CN117695278A - Ptprj激动剂在制备预防和/或治疗肾脏纤维化的药物中的应用 - Google Patents
Ptprj激动剂在制备预防和/或治疗肾脏纤维化的药物中的应用 Download PDFInfo
- Publication number
- CN117695278A CN117695278A CN202311750285.6A CN202311750285A CN117695278A CN 117695278 A CN117695278 A CN 117695278A CN 202311750285 A CN202311750285 A CN 202311750285A CN 117695278 A CN117695278 A CN 117695278A
- Authority
- CN
- China
- Prior art keywords
- ptprj
- kidney
- agonist
- kidney fibrosis
- fibrosis
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 206010023421 Kidney fibrosis Diseases 0.000 title claims abstract description 25
- 239000000556 agonist Substances 0.000 title claims abstract description 16
- 239000003814 drug Substances 0.000 title claims abstract description 10
- 229940079593 drug Drugs 0.000 title abstract description 6
- 238000002360 preparation method Methods 0.000 title abstract description 5
- 210000002950 fibroblast Anatomy 0.000 claims abstract description 32
- 230000004913 activation Effects 0.000 claims abstract description 27
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 claims abstract description 17
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 claims abstract description 17
- 230000008021 deposition Effects 0.000 claims abstract description 17
- 210000002744 extracellular matrix Anatomy 0.000 claims abstract description 17
- 210000005084 renal tissue Anatomy 0.000 claims abstract description 17
- 238000011282 treatment Methods 0.000 claims abstract description 14
- 230000035755 proliferation Effects 0.000 claims abstract description 10
- 208000028867 ischemia Diseases 0.000 claims abstract description 6
- 230000006378 damage Effects 0.000 claims abstract description 5
- 230000001575 pathological effect Effects 0.000 claims abstract description 4
- 208000004608 Ureteral Obstruction Diseases 0.000 claims description 21
- 201000002793 renal fibrosis Diseases 0.000 claims description 11
- 230000010410 reperfusion Effects 0.000 claims description 4
- 230000002265 prevention Effects 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims 1
- 230000008807 pathological lesion Effects 0.000 claims 1
- 150000003839 salts Chemical class 0.000 claims 1
- PTFQBXAUOWUATD-UHFFFAOYSA-M sodium;2-[[4-(3-methoxyphenyl)-5-pyridin-2-yl-1,2,4-triazol-3-yl]sulfanyl]acetate Chemical group [Na+].COC1=CC=CC(N2C(=NN=C2SCC([O-])=O)C=2N=CC=CC=2)=C1 PTFQBXAUOWUATD-UHFFFAOYSA-M 0.000 claims 1
- 230000002829 reductive effect Effects 0.000 abstract description 7
- 150000003384 small molecules Chemical class 0.000 abstract description 7
- 230000001681 protective effect Effects 0.000 abstract description 5
- 238000000034 method Methods 0.000 abstract description 4
- 102000004887 Transforming Growth Factor beta Human genes 0.000 abstract description 3
- 108090001012 Transforming Growth Factor beta Proteins 0.000 abstract description 3
- 230000003902 lesion Effects 0.000 abstract description 3
- ZRKFYGHZFMAOKI-QMGMOQQFSA-N tgfbeta Chemical compound C([C@H](NC(=O)[C@H](C(C)C)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CCSC)C(C)C)[C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O)C1=CC=C(O)C=C1 ZRKFYGHZFMAOKI-QMGMOQQFSA-N 0.000 abstract description 3
- 230000008569 process Effects 0.000 abstract description 2
- 230000003827 upregulation Effects 0.000 abstract description 2
- 208000020832 chronic kidney disease Diseases 0.000 description 28
- 241000699670 Mus sp. Species 0.000 description 25
- 210000004027 cell Anatomy 0.000 description 25
- 230000014509 gene expression Effects 0.000 description 20
- 230000000694 effects Effects 0.000 description 13
- 102000004169 proteins and genes Human genes 0.000 description 13
- 108090000623 proteins and genes Proteins 0.000 description 13
- 210000003734 kidney Anatomy 0.000 description 11
- 102100037362 Fibronectin Human genes 0.000 description 10
- 101001027128 Homo sapiens Fibronectin Proteins 0.000 description 10
- 102000008186 Collagen Human genes 0.000 description 8
- 108010035532 Collagen Proteins 0.000 description 8
- 229920001436 collagen Polymers 0.000 description 8
- 230000030609 dephosphorylation Effects 0.000 description 8
- 238000006209 dephosphorylation reaction Methods 0.000 description 8
- 210000000683 abdominal cavity Anatomy 0.000 description 7
- 238000004458 analytical method Methods 0.000 description 7
- 230000026731 phosphorylation Effects 0.000 description 7
- 238000006366 phosphorylation reaction Methods 0.000 description 7
- 102000012422 Collagen Type I Human genes 0.000 description 6
- 108010022452 Collagen Type I Proteins 0.000 description 6
- 108010051742 Platelet-Derived Growth Factor beta Receptor Proteins 0.000 description 6
- 102000018967 Platelet-Derived Growth Factor beta Receptor Human genes 0.000 description 6
- 238000011529 RT qPCR Methods 0.000 description 6
- 210000001015 abdomen Anatomy 0.000 description 6
- 238000002198 surface plasmon resonance spectroscopy Methods 0.000 description 6
