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Application of hypoxia-inducible factor prolyl hydroxylase activity inhibitor in preparation of drug for preventing and treating acute kidney injury

A prolyl hydroxylase activity, hypoxia-inducible factor technology, applied in the field of medicine, can solve the problems of normal tissue adverse reaction limitation, no hypoxia-inducible factor prolyl hydroxylase inhibitor found, etc.

Active Publication Date: 2018-08-24
NANJING CHILDRENS 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 bladder cancer, cervical cancer, head and neck cancer, and small cell or non-small cell lung pain. One of the most effective and commonly used drugs, but its severe adverse effects on normal tissues limit its clinical application
Current research suggests that the acute injury of the kidneys may be protected by inhibiting hypoxia-inducible factor prolyl hydroxylase, but a hypoxia-inducible factor prolyl hydroxylase inhibitor with clinical application prospects has not yet been found

Method used

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  • Application of hypoxia-inducible factor prolyl hydroxylase activity inhibitor in preparation of drug for preventing and treating acute kidney injury
  • Application of hypoxia-inducible factor prolyl hydroxylase activity inhibitor in preparation of drug for preventing and treating acute kidney injury
  • Application of hypoxia-inducible factor prolyl hydroxylase activity inhibitor in preparation of drug for preventing and treating acute kidney injury

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0016] Example 1 Materials and methods

[0017] 1) Materials and reagents

[0018] Inhibitor FG-4592 was purchased from Selleck Company. Cleaved caspase3 and Bax antibodies were purchased from CellSignaling Technology. NGAL and Kim-1 antibodies were purchased from ABCAM Company. HIF1α, β-actin was purchased from Nanjing Biotech Company. Fluorescent secondary antibodies were purchased from Invitrogen. Apoptosis detection kit was purchased from BD Company. Cisplatin, secondary antibodies required for Western Blot and other reagents were purchased from Sigma. The inflammatory factor ELISA kit was purchased from Dakota Biotechnology Company.

[0019] 2) Cell culture and treatment

[0020] Mouse renal tubular epithelial cells (mPTCs) were cultured in DMEM / F12 medium containing 10% fetal bovine serum, 0.5% penicillin and streptomycin at 37°C, 5% carbon dioxide and 95% air. In order to study the mechanism of FG-4592 on cisplatin-induced kidney injury, we pretreated mPTC with ...

Embodiment 2

[0034] Example 2 FG-4592 Improves Kidney Injury and Renal Function in Cisplatin-Induced Acute Kidney Injury Model

[0035]In order to evaluate the role of FG-4592 in protecting AKI, we detected the relevant biochemical indicators of the mouse kidney. After cisplatin was established for 72 hours, serum muscle and blood urea nitrogen indicators were significantly increased, while renal pathological damage such as tubular dilation and necrosis The manifestations were also more serious, and after FG-4592 treatment, the corresponding renal damage and renal function indicators were significantly decreased ( figure 1 A-C). In addition, renal tubular injury score also suggested that FG-4592 treatment could improve renal pathological damage caused by cisplatin ( figure 1 D). Therefore, FG-4592 can not only improve renal function, but also reduce renal pathological damage. These results suggest that FG-4592 can protect kidney damage caused by acute kidney injury.

Embodiment 3

[0036] Example 3 FG-4592 down-regulates the expression levels of NGAL and Kim-1 in the acute kidney injury model.

[0037] In order to further prove that FG-4592 has a protective effect on cisplatin-induced acute kidney injury, we detected the early specific biomarkers of acute kidney injury, NGAL and Kim-1. Such as image 3 Fluorescent quantitative PCR and western blot detection from A to 3C showed that kim1 and NGAL were highly expressed in the kidneys of mice with acute kidney injury, and their expression levels decreased significantly after FG-4592 treatment, indicating that FG-4592 is effective in the acute kidney injury model Kidney tissue has a certain protective effect.

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Abstract

The invention discloses a use of a hypoxia-inducible factor prolyl hydroxylase activity inhibitor in the preparation of a drug for preventing and treating acute kidney injury. The HIF prolyl hydroxylase activity inhibitor is Roxadustat (FG-4592). The HIF prolyl hydroxylase activity inhibitor is an HIF family selective inhibitor, and can alleviate pathological damages of cisplatin-induced acute kidney injury to kidneys and improve the functions of the kidneys. The FG-4592 can reduce apoptosis of renal tubular cells and renal tubular functions, improve the pathological injury and renal functionsof the kidneys and protect the structures and the functions of the kidneys in the acute kidney injury by activating HIF1alpha, promoting the expression of EPO and HO-1, inhibit apoptosis and down-regulate the release of inflammatory factors. The FG-4592 is currently in a Phase III clinical research stage in the field of prevention and treatment of chronic renal anemia, and it is found that the FG-4592 is highly possible to provide the effective clinical drug for preventing and treating the AKI.

Description

technical field [0001] The invention belongs to the field of medicine, and in particular relates to the application of a hypoxia-inducible factor (Hypoxia-Inducible Factor, HIF) prolyl hydroxylase activity inhibitor in the preparation of medicines for preventing and treating acute kidney injury. Background technique [0002] Acute kidney injury (acute kidney in jury, AKI) is a common clinical syndrome, mainly manifested as a rapid decline in renal function and accumulation of metabolic waste, an increase in serum creatinine (Scr) and a decrease in urine output Is the basis for the diagnosis of AKI. The incidence of AKI is high and is increasing year by year. A cross-sectional study in 2013 showed that the detection rate of AKI among hospitalized patients in my country was as high as 2%. It is predicted that 2.9 million AKI patients will be hospitalized and about 700,000 patients will die of AKI. At present, there is no specific drug for the treatment of AK1, and renal repla...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/472A61P13/12
CPCA61K31/472A61P13/12
Inventor 张爱华杨运文贾占军刘素雯王佩培张文李树珍夏薇薇公伟于婧
Owner NANJING CHILDRENS HOSPITAL
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