Application of CDN1163 in preparation of medicine for preventing or / and treating acute kidney injury

Abstract

The invention belongs to the technical field of biological medicines, and particularly discloses application of CDN1163 in preparation of a medicine for preventing or / and treating acute kidney injury. It is found for the first time that CDN1163 can relieve ischemia reperfusion induced AKI and reduce serum urea nitrogen and creatinine levels so as to play a role in protecting the kidney in the ischemia reperfusion induced AKI, and therefore the CDN1163 can be used for preparing the medicine for preventing or / and treating the acute kidney injury.

Description

Technical Field

[0001] This invention belongs to the field of biomedicine, and in particular relates to the application of CDN1163 in the preparation of drugs for the prevention and / or treatment of acute kidney injury. Background Technology

[0002] Acute kidney injury (AKI) is a common clinical syndrome, often accompanied by prolonged hospital stays, and some patients have a poor prognosis and may progress to chronic kidney disease. AKI has a high incidence and poor prognosis; globally, approximately 13 million people develop AKI each year, and about 1.7 million die from AKI and its complications. In recent years, the global prevalence of AKI has continued to rise rapidly, with up to 57.3% of ICU patients developing AKI. The main factors causing AKI include renal ischemia-reperfusion, sepsis, and drug-induced kidney damage. Currently, the main clinical strategies for treating AKI include treating the underlying disease, symptomatic treatment, and renal replacement therapy; to date, there are no specific drugs for treating AKI.

[0003] CDN1163 is an allosteric activator of sarcoplasmic / endoplasmic reticulum calcium ATPase 2 (SERCA2), which regulates intracellular calcium homeostasis. SERCA2 is a key enzyme on the endoplasmic reticulum membrane regulating calcium transport and is expressed in multiple organs, including the kidneys. The core function of SERCA2 is the active transport of cytoplasmic calcium ions back to the endoplasmic reticulum, which is crucial for maintaining intracellular calcium homeostasis and endoplasmic reticulum function. Currently, there are no studies on the use of CDN1163 in the treatment of acute kidney injury (AKI). Summary of the Invention

[0004] The technical problem to be solved by the present invention is to overcome the deficiencies and defects mentioned in the background art above. The present invention provides the use of CDN1163 in the preparation of a medicament for the prevention and / or treatment of acute kidney injury.

[0005] To solve the above-mentioned technical problems, the technical solution proposed by this invention is as follows: The use of CDN1163 in the preparation of a drug for the prevention and / or treatment of acute kidney injury.

[0006] In the above-described application, preferably, the acute kidney injury is an acute kidney injury induced by ischemia-reperfusion injury (IRI).

[0007] During the research process, the applicant discovered that CDN1163 can reduce serum creatinine and blood urea nitrogen levels, improve renal tissue pathological damage, reduce Ngal expression in the kidneys of mice with acute kidney injury, and reduce the protein expression levels of CHOP, ATF4, ATF6 and p-IRE1 in the kidneys during acute kidney injury, thereby improving renal endoplasmic reticulum stress. This provides a guarantee for its application in drugs for the prevention and / or treatment of acute kidney injury, and provides a new target and treatment method for the treatment of acute kidney injury.

[0008] Compared with the prior art, the beneficial effects of the present invention are as follows: This invention is the first to discover that CDN1163 can alleviate ischemia-reperfusion-induced acute kidney injury (AKI), reduce serum urea nitrogen and creatinine levels, and thus play a protective role in the kidneys during ischemia-reperfusion-induced AKI. Therefore, it can be used to prepare drugs for the prevention and / or treatment of acute kidney injury. Attached Figure Description

[0009] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0010] Figure 1 This is the dosing regimen for treating ischemia-reperfusion-induced AKI model mice with CDN1163 in Example 1 of the present invention; Figure 2 The graphs show the results of serum biochemical indicators in mice in Example 2 of this invention. Graph A shows the serum creatinine level, and graph B shows the serum urea nitrogen level. Figure 3 This is a comparison of the HE staining (200×) effects on the kidneys of mice in different groups in Example 3 of the present invention; Figure 4 This shows the Ngal protein expression levels in the kidney tissues of mice in each group in Example 4 of the present invention; Figure 5 This shows the expression levels of endoplasmic reticulum stress-related proteins in the kidney tissues of mice in Example 5 of this invention. Detailed Implementation

[0011] To facilitate understanding of the present invention, the present invention will be described more fully and in detail below with reference to the accompanying drawings and preferred embodiments, but the scope of protection of the present invention is not limited to the following specific embodiments.

[0012] Unless otherwise defined, all technical terms used herein have the same meaning as commonly understood by those skilled in the art. The technical terms used herein are for the purpose of describing particular embodiments only and are not intended to limit the scope of the invention.

[0013] Unless otherwise specified, all raw materials, reagents, instruments and equipment used in this invention can be purchased from the market or prepared by existing methods.

[0014] All statistical analyses below were performed using SPSS Statistics 27.0 software. All measurement data are expressed as mean ± standard deviation (X±S), and one-way ANOVA was used for comparisons among multiple groups. (Two-tailed) P A value <0.05 is considered statistically significant.

[0015] To demonstrate the efficacy of CDN1163 in the prevention and / or treatment of acute kidney injury, the following examples provide animal experimental verification.

[0016] Example 1: This embodiment provides an animal model, grouping, and administration method.

[0017] SPF-grade C57BL / 6 mice (7-8 weeks old, male, weighing 20-22g) were used as experimental subjects and were divided into 5 groups: sham operation group, IRI24h model group, IRI24h + CDN1163 group, IRI48h model group, and IRI48h + CDN1163 group.