- 238000001356 surgical procedure Methods 0.000 description 6
- 238000001262 western blot Methods 0.000 description 6
- 206010016654 Fibrosis Diseases 0.000 description 5
- 241000699666 Mus <mouse, genus> Species 0.000 description 5
- 230000004761 fibrosis Effects 0.000 description 5
- 238000000338 in vitro Methods 0.000 description 5
- 108020004999 messenger RNA Proteins 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 230000000638 stimulation Effects 0.000 description 5
- 241001465754 Metazoa Species 0.000 description 4
- 108020004485 Nonsense Codon Proteins 0.000 description 4
- KPKZJLCSROULON-QKGLWVMZSA-N Phalloidin Chemical compound N1C(=O)[C@@H]([C@@H](O)C)NC(=O)[C@H](C)NC(=O)[C@H](C[C@@](C)(O)CO)NC(=O)[C@H](C2)NC(=O)[C@H](C)NC(=O)[C@@H]3C[C@H](O)CN3C(=O)[C@@H]1CSC1=C2C2=CC=CC=C2N1 KPKZJLCSROULON-QKGLWVMZSA-N 0.000 description 4
- 102100037236 Tyrosine-protein kinase receptor UFO Human genes 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 239000003550 marker Substances 0.000 description 4
- 238000003032 molecular docking Methods 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- 238000010186 staining Methods 0.000 description 4
- 238000012404 In vitro experiment Methods 0.000 description 3
- 229930040373 Paraformaldehyde Natural products 0.000 description 3
- 102000002727 Protein Tyrosine Phosphatase Human genes 0.000 description 3
- 238000010171 animal model Methods 0.000 description 3
- 239000011324 bead Substances 0.000 description 3
- 230000000903 blocking effect Effects 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 230000006870 function Effects 0.000 description 3
- 210000002216 heart Anatomy 0.000 description 3
- 208000017169 kidney disease Diseases 0.000 description 3
- 230000007246 mechanism Effects 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 230000002018 overexpression Effects 0.000 description 3
- 229920002866 paraformaldehyde Polymers 0.000 description 3
- 108020000494 protein-tyrosine phosphatase Proteins 0.000 description 3
- 238000004445 quantitative analysis Methods 0.000 description 3
- 230000001105 regulatory effect Effects 0.000 description 3
- 238000011287 therapeutic dose Methods 0.000 description 3
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 2
- 206010002091 Anaesthesia Diseases 0.000 description 2
- 238000011746 C57BL/6J (JAX™ mouse strain) Methods 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 102100031181 Glyceraldehyde-3-phosphate dehydrogenase Human genes 0.000 description 2
- WZUVPPKBWHMQCE-UHFFFAOYSA-N Haematoxylin Chemical compound C12=CC(O)=C(O)C=C2CC2(O)C1C1=CC=C(O)C(O)=C1OC2 WZUVPPKBWHMQCE-UHFFFAOYSA-N 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- 208000026350 Inborn Genetic disease Diseases 0.000 description 2
- PIWKPBJCKXDKJR-UHFFFAOYSA-N Isoflurane Chemical compound FC(F)OC(Cl)C(F)(F)F PIWKPBJCKXDKJR-UHFFFAOYSA-N 0.000 description 2
- 239000002033 PVDF binder Substances 0.000 description 2
- 108010009711 Phalloidine Proteins 0.000 description 2
- 102000007056 Recombinant Fusion Proteins Human genes 0.000 description 2
- 108010008281 Recombinant Fusion Proteins Proteins 0.000 description 2
- 102000013127 Vimentin Human genes 0.000 description 2
- 108010065472 Vimentin Proteins 0.000 description 2
- 239000012190 activator Substances 0.000 description 2
- 230000037005 anaesthesia Effects 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 230000000747 cardiac effect Effects 0.000 description 2
- 231100000259 cardiotoxicity Toxicity 0.000 description 2
- 238000004113 cell culture Methods 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 230000007423 decrease Effects 0.000 description 2
- 238000010494 dissociation reaction Methods 0.000 description 2
- 230000005593 dissociations Effects 0.000 description 2
- 238000012137 double-staining Methods 0.000 description 2
- 230000003828 downregulation Effects 0.000 description 2
- 238000004043 dyeing Methods 0.000 description 2
- 230000002900 effect on cell Effects 0.000 description 2
- 210000003414 extremity Anatomy 0.000 description 2
- 239000000835 fiber Substances 0.000 description 2
- 230000003176 fibrotic effect Effects 0.000 description 2
- 208000016361 genetic disease Diseases 0.000 description 2
- 108020004445 glyceraldehyde-3-phosphate dehydrogenase Proteins 0.000 description 2
- 230000002440 hepatic effect Effects 0.000 description 2
- 238000010166 immunofluorescence Methods 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 239000007928 intraperitoneal injection Substances 0.000 description 2
- 229960002725 isoflurane Drugs 0.000 description 2
- 238000013227 male C57BL/6J mice Methods 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 210000003205 muscle Anatomy 0.000 description 2
- 230000035772 mutation Effects 0.000 description 2
- 230000037434 nonsense mutation Effects 0.000 description 2
- 239000012188 paraffin wax Substances 0.000 description 2
