68-71 (FFNF) are found to be potential cleavage sites, a pN1- △ FFNF-v5 overexpression plasmid is constructed by connecting primers, FFNF deletion enables RARES 1 not to be cleaved, further, by point mutation of FFNF, the cleavage of wild-type RARES 1 can be prevented after the amino acid N at 70 is mutated into A or D (FIG. 9), and related primer sequences used in the experiment are shown in Table 1.
Table 1: plasmid construction related primer sequences
Example 5
Transfecting a 293T cell with pN 1-RARES 1-V5, changing a serum-free DMEM culture solution after 24 hours, collecting cell culture supernatant after 24 hours, and concentrating the cell culture supernatant for 30min by using an ultrafiltration centrifuge tube (Amicon 3 KD) 7000g to obtain a RARES 1 soluble shear body, transfecting pN1-EGFP by using the same method to obtain a control protein, and subpackaging and storing at-80 ℃; podocytes were cultured at 37 ℃ for 5 days for differentiation, added with 800. mu.l of the above-mentioned control supernatant and RARES 1 soluble lysates, and the supernatant cells and cells digested with trypsin were collected after 24 hours, centrifuged at 300g for 5min, washed with PBS, and then examined according to the Annexin V apoptosis test kit (Invitrogen 88-8007), Annexin V-FITC labeled apoptotic cells and Propidium Iodid labeled dead cells were examined using a FACS Caliber Flow cytometer, and further analyzed using CellQuestsoftware (BD biosciences). Podocytes were cultured as described above, and added soluble RARRES1, and cell lysates were collected after 24 hours, and western blots were used to detect expression of clear caspase-3, suggesting: the results of the soluble splice bodies of RARRES1 significantly increased the proportion of Annexin V positive podocytes (fig. 10), and increased the expression of podocyte clearcaspase-3 (fig. 11), suggesting that RARRES1 soluble splice bodies can promote the apoptosis of glomerular podocytes.
Example 6
In this example, blood and urine samples of 27 diabetic nephropathy patients and 10 healthy controls were collected and the expression level of soluble RARES 1 in the samples was measured using RARES 1 ELISA kit (MyBioSource: MBS 2019555). the urine samples were diluted 1:50 with stock solution and blood samples. The results showed that diabetic renal patients had increased expression of blood RARRES1 (shown in figure 12) and urine RARRES1 (shown in figure 13) as compared to controls; among them, the p-value in FIG. 12 is 0.0204, and the p-value in FIG. 13 is 0.0227, both of which are < 0.05, with statistical differences.
The above results suggest that increased expression of soluble RARRES1 may be associated with the development of diabetic nephropathy.
Sequence listing
<110> Zhongshan Hospital affiliated with Xiamen university
Application of <120> retinoic acid receptor response protein 1 as biomarker in chronic kidney disease
<130>2019
<160>17
<170>SIPOSequenceListing 1.0
<210>1
<211>294
<212>PRT
<213> Artificial Sequence (Artificial Sequence)
<400>1
Met Gln Pro Arg Arg Gln Arg Leu Pro Ala Pro Trp Ser Gly Pro Arg
1 5 10 15
Gly Pro Arg Pro Thr Ala Pro Leu Leu Ala Leu Leu Leu Leu Leu Ala
20 25 30
Pro Val Ala Ala Pro Ala Gly Ser Gly Asp Pro Asp Asp Pro Gly Gln
35 40 45
Pro Gln Asp Ala Gly Val Pro Arg Arg Leu Leu Gln Gln Ala Ala Arg
50 55 60
Ala Ala Leu His Phe Phe Asn Phe Arg Ser Gly Ser Pro Ser Ala Leu
65 70 75 80
Arg Val Leu Ala Glu Val Gln Glu Gly Arg Ala Trp Ile Asn Pro Lys
85 90 95
Glu Gly Cys Lys Val His Val Val Phe Ser Thr Glu Arg Tyr Asn Pro
100 105 110
Glu Ser Leu Leu Gln Glu Gly Glu Gly Arg Leu Gly Lys Cys Ser Ala
115 120 125
Arg Val Phe Phe Lys Asn Gln Lys Pro Arg Pro Thr Ile Asn Val Thr
130 135 140
Cys Thr Arg Leu Ile Glu Lys Lys Lys Arg Gln Gln Glu Asp Tyr Leu
145 150 155 160
Leu Tyr Lys Gln Met Lys Gln Leu Lys Asn Pro Leu Glu Ile Val Ser
165 170 175
Ile Pro Asp Asn His Gly His Ile Asp Pro Ser Leu Arg Leu Ile Trp
180 185 190