[0018] CDN1163 was first dissolved in DMSO to a concentration of 12.5 mg / mL, and then further diluted to 2.5 mg / mL with 10% DMSO + 10% Tween-80 + 80% physiological saline. Three days before modeling (D1), the IRI24h + CDN1163 group and the IRI48h + CDN1163 group were given intraperitoneal injections of CDN1163 solution (50 mg / kg / day) once daily; at the same time, the Sham group, the IRI24h group, and the IRI48 group were injected with an equal volume of control solvent. On the day of surgery (D4), after anesthesia, the mice were prepared, and bilateral kidneys were exposed through an incision below the spine on the back. The fascia around the bilateral renal pedicles was separated to fully expose the bilateral renal pedicles, and the renal pedicles were clamped with vascular clamps for 30 minutes. Throughout the experiment, a temperature-controlled heating device was used to maintain the body temperature of the mice at 37.0℃–37.5℃. Thirty minutes later, the vascular clamps were removed, and the peritoneum and skin on both sides were sutured in layers. Mice were then sacrificed 24 hours and 48 hours after reperfusion. In the control group, mice were anesthetized, and both kidneys were exposed through a dorsal incision. The renal pedicles were separated, and the peritoneum and skin on both sides were sutured in layers. Mice were sacrificed 24 hours (D5) and 48 hours (D6), and mouse serum and both kidneys were collected and stored at -80°C for subsequent experiments.

[0019] Example 2: This example describes the detection of biochemical indicators in mouse serum.

[0020] The serum creatinine (Scr) and blood urea nitrogen (BUN) levels of mice in each group were measured using a creatinine assay kit (sarcosine oxidase method, Nanjing Jiancheng) and a blood urea nitrogen assay kit (urease method, Nanjing Jiancheng) according to the kit instructions. The results are as follows: Figure 2 As shown.

[0021] Depend on Figure 2 It was found that, compared with the sham-operated group, the levels of serum creatinine (Scr) and serum urea nitrogen (BUN) in mice in the IRI 24h and IRI 48h model groups were significantly increased. Compared with the model group, CDN1163 treatment could significantly reduce the levels of Scr and BUN in the IRI model at different time points. P <0.05. This indicates that CDN1163 can improve ischemia-reperfusion injury-induced acute kidney injury. Example 3: This example describes the HE staining of the kidneys and the scoring of renal tubular damage in each group of mice.

[0022] The scoring criteria for renal tubular injury were based on a semi-quantitative analysis of renal tubular pathological damage, using the method employed by Capasso et al. For each kidney, 10 fields of view in the corticomembranous region were randomly selected under a 200× microscope. The area of ​​renal tubular injury (tubular necrosis, cast formation, and brush border loss) was scored according to the following criteria: 0 points: none; 1 point: 1%-25%; 2 points: 26%-50%; 3 points: 51%-75%; 4 points: 76%-100%. The average score was taken as the score for that sample.

[0023] The pathological changes of mouse kidneys were observed under an optical microscope using HE staining, and the results are as follows: Figure 3 As shown: The kidney structure of the sham-operated mice was intact, and the corticomedullary junction was clearly defined. Compared with the Sham group, the renal tubular epithelium of the IRI 24h and IRI 48h model groups showed more obvious cell swelling, vacuolar degeneration, sloughing necrosis, and luminal dilation, with clearly exposed basement membranes. The kidney injury scores were significantly higher in the Sham group (P<0.05). Compared with the model group, CDN1163 treatment significantly improved renal tubular injury induced by IRI at different time points in AKI model mice, and the pathological score of renal tubular injury was significantly reduced (P<0.05).

[0024] Example 4: In this embodiment, the expression of Ngal in the kidneys of mice in each group was detected by immunoblotting 24 h after IRI modeling.

[0025] The protein expression level of Ngal in the kidney tissue of mice in each group was detected by immunoblotting 24 h after IRI modeling.

[0026] The results are as follows Figure 4 As shown, compared with the Sham group, the expression level of Ngal protein in the kidney tissue of mice in the IRI24h group was significantly increased. However, compared with the IRI24h group, the expression level of Ngal protein in the kidney tissue of mice treated with CDN1163 was significantly decreased. This further demonstrates that CDN1163 can improve IRI-induced AKI model kidney injury.

[0027] Example 5: In this embodiment, the endoplasmic reticulum stress-related indicators in the kidneys of mice in each group were detected by immunoblotting 24 hours after IRI modeling.

[0028] The protein expression levels of endoplasmic reticulum stress-related markers in the kidney tissues of mice in each group 24 hours after IRI modeling were detected by Western blotting. Figure 5As shown, the results indicated that, compared with the Sham group, the protein expression levels of endoplasmic reticulum stress markers CHOP and ERS-sensing proteins phosphorylated IRE1, ATF6, and downstream molecule ATF4 were significantly increased in the kidney tissue of mice in the IRI24h group. Conversely, compared with the IRI24h group, the protein expression levels of CHOP, ATF4, ATF6, and p-IRE1 were significantly decreased in the kidney tissue of mice treated with CDN1163.

[0029] It is evident that CDN1163 can improve endoplasmic reticulum stress in the kidneys of an IRI-induced AKI model.

[0030] Therefore, CDN1163 can reduce serum creatinine and blood urea nitrogen levels, improve renal tissue pathological damage, reduce Ngal expression in the kidneys of mice with acute kidney injury, and reduce the protein expression levels of CHOP, ATF4, ATF6 and p-IRE1 in the kidneys during acute kidney injury, thus improving renal endoplasmic reticulum stress and providing a guarantee for its application in drugs for the prevention and / or treatment of acute kidney injury.

Claims

1. The use of CDN1163 in the preparation of a medicament for the prevention and / or treatment of acute kidney injury.

2. The application as described in claim 1, characterized in that, The acute kidney injury mentioned is ischemia-reperfusion induced acute kidney injury.

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