- 230000037361 pathway Effects 0.000 description 2
- 239000002504 physiological saline solution Substances 0.000 description 2
- 229920002981 polyvinylidene fluoride Polymers 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- 238000003753 real-time PCR Methods 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 230000037390 scarring Effects 0.000 description 2
- 238000012216 screening Methods 0.000 description 2
- 230000011664 signaling Effects 0.000 description 2
- 238000013424 sirius red staining Methods 0.000 description 2
- 159000000000 sodium salts Chemical class 0.000 description 2
- 238000007619 statistical method Methods 0.000 description 2
- 231100000057 systemic toxicity Toxicity 0.000 description 2
- 230000008685 targeting Effects 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 230000007838 tissue remodeling Effects 0.000 description 2
- 210000005239 tubule Anatomy 0.000 description 2
- 210000000626 ureter Anatomy 0.000 description 2
- 210000005048 vimentin Anatomy 0.000 description 2
- ZEXHXVOGJFGTRX-UHFFFAOYSA-N 2-(2-methyl-5-nitroimidazol-1-yl)ethyl n-[2,2,2-trichloro-1-(pyrimidin-2-ylamino)ethyl]carbamate Chemical compound CC1=NC=C([N+]([O-])=O)N1CCOC(=O)NC(C(Cl)(Cl)Cl)NC1=NC=CC=N1 ZEXHXVOGJFGTRX-UHFFFAOYSA-N 0.000 description 1
- XRKYMMUGXMWDAO-UHFFFAOYSA-N 2-(4-morpholinyl)-6-(1-thianthrenyl)-4-pyranone Chemical compound O1C(C=2C=3SC4=CC=CC=C4SC=3C=CC=2)=CC(=O)C=C1N1CCOCC1 XRKYMMUGXMWDAO-UHFFFAOYSA-N 0.000 description 1
- FWBHETKCLVMNFS-UHFFFAOYSA-N 4',6-Diamino-2-phenylindol Chemical compound C1=CC(C(=N)N)=CC=C1C1=CC2=CC=C(C(N)=N)C=C2N1 FWBHETKCLVMNFS-UHFFFAOYSA-N 0.000 description 1
- 238000009020 BCA Protein Assay Kit Methods 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 102000001187 Collagen Type III Human genes 0.000 description 1
- 108010069502 Collagen Type III Proteins 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 102100021238 Dynamin-2 Human genes 0.000 description 1
- 102000002090 Fibronectin type III Human genes 0.000 description 1
- 108050009401 Fibronectin type III Proteins 0.000 description 1
- 101000817607 Homo sapiens Dynamin-2 Proteins 0.000 description 1
- 101000609255 Homo sapiens Plasminogen activator inhibitor 1 Proteins 0.000 description 1
- 101000692455 Homo sapiens Platelet-derived growth factor receptor beta Proteins 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 102100039418 Plasminogen activator inhibitor 1 Human genes 0.000 description 1
- 102100026547 Platelet-derived growth factor receptor beta Human genes 0.000 description 1
- 229940124158 Protease/peptidase inhibitor Drugs 0.000 description 1
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 1
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 1
- 239000012083 RIPA buffer Substances 0.000 description 1
- 108010087230 Sincalide Proteins 0.000 description 1
- 238000000692 Student's t-test Methods 0.000 description 1
- 229920004890 Triton X-100 Polymers 0.000 description 1
- 239000013504 Triton X-100 Substances 0.000 description 1
- 102000004142 Trypsin Human genes 0.000 description 1
- 108090000631 Trypsin Proteins 0.000 description 1
- 230000003187 abdominal effect Effects 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- 230000002238 attenuated effect Effects 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000010609 cell counting kit-8 assay Methods 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 230000012292 cell migration Effects 0.000 description 1
- 210000003855 cell nucleus Anatomy 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 238000001516 cell proliferation assay Methods 0.000 description 1
- 230000033077 cellular process Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 238000012650 click reaction Methods 0.000 description 1
- 230000008045 co-localization Effects 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 238000002784 cytotoxicity assay Methods 0.000 description 1
- 231100000263 cytotoxicity test Toxicity 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 230000000249 desinfective effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- UQLDLKMNUJERMK-UHFFFAOYSA-L di(octadecanoyloxy)lead Chemical compound [Pb+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O UQLDLKMNUJERMK-UHFFFAOYSA-L 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000012636 effector Substances 0.000 description 1
- 210000002889 endothelial cell Anatomy 0.000 description 1
- 238000000556 factor analysis Methods 0.000 description 1
- 235000013861 fat-free Nutrition 0.000 description 1
- 210000003958 hematopoietic stem cell Anatomy 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 238000010191 image analysis Methods 0.000 description 1
- 238000003125 immunofluorescent labeling Methods 0.000 description 1
- 230000002055 immunohistochemical effect Effects 0.000 description 1
- 238000011532 immunohistochemical staining Methods 0.000 description 1