Asp Leu Ala Phe Leu Gly Ser Ser Tyr Val Met Trp Glu Met Thr Thr
195 200 205
Gln Val Ser His Tyr Tyr Leu Ala Gln Leu Thr Ser Val Arg Gln Trp
210 215 220
Lys Thr Asn Asp Asp Thr Ile Asp Phe Asp Tyr Thr Val Leu Leu His
225 230 235 240
Glu Leu Ser Thr Gln Glu Ile Ile Pro Cys Arg Ile His Leu Val Trp
245 250 255
Tyr Pro Gly Lys Pro Leu Lys Val Lys Tyr His Cys Gln Glu Leu Gln
260 265 270
Thr Pro Glu Glu Ala Ser Gly Thr Glu Glu Gly Ser Ala Val Val Pro
275 280 285
Thr Glu Leu Ser Asn Phe
290
<210>2
<211>36
<212>DNA
<213> Artificial Sequence (Artificial Sequence)
<400>2
gaattcgact acaaggacga cgatgacaaa gccggc 36
<210>3
<211>36
<212>DNA
<213> Artificial Sequence (Artificial Sequence)
<400>3
gccggctttg tcatcgtcgt ccttgtagtc gaattc 36
<210>4
<211>18
<212>DNA
<213> Artificial Sequence (Artificial Sequence)
<400>4
ggggtccggg gatcccag 18
<210>5
<211>24
<212>DNA
<213> Artificial Sequence (Artificial Sequence)
<400>5
cgcgctggga tccccggacc ccgc 24
<210>6
<211>27
<212>DNA
<213> Artificial Sequence (Artificial Sequence)
<400>6
ggggtccggg gaccgcaggc tcctgca 27
<210>7
<211>25
<212>DNA
<213> Artificial Sequence (Artificial Sequence)
<400>7
ggagcctgcg gtccccggac cccgc 25
<210>8
<211>42
<212>DNA
<213> Artificial Sequence (Artificial Sequence)
<400>8
gcaggcggcg agggcggcgc ttcacagatc tggctcgcct ag 42
<210>9
<211>50
<212>DNA
<213> Artificial Sequence (Artificial Sequence)
<400>9
cgcgctaggc gagccagatc tgtgaagcgc cgccctcgcc gcctgctgca 50
<210>10
<211>54
<212>DNA
<213> Artificial Sequence (Artificial Sequence)
<400>10
gcaggcggcg agggcggcgc ttcacgcggc tgctgctaga tctggctcgc ctag 54
<210>11
<211>62
<212>DNA
<213> Artificial Sequence (Artificial Sequence)
<400>11
cgcgctaggc gagccagatc tagcagcagc cgcgtgaagc gccgccctcg ccgcctgctg 60
ca 62
<210>12
<211>54
<212>DNA
<213> Artificial Sequence (Artificial Sequence)
<400>12
gcaggcggcg agggcggcgc ttcacgcggc taacgctaga tctggctcgc ctag 54
<210>13
<211>62
<212>DNA
<213> Artificial Sequence (Artificial Sequence)
<400>13
cgcgctaggc gagccagatc tagcgttagc cgcgtgaagc gccgccctcg ccgcctgctg 60
ca 62
<210>14
<211>54
<212>DNA
<213> Artificial Sequence (Artificial Sequence)
<400>14
gcaggcggcg agggcggcgc ttcacttctt cgctttcaga tctggctcgc ctag 54
<210>15
<211>62
<212>DNA
<213> Artificial Sequence (Artificial Sequence)
<400>15
cgcgctaggc gagccagatc tgaaagcgaa gaagtgaagc gccgccctcg ccgcctgctg 60
ca 62
<210>16
<211>54
<212>DNA
<213> Artificial Sequence (Artificial Sequence)
<400>16
gcaggcggcg agggcggcgc ttcacttctt cgatttcaga tctggctcgc ctag 54
<210>17
<211>62
<212>DNA
<213> Artificial Sequence (Artificial Sequence)
<400>17
cgcgctaggc gagccagatc tgaaatcgaa gaagtgaagc gccgccctcg ccgcctgctg 60
ca 62
Claims (10)
1. The application of retinoic acid receptor-reactive protein 1 as a biomarker in chronic kidney disease.
2. The use according to claim 1, wherein the prognosis of chronic kidney disease is predicted by detecting a change in the expression level of retinoic acid receptor-responsive protein 1 in a body fluid of a patient with chronic kidney disease.
3. Use according to claim 2, wherein the body fluid is blood and/or urine.
4. Use according to claim 2, wherein the detection method is the Elisa method.
5. The use of claim 1 or 2 or 3, wherein the chronic kidney disease is focal segmental glomerulosclerosis or diabetic nephropathy.
6. The use according to claim 5, wherein the chronic kidney disease is diabetic nephropathy.
7. A product for predicting the prognosis of renal disease, comprising a substance for detecting the expression level of retinoic acid receptor-responsive protein 1 in a body fluid of a patient with chronic kidney disease.
8. The product of claim 7, wherein the bodily fluid is blood and/or urine.
9. The product according to claim 7, wherein the chronic kidney disease is focal segmental glomerulosclerosis or diabetic nephropathy.
10. The product of claim 9, wherein the chronic kidney disease is diabetic nephropathy.
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