Protective effect of dexamethasone implant on nephrotoxicity of adriamycin in rats

doi:10.12092/j.issn.1009-2501.2020.06.002

Abstract

Abstract: AIM: To study the establishment of adriamycin nephropathy rat model and the protective effects and mechanisms of dexamethasone implants (DEXI) through renal capsule implantation. METHODS: The adriamycin-induced nephropathy model was built by injecting Adriamycin (4 mg/kg) and Adriamycin (3.5 mg/kg) was injected again after week into tail-vein in SD rats. Renal capsule puncture was performed in model group. The excipient control group injected intra-renal capsule with drug-free excipient (1.4 mg/kg). The experimental group (2.8, 1.4, 0.7 mg/kg) was given by intrarenal capsule injection and positive drug group (0.1 mg/kg, qd × 8 w) was made by intragastric administration. The rat weight, kidney function and blood biochemical were observed and detected during the experiment. After the experiment, rat kidneys were stained with periodic acid-schiff to observe the morphological changes of mesangial and basement and sirius red to observe the renal tissue collagen fibers, expression of podocin and CD2AP were detected by immunohistochemistry. RESULTS: The blood protein content of adriamycin rats decreased, total blood cholesterol, uric acid, blood creatinine and urea nitrogen increased (P<0.05 or P<0.01), mesangium and fibers increased. The expression of Podocin protein in kidney tissue decreased and the expression of CD2AP protein increased (P<0.05 or P<0.01). DEXI increased the weight and blood protein levels of adriamycin rats, reduced blood lipids and blood uric acid levels (P<0.05 or P<0.01), improved renal function and tissue damage, and regulated the abnormal expression and distribution of Podocin and CD2AP proteins (P<0.05 or P<0.01). CONCLUSION: These results suggest that injecting adriamycin into the tail vein can establish a stable kidney disease model. DEXI renal capsule implantation can improve adriamycin nephropathy injury, and its mechanism may be related to restoration the expression and distribution of Podocin and CD2AP proteins on podocyte slit diaphragm.

Key words: dexamethasone implants, renal capsule implantation, podocyte, slit diaphragm

CLC Number:

R692
R965.2

ZHANG Cheng, FAN Manli, WANG Kun, QIN Zhiqiang, ZHOU Lanlan. Protective effect of dexamethasone implant on nephrotoxicity of adriamycin in rats[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2020, 25(6): 610-617.

References 20

[1]	李丽玲, 杜雅钦. 老年肾病综合征的临床观察 [J]. 老年医学与保健, 2017, 23(6): 546-548+556.
[2]	黄雯静, 刘娜, 杨馨, 等. 肾炎消白颗粒对阿霉素肾病大鼠Podocin、α-actinin-4蛋白的影响 [J]. 中医药学报, 2015, 43(5): 44-47.
[3]	朱雪玲, 曹英杰, 刘静, 等. EP1受体通过激活p38 MAPK通路介导阿霉素诱导的足细胞损伤 [J].中华肾脏病杂志, 2018, 34(7): 539-549.
[4]	George B, Holzman LB. Signaling from the podocyte intercellular junction to the actin cytoskeleton [C]//Seminars in nephrology. WB Saunders, 2012, 32(4): 307-318.
[5]	Tryggvason K, Patrakka J, Wartiovaara J. Hereditary proteinuria syndromes and mechanisms of proteinuria [J]. New Engl J Med, 2006, 354(13): 1387-1401.
[6]	龙红英, 胡延毅. 糖皮质激素长期用于肾病综合征治疗中的不良反应分析 [J]. 基层医学论坛, 2018, 22(13): 1765-1766.
[7]	蔡美顺, 于仲元, 田松, 等. 肾囊药物向肾组织内转运的实验研究 [J]. 中华医学杂志, 2001, (6): 43-46.
[8]	Miller WG, Bruns DE, Hortin GL, et al. Current issues in measurement and reporting of urinary albumin excretion [J]. Clin Chem, 2009, 55(1): 24-38.
[9]	Shankland SJ. The podocyte's response to injury: role in proteinuria and glomerulosclerosis [J]. Kidney Int, 2006, 69(12): 2131-2147.
[10]	蒋文功, 吕路, 林忠伟, 等. HIF-VEGF-Notch信号通路相关因子在阿霉素肾病大鼠肾小球硬化过程中的表达研究 [J]. 中国中西医结合肾病杂志, 2019, 20(1): 11-14.
[11]	黄青, 凌志杰, 邹毓华, 等. 骨髓间充质干细胞保护阿霉素诱导的肾病综合征模型鼠肾小球的实验研究 [J]. 中国当代医药, 2019, 26(29): 16-21.
[12]	Solanki AK, Widmeier E, Arif E, et al. Mutations in KIRREL1, a slit diaphragm component, cause steroid-resistant nephrotic syndrome[J]. Kidney Int, 2019, 96(4): 883-889. doi:10.1016/j.kint.2019.06.016.
[13]	梁勇华, 刘运广, 罗秀状. CD2相关蛋白在肾脏疾病中的作用机制及相关研究进展 [J]. 广西医学, 2019, 41(3): 361-365.
[14]	Yu SM, Nissaisorakarn P, Husain I, et al. Proteinuric kidney diseases: a podocyte's slit diaphragm and cytoskeleton approach [J]. Front Med (Lausanne), 2018, 5: 221. Published 2018 Sep 11. doi:10.3389/fmed.2018.00221.
[15]	Sönmez F, Mir S, Berdeli A, et al. Podocin mutations in a patient with congenital nephrotic syndrome and cardiac malformation [J]. Pedia Int, 2008, 50(6): 828-830.
[16]	Guo B, Lyu Q, Slivano OJ, et al. Serum response factor is essential for maintenance of podocyte structure and function [J]. J Am Soc Nephrol, 2018, 29(2): 416-422.
[17]	Hinkes B, Vlangos C, Heeringa S, et al. Specific podocin mutations correlate with age of onset in steroid-resistant nephrotic syndrome [J]. J Am Soc Nephrol, 2008, 19(2): 365-371.
[18]	苏衍进, 王郁金, 王琴, 等. 糖肾一号胶囊对糖尿病肾病大鼠血清SREBP-1c、SREBP-2c水平及肾组织IRS-1、PI3K、podocin、CD2AP蛋白表达影响 [J]. 中药药理与临床, 2017, 33(5): 140-143.
[19]	赵非, 黄松明, 张爱华, 等. CD2AP, F-actin在肾病大鼠中的表达及意义 [J]. 中国病理生理杂志, 2006, 22(1): 182-186.
[20]	Xing Y, Ding J, Fan Q, et al. Diversities of podocyte molecular changes induced by different antiproteinuria drugs[J]. Exp Biol Med, 2006, 231(5): 585-593.