- 238000003364 immunohistochemistry Methods 0.000 description 1
- 238000012744 immunostaining Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
- 230000003907 kidney function Effects 0.000 description 1
- 210000000244 kidney pelvis Anatomy 0.000 description 1
- 238000011813 knockout mouse model Methods 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000004807 localization Effects 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- 210000004080 milk Anatomy 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
- 230000011278 mitosis Effects 0.000 description 1
- 230000009456 molecular mechanism Effects 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 210000004940 nucleus Anatomy 0.000 description 1
- 230000006548 oncogenic transformation Effects 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 238000012261 overproduction Methods 0.000 description 1
- 230000007119 pathological manifestation Effects 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 230000008289 pathophysiological mechanism Effects 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 239000013612 plasmid Substances 0.000 description 1
- 229920002401 polyacrylamide Polymers 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 239000011546 protein dye Substances 0.000 description 1
- 230000005180 public health Effects 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 238000010839 reverse transcription Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 1
- -1 small molecule compounds Chemical class 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 238000012353 t test Methods 0.000 description 1
- 210000001685 thyroid gland Anatomy 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 108091005703 transmembrane proteins Proteins 0.000 description 1
- 102000035160 transmembrane proteins Human genes 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
- 210000001835 viscera Anatomy 0.000 description 1
- 239000011534 wash buffer Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000012224 working solution Substances 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Landscapes
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
本发明公开了Ptprj激动剂GJ103在制备预防和/或治疗肾脏纤维化的药物中的应用。本申请揭示了主动上调Ptprj可明显抑制TGF‑β1引起的成纤维细胞的增殖与活化,而敲除Ptprj则加重UUO引起的肾脏纤维化病变以及促进成纤维细胞的激活。作为Ptprj小分子激动剂,GJ103治疗不仅明显抑制了TGF‑β1诱导的肾脏成纤维细胞激活,也显著改善了梗阻和缺血引起的肾组织病理损害和减少细胞外基质的沉积。结果表明:Ptprj在肾脏纤维化的进程中起保护作用,其激动剂GJ103,为预防和诊治CKD提高新靶点。
Description
技术领域
本发明涉及一种医药领域,具体涉及Ptprj激动剂在制备预防和/或治疗肾脏纤维化的药物中的应用。
背景技术
慢性肾脏疾病(Chronic Kidney Disease,CKD)是一种以渐进性和不可逆的肾功能丧失或持续性肾损害为特征的长期疾病[1]。预计到2040年,它将成为全球第五大死因。CKD高发病率、高死亡率的特点已使其成为全球性的公共卫生问题。无论是何种病因导致的CKD,其共同的病理表现都是肾脏纤维化。它的特点是过度产生/沉积的细胞外基质(Extracellular matrix,ECM)[2],导致组织重塑和肾实质瘢痕形成。在此过程中,成纤维细胞的增殖和活化,是肾纤维化的明确效应和驱动因素[3]。CKD的病理生理机制较为复杂,临床上也缺乏有效且特异的防治手段。因此,深入探讨肾脏纤维化背后的分子机制,寻找有效靶点,是延缓肾脏病慢性进展、阻断肾脏纤维化的关键所在。
蛋白酪氨酸磷酸酶受体J(Protein Tyrosine Phosphatase Receptor J,Ptprj)是一种220kda的跨膜蛋白,属于受体型蛋白酪氨酸磷酸酶家族,参与多种信号通路[4]。Ptprj在造血细胞、内皮细胞、成纤维细胞、甲状腺细胞和乳腺细胞等多种细胞类型中均有表达。其结构由单个胞内催化PTP结构域、跨膜结构域和由9个纤连蛋白III型重复序列组成的胞外结构域组成,通过去磷酸化或者参与其他蛋白酪氨酸激酶去磷酸化,从而调节多种细胞过程,包括细胞生长、分化、有丝分裂和致癌转化[5-7]。研究发现:纤维化涉及多条途径,PDGF信号转导是其中的中心介质之一。Ptprj既可以下调PDGFRβ磷酸化水平,对细胞增殖和迁移也有负向调控作用[8-10]。Ptprj在肾脏纤维化中的作用尚不明确。
GJ103是一种通读化合物,CAS号为1459687-89-8,结构式为:
GJ103可以诱导过早终止密码子的通读,在无义突变引起的遗传病中具有研究潜力。作为GJ072类似物,GJ103在具有纯合TGA突变和纯合TAA突变的AT153LA细胞中可诱导ATM激酶活性。目前GJ103在肾脏疾病中暂无研究。
参考文献如下:
1.Zhong,J.,H.C.Yang,and A.B.Fogo,A perspective on chronic kidneydisease progression.Am J Physiol Renal Physiol,2017.312(3):p.F375-F384.
2.Bulow,R.D.and P.Boor,Extracellular Matrix in Kidney Fibrosis:MoreThan Just aScaffold.J Histochem Cytochem,2019.67(9):p.643-661.
3.Falke L L,Gholizadeh S,Goldschmeding R,et al.Diverse origins of themyofibroblast-implications for kidney fibrosis[J].Nat Rev Nephrol,2015,11(4):233-244.
4.Keane M M,Lowrey G A,Ettenberg S A,et al.The protein tyrosinephosphatase DEP-1is induced during differentiation and inhibits growth ofbreast cancer cells[J].Cancer Res,1996,56(18):4236-4243.
5.Grazia Lampugnani,M.,et al.,Contact inhibition of VEGF-inducedproliferation requires vascular endothelial cadherin,beta-catenin,and thephosphatase DEP-1/CD148.JCell Biol,2003.161(4):p.793-804.
6.Schwarz,M.,et al.,Disrupting PTPRJ transmembrane-mediatedoligomerization counteracts oncogenic receptor tyrosine kinase FLT3 ITD.FrontOncol,2022.12:p.1017947.
7.Hendriks,W.,et al.,Proteinaceous Regulators and Inhibitors ofProtein Tyrosine Phosphatases.Molecules,2018.23(2).
8.Sala M,Spensiero A,Scala MC,et al.Design,Synthesis,BiologicalActivity,and Structural Analysis of Lactam-Constrained PTPRJ AgonistPeptides.ChemMedChem 2018;13:1673-1680.
9.Buhl EM,Djudjaj S,Klinkhammer BM,et al.Dysregulated mesenchymalPDGFR-beta drives kidney fibrosis.EMBO Mol Med 2020;12:e11021.
10.Chen YT,Chang FC,Wu CF,et al.Platelet-derived growth factorreceptor signaling activates pericyte-myofibroblast transition in obstructiveand post-ischemic kidney fibrosis.Kidney international 2011;80:1170-1181.
