CN107158390A - Purposes of the histon deacetylase (HDAC) HDAC6 inhibitor in preventing and treating acute injury of kidney medicine is prepared - Google Patents
Purposes of the histon deacetylase (HDAC) HDAC6 inhibitor in preventing and treating acute injury of kidney medicine is prepared Download PDFInfo
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Abstract
The invention provides a kind of purposes of histon deacetylase (HDAC) HDAC6 inhibitor in preventing and treating acute injury of kidney medicine is prepared.Further, described histon deacetylase (HDAC) HDAC6 is Tubastatin A.The HDAC6 of present invention selective depressant can mitigate the acute injury of kidney Pathological infringement of cisplatin induction, improve renal function.HDAC6 inhibitor TA can lower the release of inflammatory factor by regulating and controlling AKT signal paths, NF κ B Inflammatory Pathways, autophagy level and E cadherin expression; mitigate response to oxidative stress; so as to reduce apoptosis and the tubule dilatation necrosis of renal tubular cell; improve Pathological damage and renal function, play a part of kidney structure and function in protection acute injury of kidney.Therefore, HDAC6 is likely to become the important target spot of preventing and treating acute injury of kidney.
Description
Technical field
The invention belongs to field of pharmacology, it is related to a kind of histon deacetylase (HDAC) HDAC6, specifically a kind of group egg
Purposes of the white deacetylase HDAC6 inhibitor in preventing and treating acute injury of kidney medicine is prepared.
Background technology
Acute injury of kidney (acute kidney injury, AKI) is a kind of common clinical syndrome, is mainly shown as
The accumulation of the rapid decrease and metabolic waste of renal function, its diagnosis depends on serum creatinine (serum creatinine, Scr)
Rise and the reduction of urine volume.The proposition of AKI concepts is used to replace acute renal failure (the acute renal using for many years
failure,ARF).The AKI incidence of disease is high, and in ascendant trend year by year, it is very normal in inpatient especially patient with severe symptoms
See, severe AKI patient case fatality rate is high.Nearest epidemiologic data shows：Even slight, reversible AKI will also result in
The lasting damage of renal tissue, serious AKI causes the irreversible decline of renal function, increases dead risk.It there is no and control at present
AKI specific medicament is treated, renal replacement therapies need to be carried out when serious.AKI patient evolutions turn into the risk of CKD significantly
Increase, has some patientss directly to proceed to ESRD.If identification in time, removal hazards or active intervention, are permitted
Many AKI renal function can recover completely or partially, and depart from dialysis, therefore, and early diagnosis, early intervention are to improve AKI prognosis
Key.
Since 1970s, cis-platinum is widely used in treatment Several Kinds of Malignancy, including carcinoma of testis, ovary by clinic
Cancer, carcinoma of urinary bladder, cervical carcinoma, head-neck malignant tumor and cellule or non-small cell lung cancer etc., are that treatment entity tumor most has
One of effect and conventional medicine, but serious adverse reaction in the normal tissue often limits its clinical practice, cis-platinum adverse reaction
There are ototoxicity, gastrointestinal toxicity, bone marrow suppression, allergy and renal toxicity, wherein renal toxicity is most common, after plus cisplatin in treatment, about
Renal dysfunction, which occurs, in 1/3 patient causes acute renal failure, and its dose-dependent renal toxicity greatly limit clinical practice.At present
Cis-platinum causes injury of kidney mechanism completely clear and definite not yet, and research in recent years finds inflammatory mediator, necrosis, apoptosis, oxidative stress, autophagy etc.
Acute injury of kidney reason may be caused for cis-platinum.
The inflammatory reaction of cis-platinum triggering can cause Renal tissues damage and dysfunction, acute injury of kidney occur.Research in recent years
Show, various inflammation gene expressions include tumor necrosis factor α (tumor necrosis factor, TNF-α), Toll-like receptor 4,
Interleukin-18, interleukin-6, interleukin-1 beta, Intercellular surface adhesion molecule-1 (intercellular adhesion
Molecule-1, ICAM-1) expression cis-platinum cause acute injury of kidney in have increase.Nuclear factor kappa B is quilt in cis-platinum injury of kidney
The transcription factor of TNF-α activation, its activation causes many cell factors, chemotactic factor (CF), intercellular adhesion molecule and kidney trouble
The expression of associated receptor, cisplatin-induced nephrotoxicity can be weakened by suppressing Nuclear factor kappa B indirectly.
