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Original Article Combined Anisodamine and Probucol Int J Clin Exp Med 2019;12(4):3250-3260 www.ijcem.com /ISSN:1940-5901/IJCEM0074736 Original Article Combined anisodamine and probucol prevents contrast-induced nephropathy in diabetic rats by inhibiting p38 MAPK and Akt/mTOR/P70S6K signaling pathways Kai Zhao1*, Qiaoying Gao2*, Chunhui Zong2, Yongjian Li1 Departments of 1Cardiology, 2Pharmacology, Institute of Acute Abdominal Diseases, Tianjin Nankai Hospital, Tianjin 300100, China. *Equal contributors. Received February 21, 2018; Accepted October 12, 2018; Epub April 15, 2019; Published April 30, 2019 Abstract: Apoptosis is recognized as an important mechanism in contrast-induced nephropathy (CIN). As anisoda- mine and probucol have been found to be renoprotective and anti-apoptotic in multiple kidney injuries, we hypoth- esized that they would prevent CIN. An experimental model of CIN was established in rats. Serum creatinine, blood urea nitrogen, urinary kidney injury molecule-1 (KIM-1), interleukin (IL)-18, and neutrophil gelatinase associated lipocalin (NGAL) levels were measured to evaluate kidney function. Superoxide dismutase (SOD), malondialdehyde (MDA) levels were assessed to discuss the effect of anisodamine and probucol on oxidative stress. The pathological changes of kidney were observed by hematoxylin and eosin (HE) staining and immunohistochemistry (IHC) analysis. Apoptosis was assessed by transferase-mediated deoxyuridine triphosphate nick end-labeling (TUNEL) staining. Phospho-p38 mitoge-activated protein kinase (MAPK) and Akt/mTOR/P70S6K protein expression was assessed by Western blotting. Anisodamine and probucol significantly attenuated the resulting renal dysfunction and renal tubular cell apoptosis. Mechanistically, anisodamine and probucol decreased the expression of MAPK and Akt/ mTOR/P70S6K protein expression. In addition, anisodamine and probucol inhibited Bax protein expression while it upregulated Bcl-2. The results suggested that anisodamine and probucol can accelerate the recovery of renal function by reducing renal oxidative stress and influencing p38 MAPK and Akt/mTOR/P70S6K signal pathways. Combined anisodamine and probucol might be more effectively. Keywords: Anisodamine, probucol, contrast-induced nephropathy, phospho-p38 mitoge-activated protein kinase, Akt/mTOR/P70S6K signals Introduction kidney injury cases, and nearly 150,000 patients are estimated to develop CIN each The prevalence of contrast-induced nephropa- year worldwide [4, 5]. Despite the advent of thy (CIN) is rising due to the increased use of advanced CM and improvements in preventive contrast medium (CM) in percutaneous coro- strategies, the prevention of CIN remains chal- nary intervention (PCI). CIN is generally defined lenging, and no specific prevention besides as an otherwise unexplained acute impairment adequate periprocedural hydration is available in renal function, manifested as serum creati- [6]. Thus, it is urgent to uncover the pathogen- nine (Scr) increases of 44.2 μmol/L or ≥ 25% esis of CIN and to identify novel preventive ther- from the baseline value within 3 days after the apies decrease CIN incidence and to improve administration of CM [1, 2]. To date, chronic kid- clinical prognosis. ney disease, dehydration, diabetes mellitus (DM), advanced age, increased volume of CM Although the exact pathophysiological mecha- and recurrent administration are well-known nism of CIN still remains poorly understood, it risk factors of CIN [3]. CIN is the third most has been generally demonstrated that CIN common cause of hospital-acquired acute appears to be the result of combined effects of renal failure, accounting for 10~25% of acute direct nephrotoxicity of CM and hypoxic renal Anisodamine and probucol prevents contrast-induced nephropathy in diabetic rats injury. Mounting evidence has shown that from the Motic Med 6.0 CMIAS Image Analysis impaired renal blood flow and ischemia-reper- System (Motic China Group Co., Ltd). fusion injury plays an important part in the pathogenesis of CIN [7]. In addition, reactive Model and grouping oxygen species (ROS), inflammation and apop- tosis also contribute to the renal tubular cell 40 rats were randomly divided into 5 groups of injury. Recently, clinical studies reported that 8 rats each: control (C) group, model (M) group, rats treated with anisodamine (A) group, rats several potent free radicals scavenger, for treated with probucol (P) group, and rats treat- example, probucol can effectively reduce the ed with both anisodamine and probucol (A+P) incidence of CIN [8]. Anisodamine, which is a group. First, we used streptozotocin (STZ, Si- muscarinic acetylcholine receptor antagonist, gma Company) to induce diabetiac rats model. has been used for clinical treatment of various Diabetic rat