发明内容
发明目的:本发明的目的是提出Ptprj激动剂GJ103在制备预防和/或治疗肾脏纤维化的药物中的应用,为GJ103提供了一种新的制药用途,同时,为慢性肾脏疾病提供一种新的治疗策略。
本申请揭示了主动上调Ptprj可明显抑制TGF-β1引起的成纤维细胞的增殖与活化,而敲除Ptprj则加重UUO引起的肾脏纤维化病变以及促进成纤维细胞的激活。作为Ptprj小分子激动剂,GJ103治疗不仅明显抑制了TGF-β1诱导的肾脏成纤维细胞激活,也显著改善了梗阻和缺血引起的肾组织病理损害和减少细胞外基质的沉积。
具体地,本申请首先发现了Ptprj在CKD患者肾组织中的表达及定位,通过免疫组化发现:Ptprj在正Ptprj常肾组织中表达水平较低,但在CKD患者的肾小管和间质中表达显著升高。进一步通过Ptprj和Fsp1的双重染色也证实了间质中其表达增加。开展体内外实验探讨Ptprj在CKD中的潜在功能,我们在体外培养的大鼠成纤维细胞(NRK49F)中过表达Ptprj,显著抑制TGF-β1诱导的Collagen I、Collagen III的mRNA表达和FN1、Vimentin的蛋白表达,同时也抑制了成纤维细胞活化指标α-SMA的表达。通过构建Ptprj杂合子敲除鼠,更深入明确Ptprj在CKD中的功能。qRT-PCR分析显示,Ptprj敲低可加重细胞外基质成分FN1的沉积,Western blot显示检测FN1、Collagen I和Collagen III蛋白表达也明显增加。在UUO小鼠中,Ptprj敲低后,以α-SMA高度表达为特征的成纤维细胞的增殖和活化能力也随之升高。同样我们发现:与对照组相比,Ptprj敲低使纤维化病变的肾脏中PDGFRβ磷酸化水平升高,这表明Ptprj可能通过PDGFRβ调节肾脏纤维化。
上述数据提示我们靶向Ptprj在CKD分子干预机制中具有治疗潜力。因此,我们通过分子对接筛选有效的Ptprj激活剂,并通过检测Ptprj对PDGFRβ的去磷酸化活性进一步筛选对接得分较高的小分子激动剂。首先用10个小分子刺激NRK49F细胞后,我们发现AS252424和GJ103显著抑制了PDGFRβ的磷酸化水平,与TGF-β1共同刺激后,也促进了PDGFRβ的去磷酸化。接着通过体外对PDGFRβ去磷酸化,我们发现GJ103能更好地激活Ptprj。最后利用表面等离子体共振(SPR)定量分析发现:GJ103与Ptprj重组蛋白具有较高的亲和力。
为进一步验证GJ103在CKD肾纤维化中的保护作用,我们用5、10、20、40μM不同浓度的GJ103预处理NRK49F细胞2h后,TGF-β1刺激NRK49F细胞。实验结果表明,当GJ103浓度高于20μM时,PDGFRβ的磷酸化水平被显著抑制。随着p-PDGFRβ表达的降低,纤维化标志物FN1的蛋白水平也进一步下降。随后在动物模型中验证GJ103的功能。研究结果表明:GJ103高剂量(30mg/kg/天)可以明显改善UUO和UIRI诱导的肾纤维化。主要表现为:肾间质胶原沉积和细胞外基质减少以及成纤维细胞的激活被抑制。在UUO和UIRI模型中,治疗剂量的GJ103对肾、肝、心或全身没有明显毒性。
综上结果表明,GJ103及其钠盐在制备用于预防和/或治疗慢性肾脏疾病的药物中具有巨大潜力,可以有效地减轻慢性肾脏疾病导致的肾纤维化。
附图说明
图1为Ptprj与CKD肾脏纤维化发生发展的时空表达关系图;
图2为过表达Ptprj对TGF-β1诱导的肾脏成纤维细胞活化的影响图;
图3为敲除Ptprj对UUO诱导的细胞外基质沉积和成纤维细胞活化的影响图;
图4为筛选Ptprj小分子激动剂GJ103的机制图;
图5为GJ103治疗对TGF-β1诱导的肾脏成纤维细胞活化的影响图;
图6为GJ103治疗对UUO诱导的细胞外基质沉积和成纤维细胞活化的影响图;
图7为GJ103治疗对UIRI诱导的细胞外基质沉积和成纤维细胞活化的影响图。
具体实施方式
下面结合具体实施例进一步阐明本发明。除非另外指明,本发明中所使用的试剂均为市售试剂。大鼠成纤维细胞(NRK-49F)来自ATCC(American Type CultureCollection)。Ptprj-KO小鼠和C57BL/6J小鼠均来源于集萃药康(中国南京),GJ103采用其钠盐形式。
下述实施例中采用的实验方法和材料具体如下:
动物模型制备:构建单侧输尿管梗阻(UUO)模型来评估Ptprj对CKD的影响。Ptprj杂合敲除(Ptprj+/-)小鼠随机分为4组(假手术组:WT+Sham组和Ptprj+/-+Sham组;模型组:WT+UUO组和Ptprj+/-+UUO小组)。用异氟烷来麻醉小鼠,麻醉成功后,固定小鼠四肢,腹部向上。消毒腹部,沿小鼠腹中线用眼科剪打开并暴露小鼠腹腔,找到并分离出左侧输尿管。在接近肾盂端位置用4-0缝线结扎左侧输尿管。将小鼠脏器完整归位,关闭小鼠腹腔,缝合小鼠的腹膜肌层和皮肤。假手术组只需要打开小鼠腹腔,缝合小鼠腹部。手术完毕后,在南京医科大学实验动物中心SPF级动物房接着喂养小鼠,术后每天监测小鼠身体情况。UUO术后7天,给予小鼠安乐死,抽取心脏血液并留取肾组织。用于组织学分析的肾组织固定在4%多聚甲醛中,剩余的肾组织储存在-80℃下进行mRNA和蛋白质分析。所有动物饲养与操作均经南京医科大学机构动物护理和使用委员会批准。
构建单侧输尿管梗阻(UUO)模型来评估GJ103对CKD的影响。8周龄雄性C57BL/6J小鼠被随机分为4组(假手术组:Sham组;模型组:UUO组,UUO+GJ103-15mg/kg/天组,UUO+GJ103-30 mg/kg/天组)。小鼠通过腹腔注射用GJ103两种浓度(15mg/kg/天和30mg/kg/天)各预处理1天。然后进行UUO手术,步骤同上。在随后7天连续用GJ103两种浓度(15mg/kg/天和30mg/kg/天)进行治疗。UUO术后7天,给予小鼠安乐死,余下步骤同上。
构建单侧缺血再灌注(UIRI)模型来评估GJ103对CKD的影响。8周龄雄性C57BL/6J小鼠被随机分为3组(假手术组:Sham组;模型组:UIRI组和UIRI+GJ103-30mg/kg/天组)。小鼠通过腹腔注射用GJ103(30mg/kg/天)预处理1天。而后进行UIRI手术,步骤如下:用异氟烷来麻醉小鼠。麻醉成功后,在37℃恒温台上固定小鼠四肢,腹部向上。消毒腹部,用眼科剪小心打开并暴露小鼠腹腔,游离左侧的肾蒂,采用无创动脉夹进行夹闭,肾脏由鲜红色逐步转变成暗红色表明夹闭成功,小鼠腹部需要覆盖温热的生理盐水湿纱布。32min后解除夹闭。左肾由暗红色逐渐转变为鲜红色时表明肾恢复血液再灌注。腹腔脏器归位,注射1mL温热的生理盐水补充流失体液。关闭小鼠腹腔,缝合小鼠的腹膜肌层和皮肤。对照组只需要打开小鼠腹腔,缝合小鼠腹部。手术完毕后,在SPF级动物房接着喂养小鼠,术后每天需要监测小鼠身体情况。在随后14天连续用GJ103(30mg/kg/天)进行治疗。UIRI术后2周,给予小鼠安乐死,抽取心脏血液并留取肾组织。余下步骤同上。