Cisplatin-induced nephrotoxicity causes renal tissue morphological change to be mainly shown as that renal cells is dead, including cell
Necrosis and two kinds of forms of apoptosis.The research for being related to cisplatin-induced nephrotoxicity mechanism recently focuses on the apoptosis of renal cells,
Have confirmed has the participation of some apoptosis pathway in cis-platinum causes injury of proximal cells, including is activated by death receptor
Extrinsic pathway, such as Tumor Necrosis Factor Receptors or Fas approach, intrinsic mitochondrial pathway and er stress approach.
Baliga in 1999 etc. has confirmed that oxidative stress is one of important mechanisms of cisplatin-induced nephrotoxicity, reactive oxygen species (reactive
Oxygen species, ROS) have following three kinds of mechanism, including membrane lipid peroxidatio and cellular antioxidant exhaust,
Mitochondria dysfunction and cytochrome p450 system.Autophagy is the distinctive universal biological phenomena of eukaryotic, is remaining thin
Born of the same parents self stable state, promote to play an important role in terms of cells survival, a variety of physiology of wide participation and pathologic process.In the recent period,
Takahashi and Kaushal etc. research shows, autophagy can take precautions against acute injury of kidney and proximal tubule caused by cis-platinum and wither
Die, it is believed that autophagy has protective effect to kidney damage caused by acute injury of kidney.
Epigenetics (epigenetics) is not to be related to heritable changes in gene expression research of DNA sequence dna change,
Its it is all it is multi-form in, the covalent modification of histone occupies critical role, its expression regulation close association with gene, including phosphorus
Acidifying, acetylation, methylate modification etc..It is most important mode that acetylation of histone and deacetylation, which are modified, is gene expression
Regulate and control topmost driving force, this reversible dynamic embellishment is by histone acetyltransferases (HAT) and DNA methylase inhibitor
Enzyme (histone deacetylases, HDACs) co-catalysis, the acetylation of each region core histones of co- controlling chromatin
Degree.The degree of acetylation of histone and transcriptional activity are closely related：The acetylation density of transcription activity region core histones
Height is low without zone of action acetylation density.HAT promotes the depolymerization of chromosome, activated transcription；And HDACs then closes DNA, enter
And suppress transcription.
Under normal physiological condition, the regulation and control that HAT and HDACs is acted on acetylation of histone are in poised state.And it is thin
Born of the same parents are in the state of converting, and HDACs activity is remarkably reinforced so that original gene expression poised state is broken, and is led
Cause some to influence the developed by molecule of cell propagation and cell cycle regulation unbalance, and then cause malignant change of cell.HDACs turns into apparent
The important and potentiality target spot of various clinical disease is treated in science of heredity.
HDAC families are very huge, at present, and existing 18 kinds are separated, homologous with yeast HDAC albumen according to them
Property and size, in cell Present site and comprising catalytic site be divided into four major classes：8) and yeast I types (HDAC1,2,3 and
RPD3 is the most similar, has common catalytic site, is entirely located in nucleus；(9) HDAC4 5,7 and has with HDAC1 IIa types
Common catalytic site, there is presence in nucleus and cytoplasm, and IIb types (HDAC6 and 10) have two catalytic sites,
It is mainly distributed in cytoplasm；IV types are individually composed by HDAC11, and it has I types and II types HDAC two catalytic sites.
The HDAC6 assignments of genes gene mapping are in X chromosome p11.22-23 zone, about 21923bp, by 28 between 41~677bp
Exons coding.For protein structure, HDAC6 contains 1216 amino acid, is the albumen for the human maximum having now been found that
Matter.HDAC6 high expression in the internal organs such as the heart, liver, kidney, brain, pancreas, is a kind of endocellular enzyme, with ubiquitin binding function and goes second
Acylase activity, it interacts with substrate (alpha-tubulin, HSP90 and cortactin) and is allowed to deacetylation.By this
A little interactions, HDAC6 adjusts many important bioprocess, including cell migration, microtubule stability, transmitter loss, immune
The degraded of Synaptic formation and misfolded protein.Research is thought at present, HDAC6 and tumour, nerve degenerative diseases, itself exempts from
The generation of epidemic disease disease, peritoneal fibrosiss and acute injury of kidney has certain association.
The content of the invention
For technical problem present in prior art, the invention provides a kind of histon deacetylase (HDAC) HDAC6's
Purposes of the inhibitor in preventing and treating acute injury of kidney medicine is prepared, described this histon deacetylase (HDAC) HDAC6 suppression
Agent prepare preventing and treating acute injury of kidney medicine in purposes solve in the prior art without suitable medicine be used for treat due to
The technical problem that kidney structure and function caused by acute injury of kidney is damaged.
Preventing and treating acute injury of kidney medicine is being prepared the invention provides a kind of histon deacetylase (HDAC) HDAC6 inhibitor
In purposes.
Further, described histon deacetylase (HDAC) HDAC6 inhibitor is Tubastatin A.
We use HDAC6 selective depressant Tubastatin A on the acute injury of kidney mouse model of cisplatin induction
(TA) protective effects and its mechanism of the targeted inhibition HDAC6 to acute injury of kidney are inquired into,.As a result find, to cisplatin induction
Acute injury of kidney mouse model carries out therapeutic intervention using HDAC6 inhibitor TA, can significantly mitigate acute renal injury in mice kidney
Pathological lesion, improves renal function.HDAC6 inhibitor TA can be by regulating and controlling AKT signal paths, NF- κ B Inflammatory Pathways, autophagy level
And the release of inflammatory factor is lowered in E-cadherin expression, mitigates response to oxidative stress, so as to reduce renal tubular cell
Apoptosis and tubule dilatation necrosis, improve Pathological damage and renal function, play protection acute injury of kidney in Renal Structure and
The effect of function.Therefore, HDAC6 can turn into the important target spot for clinically preventing and treating acute injury of kidney.
Brief description of the drawings
Fig. 1 shows that HDAC6 inhibitor can improve the kidney injury and renal function in cisplatin induction acute injury of kidney model.
Fig. 2 shows that in the acute injury of kidney model of cisplatin induction TA specificity suppresses the expression of HDAC6 in kidney.
Fig. 3 shows that TA significantly raises acetylated protein H3 and Acetyl α-tubulin levels in acute injury of kidney model.
Fig. 4 shows that HDAC6 inhibitor lowers NGAL and Kim-1 expressions in acute injury of kidney model.
Fig. 5 shows that HDAC6 inhibitor TA improves rat tubular cell apoptosis water caused by the acute injury of kidney of cisplatin induction
It is flat.
Fig. 6 shows protective effect and mechanism of the HDAC6 inhibitor in people's renal cells of cisplatin treated.
Fig. 7 shows that suppression HDAC6 can raise AKT phosphorylation levels and E-cadherin expression quantity.
Fig. 8 shows that in the acute injury of kidney model of cisplatin induction TA can raise kidney autophagy level.
Fig. 9 shows that TA lowers oxidative stress in acute injury of kidney.
Figure 10 shows that TA can block in the acute injury of kidney of cisplatin induction NF- κ B paths and suppress inflammatory factor IL-6's
Expression.
Figure 11 shown in the acute injury of kidney model of cisplatin induction, HDAC6 inhibitor significantly lower renal inflammation because
Sub- TNF-α expression.
Embodiment
The material of embodiment 1 and method
1) material and reagent
Inhibitor Tubastatin A are purchased from Selleckchem companies.Acetyl-Histone H3, HDAC6, Cleaved
Caspase 3, p-NF- κ B (p65), NF- κ B (p65), E-cadherin, Total histone H3, p-Akt, Akt, p-
The antibody of STAT3, STAT3, Atg 7 is purchased from Cell Signaling Technology companies.IL-6 and TNF-α antibody are purchased from
Santa Cruz companies.NGAL and Kim-1 antibody is purchased from R＆D companies.It is public that LC3B/MAP1LC3B is purchased from Novus Biological
Department.Fluorescence secondary antibody is purchased from Invitrogen companies.MDA and SOD detection kits are purchased from Nanjing and build up biotech firm.Cis-platinum, β-
Secondary antibody needed for actin, Western Blot and other reagents are purchased from Sigma companies
2) cell culture and processing
People's renal cells (HK2) is with containing 5% hyclone, the DMEM/F12 trainings of 0.5% penicillin and streptomysin
Base culture is supported, condition of culture is 37 DEG C, 5% carbon dioxide and 95% air.It is to study TA for kidney injury caused by cis-platinum
Mechanism of action, HK2 cells after hungry 24 hours, are added final concentration by us in the F12 culture mediums containing 0.5% hyclone
The cell death induced for 20ug/ml cis-platinum simulation acute injury of kidney, while adding the TA of 0 μM, 5 μM, 10 μM three concentration
Carry out intervention 24h.Finally collect cell and carry out Western Blot detections.
3) acute injury of kidney model and experiment packet
Mouse is randomly divided into four groups, every group 6.DMSO is injected intraperitoneally in Sham blank control groups；Sham+TA groups are injected intraperitoneally
70mg/kg TA, is dissolved in 50ul DMSO；The cis-platinum of 20mg/kg dosage is injected intraperitoneally in model group, is dissolved in 0.9% physiology salt
In water, acute renal injury in mice model is set up；Model dosing group injects TA inhibitor (70mg/ immediately again after cis-platinum injections
kg).Mouse is put to death after 48 hours, kidney sample and blood preparation is collected.Chinese experimental animal pipe is observed in all zooperies
Manage and use regulations.
4) renal function is detected
Mouse blood sample is examined through collected after centrifugation serum composition on full automatic biochemical apparatus (P800, Modular, USA)
Survey serum creatinine and serum urea nitrogen index.
5) oxidative stress Indexs measure
After injection cis-platinum modeling 48h, mouse kidney sample is collected, is ground to after albumen homogenate, with MDA and SOD reagents
Box detects mouse kidney MDA and SOD index content
6) Tubular damage scores
Tubular damage degree is observed in kidney PAS pathological stainings, and tubule is carried out according to sxemiquantitative damage score criteria
Lesion assessment, normal body tubular tissue be 0 point, renal damage degree be less than 30% for 1 point, renal damage degree exists
Between 30%-60% for 2 points, be 3 points more than 60%.
7) histology and immunofluorescence dyeing
Renal tissue is fixed through paraformaldehyde, histology and immunofluorescence dyeing are carried out after FFPE, histotomy.
The primary antibody concentration such as HDAC6, Acetyl-Histone H3, NGAL, Kim-1 are 1：100, fluorescence secondary antibody concentration is 1：200.
DAPI dyeing is carried out according to operating instruction.
8) protein immunoblotting
Peritoneal tissues extract albumen, are operated according to literature method.Protein immunoblotting (Western blot) result is used
ImageJ softwares carry out gray analysis.
9) statistical analysis
Data are represented using mean value ± SEM.Multigroup is compared data ratio between use one-way analysis of variance (ANOVA), two groups
Examined compared with T.With P<0.05 is with statistical significance.
The HDAC6 inhibitor of embodiment 2 improves the kidney injury and renal function in cisplatin induction acute injury of kidney model
In order to detect mechanism of action of the HDAC6 in acute injury of kidney, our acute renal injury in mice in cisplatin induction
70mg/kg HDAC6 specific inhibitors TA has been injected in model.After cis-platinum modeling 48 hours, serum creatinine and urea nitrogen refer to
Mark is significantly raised, and the Pathological such as tubule dilatation necrosis impaired performance is also more serious, and after TA treatments, its corresponding kidney is damaged
Wound and renal function index are all remarkably decreased (Figure 1A-C).Draw in addition, renal damage scoring also points out TA treatments to improve cis-platinum
The Pathological damage (Fig. 1 D) risen.Therefore, HDAC6 inhibitor TA can not only improve renal function, moreover it is possible to mitigate kidney trouble
Reason damage.These results show that HDAC6 inhibitor TA can protect kidney damage caused by acute injury of kidney.
Embodiment 3 is in the acute injury of kidney model of cisplatin induction, and TA specificity suppresses the expression of HDAC6 in kidney.
To prove TA for HDAC6 specific inhibition, we have detected acute injury of kidney model inhibiting TA
HDAC6 expression and expressive site in each packet.Immunofluorescence and immunoblot results are shown, in normal mouse kidney
In, HDAC6 expression is very low or does not express, and in the acute injury of kidney model of cisplatin induction, HDAC6 expression is significantly raised,
And use after TA treatments, its high expression level is suppressed (Fig. 2A-D).Fig. 2 C column diagrams as shown by data is in acute injury of kidney model
In, TA can suppress nearly 70% HDAC6 expression.In addition, we observe that HDAC6 is mainly expressed in expansion also in immunofluorescence
Renal tubule on (Fig. 2A).These results are pointed out, in the acute injury of kidney model of cisplatin induction, and TA specificity suppresses in kidney
HDAC6 expression.
The TA of embodiment 4 significantly raises acetylated protein H3 and Acetyl α-tubulin levels in acute injury of kidney model.
In order to inquire into influences of the HDAC6 inhibitor TA for acetylation of histone level, we have detected different realities
Test acetylated protein H3 and Acetyl α-tubulin levels in packet.As shown in figures 3 a-c, Acetyl-H3 and Acetyl α-
Tubulin levels express all relatively low in normal kidney, after HDAC6 inhibitor TA, Acetyl-H3 and Acetyl α-
Tubulin levels have notable rise.The difference is that Acetyl-H3 levels are higher than in the acute injury of kidney model group of cisplatin induction
Normal group, and Acetyl α-tubulin levels are less than normal kidney expression in acute injury of kidney.Immunofluorescence results
Prompting, Acetyl-H3 is hardly expressed in normal kidney tissue, and rise is expressed in the renal tissue of acute injury of kidney, and
After being treated using TA, its expression is significantly raised, and Acetyl-H3 positive cells mainly express on renal tubular cell (figure
3D).These results are pointed out, and TA significantly raises acetylated protein H3 and Acetyl α-tubulin levels in acute injury of kidney model.
The HDAC6 inhibitor of embodiment 5 lowers NGAL and Kim-1 expressions in acute injury of kidney model.
In order to prove that HDAC6 inhibitor TA has protective effect for the acute injury of kidney of cisplatin induction, we have detected
The earlier specificity Biological indicators of two kidney injuries, NGAL and Kim-1.Immunoblot results such as Fig. 4 A and 4C are pointed out, early
Phase, kidney injury index NGAL and Kim-1 was not expressed in normal kidney, the high expression in the kidney of acute injury of kidney mouse, and
Used after inhibitor TA, its expression is remarkably decreased again, illustrate HDAC6 inhibitor TA in acute injury of kidney model for
Renal tissue has certain protective effect.Similar result also has embodiment in the Immunofluorescence test of NGAL indexs, and TA shows
Write the expression (Fig. 4 B and 4D) for lowering NGAL.The earlier specificity Biological indicators situation of comprehensive two kidney injuries, we
Think that HDAC6 inhibitor TA has certain protective effect in acute injury of kidney model for renal tissue.
The HDAC6 inhibitor TA of embodiment 6 improves rat tubular cell apoptosis water caused by the acute injury of kidney of cisplatin induction
It is flat.
Apoptosis is one of essential step in acute injury of kidney generating process, therefore we pass through apoptosis
TUNEL fluorescent stainings and the levels of Western blotting Cleaved caspase 3 detect the acute injury of kidney model in cisplatin induction
And in HDAC6 inhibitor for treating level of apoptosis situation of change.TUNEL fluorescent stainings result is pointed out, and positive apoptosis cells exist
Do not expressed in normal kidney tissue, the high expression in acute injury of kidney kidney, and after TA treatments, its positive cell number is remarkably decreased again
(Fig. 5 A and 5C).In Cleaved caspase 3 immunoblot results, it has been found that in injury of kidney group, TA treatments can
Lower the expressions (Fig. 5 B and 5D) of Cleaved caspase 3.To sum up, it is believed that HDAC6 inhibitor TA can improve cis-platinum
Rat tubular cell apoptosis level caused by the acute injury of kidney of induction.
Protective effect and mechanism of the HDAC6 inhibitor of embodiment 7 in people's renal cells of cisplatin treated.
In order to further verify protective effect and its mechanism of the HDAC6 inhibitor for the acute injury of kidney of cisplatin induction,
We simulate the cell damaging conditions in acute injury of kidney with cisplatin treated people renal cells (HK2).Nature enemy
The cis-platinum that rear HK2 cells add 20ug/ml carrys out analog cell damaging conditions, at the same we used three concentration gradients (0,
5,10 μM) TA observe its action effect, agent-feeding treatment collects cell and does immune-blotting method after 24 hours.Such as Fig. 6 (A-H)
Shown, in the HK2 cells of cisplatin treated, TA can suppress HDAC6 expression, raise Acetyl-H3 and Acetyl α-tubulin water
It is flat.In terms of mechanism, it is observed that HDAC6 inhibitor TA can play protection renal work by raising E-cadherin levels
With.It is same in terms of Apoptosis, we have detected the levels of Cleaved caspase 3, as a result find that TA treatments can be lowered
The level of apoptosis of HK2 cells caused by cis-platinum, and in dose dependent.The cell experiment of this part is as a result, it was confirmed that HDAC6 suppresses
Agent has a certain protective role for people's renal cells of cisplatin treated, and may by raise E-cadherin levels come
Play its protection renal mechanism.
Embodiment 8, which suppresses HDAC6, can raise AKT phosphorylation levels and E-cadherin expression quantity.
Studies have found that AKT is an important signal path during mediation renal tubular cell Proliferation, Differentiation, therefore
In research, we have detected influence situations of the inhibitor TA for AKT paths in acute injury of kidney model.Immunoblot results
Prompting is when acute injury of kidney occurs, and phosphorylation AKT levels are higher than normal group, its phosphorylation level after TA is added in model group aobvious
Rise is write, and total protein AKT levels do not change (Fig. 7 A-7C).On the other hand, E-cadherin be a kind of Ca-dependent across
Memebrane protein, is primarily involved in cell and intercellular adhesion, is distributed in each epithelioid cell of humans and animals, is maintaining the pole of cell
Played an important role in terms of property and integrality.In normal mouse kidney, E-cadherin height expression.When injection cis-platinum causes urgency
Property injury of kidney occur when, tubule dilatation, meronecrosis comes off, and E-cadherin expression quantity is substantially lowered.If injection has simultaneously
Have after the TA of protective effect, E-cadherin expressions rise (Fig. 7 D and 7E), the prompting of this result, TA suppresses HDAC6 can
Kidney is shielded by AKT signal paths and E-cadherin mechanism.
Embodiment 9 is in the acute injury of kidney model of cisplatin induction, and TA can raise kidney autophagy level.
Generally believe that autophagy is a kind of defence and stress regulatory mechanism at present.Cell can be by autophagy and lysosome, clearly
Remove, degrade and digest impaired, denaturation, aging and lose the biology such as cell, organelle and denatured protein and nucleic acid of function greatly
Molecule.Necessary raw material is provided for the reconstruction of cell, regeneration and reparation, recycling and the recycling of cell is realized.Previously research is demonstrate,proved
Real autophagy has certain protective role to the tubule cells apoptosis in acute injury of kidney.Therefore, we to have chosen two autophagy special
Property marker protein Atg7 and LC3 come detect acute renal injury in mice model and HDAC6 inhibitor TA in cisplatin induction for
The influence situation of autophagy level.Fig. 8 (A-C) result is pointed out, when injury of kidney occurs, the rise of mouse kidney autophagy level, and is made
After TA therapeutic interventions, its autophagy level significantly rises again, illustrates TA to the protective effect of kidney tubule cells and swashing for autophagy
Work is relevant.
The TA of embodiment 10 lowers oxidative stress in acute injury of kidney.
Oxidative stress refers to body when by various destructive stimuluses, internal high activity molecule such as active oxygen radical
(ROS) produced excessively with active nitrogen free radical (RNS), degree of oxidation exceeds the removing of oxide, oxidative system and anti-oxidant system
System is unbalance, causes neutrophil leucocyte inflammatory infiltration, albumen enzyme secretion increases, so that mediate tissue damage.Superoxide dismutase
(SOD) it is antioxidase important in organism, is the primary material of scavenging activated oxygen.Lipid oxidation end-product MDA
(MDA) it is one of important oxidation product of response to oxidative stress, the oxidative stress of body can be reacted to a certain extent.I
Oxidative stress in different grouping in mouse body is detected using SOD and MDA biotinylation kits respectively.Such as Fig. 9 (A-B)
Shown, compared with control group, kidney SOD levels decline in damage group, the rise of MDA contents.And use TA to carry out after therapeutic intervention,
SOD and MDA indexs have improvement.This result is pointed out, and oxidative stress take part in the pathological process of acute injury of kidney, and HDAC6
Inhibitor can protect renal function by lowering body oxidative stress.