model was established by abdomi- types of shock in China since 1965 [9]. Re- nal single dose injection STZ 60 mg/kg. The cently, anisodamine is used in the treatment of blood glucose ≥ 16.7 μmol/L is used as the acute glomerulonephritis and diabetic nephrop- standard for the success of diabetiac rats athy, because it can improve renal microcircula- model. After ten weeks feeding, we use urogra- tion. It was reported that anisodamine treat- fin to induce CIN. Rats in the P and A+P groups ment may protect against CIN in patients with received intragastric administration of probu- type 2 diabete and renal insufficiency undergo- col (500 mg/kg) for 7 days [11]. Thereafter ing coronary angiography [10]. As far as we water forbidden was conducted for 24 hours, know, there was no study in the literature to and then the diabetic SD rats were injected investigate combine anisodamine and probucol intravenously with urografin to induce CIN. to prevent CIN in diabetic rats. So in the pres- Drugs administered consisted of urografin at a ent study, we established diabetic CIN rat mod- dose of 10 mg/kg [12]. A relative (≥ 25%) or an els, evaluated whether combine anisodamine absolute (≥ 44.2 μmol/L) increase in Scr from and probucol have beneficial effects on CIN. the baseline is used as the standard for the Besides, the underlying mechanisms were also success of CIN rats model [13]. Rats were investigated. anesthetized with 60 mg/kg pentobarbital. Pentobarbital sodium anesthesia was followed Materials and methods by CIN induction, which was performed with drug administration into a tail vein. After inject- Animal experimental protocol ing CM, rats in the A and A+P groups received abdominal injection anisodamine (100 μg/100 The study protocol was approved by the g) one time per hour [14]. After injecting CM 4 Medicine Animal Ethics Committee of Tianjin times, anisodamine was used every 4 hours in Nankai Hospital (Tianjin, China). A total of 40 the following 8 hours. At the same time, rats in adult 8- to 10-week-old male Sprague-Dawley the C, M and P groups received the same dose rats weighing 200~250 g from the Tianjin Acute of abdominal injection saline. Baseline blood Abdominal Diseases Institute Animal Research samples were collected from the tail vein under Center were used. Rats were housed in an air- ether anesthesia for analysis of Scr and blood conditioned room maintained at 23°C with a glucose. Baseline 24-hour urine samples were 12/12-hour light/dark cycle. Food and water collected for determination of interleukin-18 (IL- were provided ad libitum except for the day of 18), neutrophil-gelatinase-associates-lipocalin dehydration. (NGAL). Experimental materials Observation indicators Probucol was purchased from Chengde Jing General condition: The mental state, activity, Fukang Pharmaceutical Co. Ltd. (China); Aniso- body weight, food intake, and mortality of rats damine and urografin were purchased from were observed after the procedure. After mod- Tianjin Jinyao Pharmaceutical Co. Ltd. (China); eling, all rats were killed. After the rats were Superoxide dismutase (SOD), malondialdehyde anesthetized for the modeling procedure, 1 ml (MDA) kit were purchased from Nanjing of blood was obtained from the inner canthus Jiancheng Company (China). The microscopic for blood biochemical examination prior to image acquisition and analysis system was modeling. 3251 Int J Clin Exp Med 2019;12(4):3250-3260 Anisodamine and probucol prevents contrast-induced nephropathy in diabetic rats Detection of relevant renal oxidative stress The area density representing the positive indicators: After the rats were killed, the kidney staining intensity was calculated as the ratio tissues were quickly removed. In addition, 3 ml between the stained area and the total ana- of blood was obtained from the abdominal lyzed field. All slides were observed by two aorta. Tissue blocks of the appropriate size blinded examiners independently. were taken, placed in pre-cooled ice-cold nor- mal saline, and made into tissue homogenate Western blotting analysis: Renal cortexes were at a ratio of 1:9. The supernatant was removed lysed in lysis buffer. Proteins (30 μg) were sub- after 15 min of centrifugation at 3000 rpm, jected to electrophoresis on 6~12% polyacryl- and the purchased kits were used to measure amide gel and transferred to polyvinylidene flu- the levels of SOD, MDA in renal tissues. oride (PVDF) membrane. The membranes were blocked with 5% non-fat milk in TBST for 2 h at Renal pathological examination: Tissue blocks room temperature, and incubated with the pri- from rat kidney were fixed in 10% formalin and mary antibodies overnight at 4°C. The bands prepared for hematoxylin and eosin (HE) stain- were detected by GelDoc XR (BioRad, USA) ing, transferase-mediated deoxyuridine
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