组织学分析:在4%多聚甲醛中固定肾组织大于24小时,脱水包埋。石蜡切片(3μm)经脱蜡水化后,用马松三色染色和天狼星红染色来显示胶原纤维。使用Image Pro Plus软件分析纤维化面积与总面积。
免疫组化染色:石蜡切片(3μm)经脱蜡、二甲苯及梯度乙醇水化后,3%过氧化氢孵育20分钟,而后在柠檬酸盐抗原提取液中煮沸20分钟。用免疫染色阻断液封闭1h后和一抗在4℃下孵育过夜。DAB进行显色反应,苏木素复染细胞核。使用Image Pro Plus进行图像分析和定量。
细胞培养:NRK-49F细胞在添加10% FBS的DMEM培养基中贴壁生长,置于37℃、5%CO2的细胞培养箱中。用0.25%胰蛋白酶在70-80%的融合度下传代培养细胞。在特定实验中,细胞用GJ103预处理2小时或用Ptprj质粒转染6小时,然后用TGF-β1刺激。24小时后收集细胞进行mRNA分析或48小时后收集细胞进行蛋白质分析。
EdU染色:用EdU工作液(10μM)在6孔板上培养NRK-49F,培养2小时。取出培养液,加入固定液1ml,室温固定15min。再加入渗透性溶液1ml,室温孵育10min。最后每孔加入Click反应液0.5ml,室温避光孵育30min。细胞核用DAPI染色。
细胞增殖和细胞毒性测定:将NRK-49F细胞接种在96孔板中,并用不同浓度的GJ103(0-40nM)处理。培养24小时后,向每个孔中添加10μl CCK-8试剂,并孵育2小时。用微孔板读取器测量450nm处的吸光度。
实时定量PCR:使用RNA isoPlus试剂从组织或细胞中提取总RNA。用HiScript IIQ RT SuperMix进行qPCR反转录。采用AceQ qPCR SYBR Green Master Mix,在LightCycler96仪器实时PCR检测系统上进行实时PCR扩增。使用GAPDH作为内参,使用ΔΔCt法计算相对值。
Western blotting(WB):用含有1×Protease抑制剂和1×Phosphatase抑制剂的RIPA缓冲液裂解组织或细胞。将样品以5000rpm离心30min。使用BCA蛋白检测试剂盒测定蛋白浓度。在10%聚丙烯酰胺凝胶上等质量点样,将凝胶转移到PVDF膜上。用5%脱脂奶粉封闭PVDF膜1小时,然后与FN1(1:1000)、I型胶原(1:000)、III型胶原(1:1000)和GAPDH(1:10000)抗体孵育过夜。使用Amersham Biosciences ECL检测系统对条带进行可视化。用Image J进行灰度值相对定量分析。
免疫荧光染色:将NRK-49F细胞培养在玻璃底细胞培养皿(NEST,中国)上,用Apcin(50nm)预处理0.5小时,然后用重组人TGF-β1(10ng/ml)处理。然后,在用PBS多次洗涤后,将细胞在室温下用4%多聚甲醛固定20分钟,用PBS广泛洗涤,用PBS+1%Triton X-100渗透10分钟,用2%BSA封闭1小时。将一抗α-SMA以1:100稀释度加入培养皿中,同时加入细胞骨架蛋白染料鬼笔环肽(phalloidin)并在4℃的潮湿室内培养过夜;在用PBST洗涤后施用二级抗体。然后,在激光共聚焦扫描显微镜(蔡司)下观察细胞,拍照并记录。
SPR:采用BIAcore T200 SPR生物传感器系统和NTA传感器芯片(Cytiva)检测GJ103与Ptprj的结合亲和力。首先将纯化蛋白Ptprj稀释至20μg/mL,此时Ptprj和芯片偶联达到最适程度。其次,检测GJ103和Ptprj结合与解离效率。GJ103设定为7个分析浓度:0μM、3.125μM、6.25μM、12.5μM、25μM、50μM和100μM。流速设定为30μL/min。结合时间为120s,解离时间为120s。最后,确定动态参数。实验分多个循环进行,所得数据采用BIAcore T200分析软件进行拟合。
体外PDGFRβ去磷酸化:NRK49F细胞在融合至70%时用TGF-β1(10ng/ml)刺激。24h后,用预冷的PBS洗涤细胞2次。细胞经裂解离心后与PDGFRβ抗体和磁珠在4℃下翻转过夜。收集磁珠上的免疫复合物,用洗涤缓冲液冲洗四次。将固定在磁珠上的PDGFRβ免疫复合物均分至40μl缓冲液中,与纯化蛋白Ptprj、GJ103和AS252424在30℃下孵育30分钟。体积总量为60μl。随后加入SDS缓冲液终止去磷酸化,并进行Western印迹分析。
统计分析:应用Graphpad6.0统计学软件对所有实验数据进行统计学分析,实验数据采用均数±均数标准误(SEM)表示,两组之间的实验比较用双尾t检验,多组数据之间的比较用单因素方差分析。P<0.05,则具有统计学差异。
实施例1Ptprj与CKD肾脏纤维化发生发展的时空表达关系。
利用临床CKD患者的肾组织标本,免疫组化结果显示:与正常人肾组织相比,发现Ptprj在CKD患者肾组织中的表达显著上调,主要增加在肾小管及间质(图1中a和b)。进一步我们通过免疫荧光共定位发现,Fsp1(间质成纤维细胞标志物)和Ptprj双染色证实了间质中Ptprj表达增加(图1中c)。以上结果表明:Ptprj可能参与了CKD的进展过程。
实施例2过表达Ptprj抑制TGF-β1诱导的肾脏成纤维细胞活化。
我们在大鼠成纤维细胞(NRK-49F)中过表达Ptprj进行验证,EdU染色结果显示:过表达Ptprj显著抑制TGF-β1诱导的成纤维细胞的增殖和活化(图2a)。WB和qRT-PCR表明:PAI1、FN1、Vimentin的蛋白水平(图2b和c)、纤维化相关分子Collagen I、Collagen III的mRNA水平(图2d和e)也明显下调,免疫荧光亦显示α-SMA蛋白水平显著降低(图2f)。体外实验初步表明,Ptprj在CKD肾纤维化的进程中发挥一定的保护作用。
实施例3下调Ptprj加重UUO诱导的细胞外基质沉积和成纤维细胞活化。
