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Application of inhibitor of histone deacetylase HDAC 6 in preparing drugs for preventing and treating acute kidney injury

A sirtuin and acute kidney injury technology, applied in the field of pharmaceuticals, can solve problems such as molecular expression imbalance, limited clinical application, and cell malignant transformation

Inactive Publication Date: 2017-09-15
SHANGHAI EAST HOSPITAL
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] Since the 1970s, cisplatin has been widely used clinically to treat a variety of malignant tumors, including testicular cancer, ovarian cancer, bladder cancer, cervical cancer, head and neck cancer, and small cell or non-small cell lung cancer. One of the most effective and commonly used drugs for solid tumors, but severe adverse reactions in normal tissues often limit its clinical application. Adverse reactions of cisplatin include ototoxicity, gastrointestinal toxicity, bone marrow suppression, allergy and renal toxicity, among which renal Toxicity is the most common. After cisplatin treatment, about 1 / 3 of the patients develop renal dysfunction leading to acute renal failure. The dose-related nephrotoxicity greatly limits the clinical application
In the state of cell transformation, the activity of HDACs is significantly enhanced, which breaks the original balance of gene expression, leading to an imbalance in the expression of some molecules that affect cell proliferation and regulation of the cell cycle, which in turn leads to malignant transformation of cells.

Method used

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  • Application of inhibitor of histone deacetylase HDAC 6 in preparing drugs for preventing and treating acute kidney injury
  • Application of inhibitor of histone deacetylase HDAC 6 in preparing drugs for preventing and treating acute kidney injury
  • Application of inhibitor of histone deacetylase HDAC 6 in preparing drugs for preventing and treating acute kidney injury

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] Example 1 Materials and methods

[0026] 1) Materials and reagents

[0027]Inhibitor Tubastatin A was purchased from Selleckchem. Acetyl-Histone H3, HDAC6, Cleavedcaspase 3, p-NF-κB(p65), NF-κB(p65), E-cadherin, Total histone H3, p-Akt, Akt, p-STAT3, STAT3, Atg 7 antibodies Purchased from Cell Signaling Technology Company. IL-6 and TNF-α antibodies were purchased from Santa Cruz Company. NGAL and Kim-1 antibodies were purchased from R&D Company. LC3B / MAP1LC3B was purchased from Novus Biological Company. Fluorescent secondary antibodies were purchased from Invitrogen. MDA and SOD detection kits were purchased from Nanjing Jiancheng Biological Company. Cisplatin, β-actin, secondary antibodies required for Western Blot and other reagents were purchased from Sigma

[0028] 2) Cell culture and treatment

[0029] Human renal tubular epithelial cells (HK2) were cultured in DMEM / F12 medium containing 5% fetal bovine serum, 0.5% penicillin and streptomycin, and the cultu...

Embodiment 2

[0044] Example 2 HDAC6 Inhibitor Improves Renal Injury and Renal Function in Cisplatin-Induced Acute Kidney Injury Model

[0045] To examine the mechanism of action of HDAC6 in acute kidney injury, we injected 70 mg / kg of HDAC6-specific inhibitor TA in a cisplatin-induced acute kidney injury model in mice. After 48 hours of cisplatin modeling, serum creatinine and blood urea nitrogen indexes were significantly increased, and renal pathological damage such as tubule dilation and necrosis was also more serious. After TA treatment, the corresponding renal damage and renal function indexes were significantly decreased ( figure 1 A-C). In addition, the renal tubular injury score also suggested that TA treatment could improve renal pathological damage caused by cisplatin ( figure 1 D). Therefore, TA, an inhibitor of HDAC6, can not only improve renal function, but also reduce renal pathological damage. These results suggest that HDAC6 inhibitor TA can protect kidney damage caused ...

Embodiment 3

[0046] Example 3 In the cisplatin-induced acute kidney injury model, TA specifically inhibited the expression of HDAC6 in the kidney.

[0047] In order to prove the specific inhibitory effect of TA on HDAC6, we detected the expression and expression site of HDAC6 in each group of acute kidney injury model plus inhibitor TA. The results of immunofluorescence and western blot showed that the expression of HDAC6 was very low or not expressed in the normal mouse kidney, and the expression of HDAC6 was significantly increased in the cisplatin-induced acute kidney injury model, and its high expression was observed after TA treatment. levels are suppressed ( figure 2 A-D). figure 2 C column graph data show that in the acute kidney injury model, TA can inhibit nearly 70% of HDAC6 expression. In addition, we also observed in immunofluorescence that HDAC6 was mainly expressed on dilated renal tubules ( figure 2 A). These results suggest that TA specifically inhibits HDAC6 express...

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Abstract

The invention provides an application of inhibitor of histone deacetylase HDAC 6 in preparing drugs for preventing and treating acute kidney injury. Furthermore, the histone deacetylase HDAC 6 is Tubastatin A. The selective inhibitor of HDAC 6 can lighten the renal pathology damage of acute kidney injury induced by cis-platinum and improve the kidney function. The HDAC6 inhibitor TA can lower the release of inflammatory factors and lighten the oxidative stress reaction through regulating an AKT signal access, an NF-KB inflammation access, an autophagy level and an E-cadherin expression; thus the apoptosis of kidney tubule cell and necrosis of tubule expansion are reduced, the renal pathology damage and kidney function are improved; the inhibitor can protect the kidney structure and function in the acute kidney injury. Therefore, HDAC6 is likely to be an important target point to prevent and treat the acute kidney injury.

Description

technical field [0001] The invention belongs to the field of pharmacy, and relates to a histone deacetylase HDAC6, in particular to the use of an inhibitor of the histone deacetylase HDAC6 in the preparation of medicines for preventing and treating acute kidney injury. Background technique [0002] Acute kidney injury (acute kidney injury, AKI) is a common clinical syndrome, mainly manifested as a rapid decline in renal function and accumulation of metabolic waste, its diagnosis depends on the increase of serum creatinine (Scr) and urine decrease in volume. The concept of AKI is proposed to replace the acute renal failure (ARF) that has been used for many years. The incidence of AKI is high, and it is increasing year by year. It is very common in hospitalized patients, especially severe patients, and the mortality rate of severe AKI patients is high. Recent epidemiological data show that even mild and reversible AKI can cause lasting damage to kidney tissue, and severe AKI...

Claims

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Application Information

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IPC IPC(8): A61K45/06A61K31/437A61P13/12
CPCA61K45/06A61K31/437
Inventor 刘娜庄守纲施映枫徐柳青陶敏汤锦花
Owner SHANGHAI EAST HOSPITAL
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