The TA of embodiment 11 can block in the acute injury of kidney of cisplatin induction NF- κ B paths and suppress inflammatory factor IL-6's
Expression.
Inflammatory reaction is one of important mechanism of acute injury of kidney, wherein NF- κ B be regulation cytokine profiles and
The transcription factor of chemotactic factor (CF).Pass through immunoblot results, it has been found that in the acute injury of kidney model of cisplatin induction, phosphorylation
NF- κ B levels are raised, and level of inflammation is significantly lowered (Figure 10 A and 10B) after TA treatments.In inflammatory factor interleukin-6 (IL-
6) in immunohistochemical analysis, it has been found that model group kidney height expression IL-6, and its positive expression region of model dosing group is aobvious
Write and reduce (Figure 10 C and 10D).Therefore, the inflammatory reaction of NF- κ B paths mediation and inflammatory factor infiltration can aggravate cisplatin induction
Kidney injury degree, and TA can suppress NF- κ B phosphorylations and inflammatory Cytokines Expression, play a part of protecting kidney.
Embodiment 12 is in the acute injury of kidney model of cisplatin induction, and HDAC6 inhibitor significantly lowers the renal inflammation factor
TNF-α expression.
Tumor necrosis factor α (TNF-α) is to activate a kind of cell factor produced by monocytes/macrophages, in inflammation
Key effect is played in a variety of physiology such as disease reaction, cellular immunity, tumour immunity and pathologic process.Its signal transduction pathway is main
Apoptosis, the transcription factor NF-KB of adaptin TRAF mediations and the JNK protein kinases mediated including caspase families
Activation.In Figure 11 (A-B) TNF-α ImmunohistochemistryResults Results, it has been found that normal mouse kidney hardly expresses TNF-α, and
In the kidney of acute injury of kidney mouse, TNF-α height expression is added after TA therapeutic interventions, its positive expression region has substantially again
Decline, illustrate in the acute injury of kidney model of cisplatin induction, HDAC6 inhibitor significantly lowers renal inflammation factor TNF-α table
Up to level, TA can protect renal function by suppressing Inflammatory Pathway.
Claims (2)
1. a kind of purposes of histon deacetylase (HDAC) HDAC6 inhibitor in preventing and treating acute injury of kidney medicine is prepared.
2. purposes according to claim 1, it is characterised in that：Described histon deacetylase (HDAC) HDAC6 inhibitor
For Tubastatin A.
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| CN115335079A (en) * | 2020-03-31 | 2022-11-11 | 伊利亚斯生物制品公司 | Use of exosome-based delivery of NF-KB inhibitors |
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| CN104056270A (en) * | 2013-02-21 | 2014-09-24 | 中国人民解放军军事医学科学院野战输血研究所 | Histone deacetylase inhibitor for preparing medicaments for treating multi-organ damage |
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| CN110229215A (en) * | 2018-03-05 | 2019-09-13 | 四川大学华西医院 | A kind of medicament slow release polypeptide hydrogel and its preparation method and application |
| CN110229215B (en) * | 2018-03-05 | 2022-03-18 | 四川大学华西医院 | Drug sustained-release polypeptide hydrogel and preparation method and application thereof |
| CN115335079A (en) * | 2020-03-31 | 2022-11-11 | 伊利亚斯生物制品公司 | Use of exosome-based delivery of NF-KB inhibitors |
| WO2023283648A1 (en) * | 2021-07-08 | 2023-01-12 | Klotho Therapeutics, Inc. | Novel combinatorial antitumor treatment methods and related compositions, kits, and systems |
| CN113456579A (en) * | 2021-07-12 | 2021-10-01 | 南开大学 | Application of nano-micelle-hydrogel preparation of HDAC (Histone-based activator of nucleic acid) inhibitor with double targets in medicine for treating acute kidney injury |
| WO2023174194A1 (en) * | 2022-03-18 | 2023-09-21 | 孙英贤 | Deacetylation-modified septin4 protein and pharmaceutical use thereof |
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