肾脏纤维化是CKD的最终共同途径和组织学表现,其典型特征在于细胞外基质过度沉积,导致组织重塑和肾实质瘢痕形成。大量研究结果表明:肾小管间质成纤维细胞增殖与活化诱发的一系列信号传递是启动和推进肾脏纤维化的主要因素。为了进一步阐明Ptprj在肾脏纤维化中的作用,我们繁育了Ptprj杂合子敲除(Ptprj+/-)小鼠,构建UUO模型。Masson染色和天狼星红染色显示:与WT组相比,Ptprj+/-小鼠进一步加重UUO诱导的肾组织病理损害,胶原纤维沉积明显增加(图3a-c)。qRT-PCR分析显示,Ptprj敲低可上调FN1的表达(图3e),WB检测FN1、Collagen I和Collagen II的蛋白表达水平也明显增加(图3f和g)。在UUO小鼠中,Ptprj敲低后,以α-SMA高度表达为特征的成纤维细胞的增殖和活化能力也随之升高(图3h-j)。同样我们发现:与对照组相比,Ptprj敲低使纤维化病变的肾脏中PDGFRβ磷酸化水平升高(图3f&g),这表明Ptprj可能通过PDGFRβ调节肾脏纤维化。
实施例4Ptprj小分子激动剂筛选。
上述数据提示我们靶向Ptprj在CKD分子干预机制中具有治疗潜力。因此,我们通过分子对接筛选有效的Ptprj激活剂,并通过检测Ptprj对PDGFRβ的去磷酸化活性进一步筛选对接得分较高的小分子激动剂。首先用10个小分子化合物刺激NRK49F细胞后,我们发现AS252424和GJ103显著抑制了PDGFRβ的磷酸化水平(图4a),与TGF-β1共同刺激后,也明显促进了PDGFRβ的去磷酸化(图4b&c)。接着通过体外对PDGFRβ去磷酸化,我们发现GJ103能更好地激活Ptprj(图4d)。2D和3D图所示的结合模型可知,GJ103可以与GLY1244和VAL1243形成两个常规氢键,与ARG1245形成一个盐桥,以及一个Pi-阳离子和一个Pi-Pi堆积(图4e&f)。最后利用表面等离子体共振(SPR)定量分析发现:GJ103与Ptprj重组蛋白具有较高的亲和力,结合亲和度(KD值)为6.399μM(图4g)。在NRK49F细胞中进一步验证GJ103对Ptprj的影响。在不同浓度GJ103的刺激下,Ptprj的表达水平基本保持不变(图4h&i)。
实施例5GJ103治疗抑制TGF-β1诱导的肾脏成纤维细胞活化。
GJ103是一种通读化合物,可以诱导过早终止密码子的通读,在无义突变引起的遗传病中具有研究潜力。目前,GJ103在肾脏疾病中的作用尚未报道。我们发现不同浓度的GJ103对细胞活力影响不大(图5a)。随后,我们评价了GJ103在体外实验的保护作用。分别用5、10、20、40μM不同浓度的GJ103预处理NRK49F细胞2h,然后用TGF-β1刺激NRK49F细胞。我们发现:当GJ103浓度高于20μM时,PDGFRβ的磷酸化水平被显著抑制(图5b&c)。随着p-PDGFRβ表达的降低,纤维化标志物FN1的蛋白表达水平也被抑制(图5d&e)。
实施例6GJ103治疗减轻UUO诱导的的细胞外基质沉积和成纤维细胞活化。
在动物模型中深入验证GJ103的保护作用,我们制备了经典的肾脏纤维化UUO模型。C57BL/6J小鼠在UUO术前分别给予GJ103 15mg/kg/d和30mg/kg/d预处理。然后连续7天每天给药。检测血清中BUN、Scr、AST、ALT、CK-MB和LDH的含量,结果显示治疗剂量的GJ103不会引起显著的肾、肝、心或全身毒性(图6a-g)。马松染色和天狼星红染色显示:GJ103刺激下,特别是高浓度,显著减轻了UUO引起的肾间质纤维化(图6h-j)。同样,FN1、Collagen I、Collagen III和α-SMA的mRNA(图k-n)和蛋白(图6o)的表达也减少,尤其是在高剂量组。
实施例7GJ103治疗抑制UIRI诱导的细胞外基质沉积和成纤维细胞活化。
我们还检测了GJ103在UIRI模型中的作用,与UUO模型结果一致,治疗剂量的GJ103没有引起明显的肾、肝、心或全身毒性(图7a-f)。同样,高剂量GJ103(30mg/kg/day)也明显改善了UIRI诱导的肾组织病理损害(图7g&h),减少了细胞外基质沉积(图7i&j)和成纤维细胞活化标志物α-SMA的表达(图7k&l)。体内外实验双重验证Ptprj激动剂在CKD肾纤维化中发挥一定的保护作用。
以上实验结果表明:Ptprj激动剂GJ103的治疗显著减弱了梗阻或缺血肾组织以及TGF-β1诱导的细胞外基质的沉积和成纤维细胞的激活。综上所述,Ptprj在CKD的发生和进展中发挥重要的作用,为预防和靶向治疗肾脏纤维化提供了新的思路。
Claims (7)
1.Ptprj激动剂在制备预防和/或治疗肾脏纤维化的药物中的应用,其特征在于,所述Ptprj激动剂为GJ103。
2.根据权利要求1所述的应用,其特征在于,所述肾脏纤维化为TGF-β1诱导的成纤维细胞的增殖与活化导致的肾纤维化。
3.根据权利要求1所述的应用,其特征在于,所述肾脏纤维化为单侧输尿管梗阻引起的肾组织病理损害和细胞外基质沉积导致的肾纤维化。
4.根据权利要求1所述的应用,其特征在于,所述肾脏纤维化为单侧缺血再灌注引起的肾组织病理损害和细胞外基质沉积导致的肾纤维化。
5.根据权利要求1所述的应用,其特征在于,所述肾脏纤维化为单侧输尿管梗阻和单侧缺血再灌注诱导的成纤维细胞增殖活化导致的肾纤维化。
6.根据权利要求1所述的应用,其特征在于,所述药物还包括其药学上可接受的盐。
7.根据权利要求1所述的应用,其特征在于,所述药物为GJ103钠盐。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202311750285.6A CN117695278A (zh) | 2023-12-19 | 2023-12-19 | Ptprj激动剂在制备预防和/或治疗肾脏纤维化的药物中的应用 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202311750285.6A CN117695278A (zh) | 2023-12-19 | 2023-12-19 | Ptprj激动剂在制备预防和/或治疗肾脏纤维化的药物中的应用 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN117695278A true CN117695278A (zh) | 2024-03-15 |
Family
ID=90149483
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202311750285.6A Pending CN117695278A (zh) | 2023-12-19 | 2023-12-19 | Ptprj激动剂在制备预防和/或治疗肾脏纤维化的药物中的应用 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN117695278A (zh) |
-
2023
- 2023-12-19 CN CN202311750285.6A patent/CN117695278A/zh active Pending
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Park et al. | Normalization of tumor vessels by Tie2 activation and Ang2 inhibition enhances drug delivery and produces a favorable tumor microenvironment | |
Loureiro et al. | Blocking TGF-β1 protects the peritoneal membrane from dialysate-induced damage | |
US20170198027A1 (en) | Process of afod and afcc and manufacturing and purification processes of proteins | |
Prakash et al. | Inhibition of renal rho kinase attenuates ischemia/reperfusion-induced injury | |
Yang et al. | TWEAK protects cardiomyocyte against apoptosis in a PI3K/AKT pathway dependent manner | |
Herrera et al. | Understanding mesangial pathobiology in AL-Amyloidosis and monoclonal Ig light chain deposition disease | |
CN107106580A (zh) | 治疗癌症干细胞的组合物 | |
CN106063928B (zh) | 一种多肽或其衍生物在治疗高血压性心肌肥厚中的应用 | |
Liu et al. | Galunisertib (LY2157299), a transforming growth factor-β receptor I kinase inhibitor, attenuates acute pancreatitis in rats | |
KR102011105B1 (ko) | 고시폴 및 펜포르민을 유효성분으로 포함하는 췌장암 예방 및 치료용 약학적 조성물 | |
US7468355B2 (en) | Methods for inhibiting cancer and scar formation | |
Matsuki et al. | Inhibition of platelet-derived growth factor pathway suppresses tubulointerstitial injury in renal congestion | |
Xin et al. | Therapeutic silencing of SMOC2 prevents kidney function loss in mouse model of chronic kidney disease | |
CN110511266A (zh) | 一种小分子多肽及其用途 | |
CN117695278A (zh) | Ptprj激动剂在制备预防和/或治疗肾脏纤维化的药物中的应用 | |
US9925238B2 (en) | Use of peptide for treating angiogenesis-related diseases | |
WO2021081580A1 (en) | Treatment of renal cystic disease | |
ES2338400B1 (es) | Conjunto de moleculas antiangiogenicas y su uso. | |
CN110974938A (zh) | 整合素α1β1抑制剂在制备预防或治疗主动脉疾病药物中的应用 | |
Beverborg et al. | Phospholamban antisense oligonucleotides improve cardiac function in murine cardiomyopathy. | |
Zhong et al. | Berberine inhibits NLRP3 inflammasome activation by regulating mTOR/mtROS axis to alleviate diabetic cardiomyopathy | |
US20210179680A1 (en) | Polypeptide, derivatives thereof, and application thereof in preparation of drugs having resistance to pulmonary fibrosis | |
Monogiou Belik et al. | The Flt3-inhibitor quizartinib augments apoptosis and promotes maladaptive remodeling after myocardial infarction in mice | |
KR102057441B1 (ko) | 벤조[d]싸이아졸 유도체 또는 이의 염을 유효성분으로 포함하는 면역세포 이동 관련 질환의 예방 또는 치료용 약학적 조성물 | |
TWI465241B (zh) | 圓柏(Juniperus chinensis)萃取物或木酚素(lignan)用於製造抑制血管新生之藥物的用途 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination |