腺嘌呤诱导的慢性肾损伤大鼠体内肾脏排泄通道变化

doi:10.5246/jcps.2021.04.026

中国药学(英文版) ›› 2021, Vol. 30 ›› Issue (4): 319-333.DOI: 10.5246/jcps.2021.04.026

腺嘌呤诱导的慢性肾损伤大鼠体内肾脏排泄通道变化

马彦荣¹^,³, 辛明彦³, 吴娟丽², 王菪菊², 王欢³, 武新安¹^,^*()

1. 兰州大学第一医院药剂科, 甘肃兰州 730000
2. 兰州大学第一临床医学院, 甘肃兰州 730000
3. 兰州大学药学院, 甘肃兰州 730000

收稿日期:2020-12-26 修回日期:2021-01-07 接受日期:2021-01-21 出版日期:2021-04-30 发布日期:2021-04-30
通讯作者: 武新安
作者简介:
+ Tel.: +86-931-8356511, Fax: +86-931-8616392, E-mail: xinanwu6511@163.com
基金资助:
The National Natural Science Foundation of China (Grant No. 81803611) and Innovation and Entrepreneurship Project of the First Clinical Medical College of Lanzhou University (Grant No. 20190060133).

Changes in renal excretion pathways in rats with adenine-induced chronic renal failure

Yanrong Ma¹^,³, Mingyan Xin³, Juanli Wu², Dangju Wang², Huan Wang³, Xin'an Wu¹^,^*()

1 Department of Pharmacy, the First Hospital of Lanzhou University, Lanzhou 730000 China
2 The First Clinical Medical College of Lanzhou University, Lanzhou 730000 China
3 School of Pharmacy, Lanzhou University, Lanzhou 730000, China

Received:2020-12-26 Revised:2021-01-07 Accepted:2021-01-21 Online:2021-04-30 Published:2021-04-30
Contact: Xin'an Wu

摘要/Abstract

摘要：

慢性肾功能衰竭(CRF)是一种进行性慢性肾脏疾病, 并伴随着物质排泄的改变。然而, 在CRF后肾脏排泄通道的变化尚不明确。本研究的目的是评价CRF后大鼠体内内源性和外源性物质肾脏排泄的变化。结果显示, 在腺嘌呤(50和100 mg/kg)诱导的CRF大鼠中血清胱抑素C、肌酐和尿素氮水平显著增加, 肾脏转运体rOCT2表达剂量依赖性增加, rMRP2和rMATE1水平剂量依赖性降低, rMPR4水平在腺嘌呤(50 mg/kg)诱导的CRF大鼠中显著增加。与正常大鼠相比, 在腺嘌呤(100 mg/kg)诱导的CRF大鼠中血浆二甲双胍、对氨基马尿酸和呋塞米的浓度显著增加。然而, 在腺嘌呤(50 mg/kg)诱导的CRF大鼠血中二甲双胍和对氨基马尿酸浓度没有明显的改变。与此一致, 在腺嘌呤(50 mg/kg)诱导的CRF大鼠中二甲双胍和对氨基马尿酸的尿排泄也未发生明显的改变。此外, 腺嘌呤(50和100 mg/kg)诱导的CRF大鼠肾脏N1-甲基烟酰胺摄取增加, 腺嘌呤(50 mg/kg)诱导CRF大鼠肾脏苯基-β-D-葡萄糖醛酸和马尿酸摄取增加。这些结果表明腺嘌呤(100 mg/kg)诱导的CRF大鼠中肾脏GFR-rOCTs-RMAT1和GFR-rOAT1/rOAT3-rMRP通路功能降低, 而腺嘌呤(50 mg/kg)诱导的CRF大鼠中肾小管rOCTs-RMAT1和rOAT1-MRPs通路转运功能增加。

关键词: 慢性肾衰竭, 肾排泄通道, 转运体, 腺嘌呤

Abstract:

Chronic renal failure (CRF) is a type of progressive chronic kidney disease with the alteration of substrates excretion. However, changes in renal excretion pathways remain unclear in CRF. This study aimed to evaluate the changes in renal excretion pathways of exogenous and endogenous substrates in CRF rats. Results showed that the levels of cystatin C, creatinine, and urea nitrogen were dramatically increased in the adenine (50 or 100 mg/kg)-induced CRF rats. The levels of rOCT2 were dose-dependently up-regulated by adenine, and rMRP2 and rMATE1 levels were dose-dependently down-regulated, while rMRP4 was induced by adenine (50). Plasma concentrations of metformin, p-aminohippurate, and furosemide in the adenine (100) group were significantly increased compared with the control group. However, plasma concentrations of metformin and p-aminohippurate were slightly changed in the adenine (50) group. Consistently, urinary excretions of metformin and p-aminohippurate were unaffected. In addition, renal N1-methylnicotinamide uptakes were increased in rats treated with adenine, and renal phenyl-β-D-glucuronide and hippuric acid uptakes were induced by adenine (50). These results showed that adenine (100)-induced CRF caused the reduced function of GFR-rOCTs-rMATE1 and GFR-rOAT1/rOAT3-rMRP pathway, and oppositely the renal tubular transport pathways of rOCTs-rMATE1 and rOAT1-MRPs were induced in rats with the treatment of adenine (50).

Key words: Chronic renal failure, Renal excretion pathways, Transporter, Adenine

Supporting:

马彦荣, 辛明彦, 吴娟丽, 王菪菊, 王欢, 武新安. 腺嘌呤诱导的慢性肾损伤大鼠体内肾脏排泄通道变化[J]. 中国药学(英文版), 2021, 30(4): 319-333.

Yanrong Ma, Mingyan Xin, Juanli Wu, Dangju Wang, Huan Wang, Xin'an Wu. Changes in renal excretion pathways in rats with adenine-induced chronic renal failure[J]. Journal of Chinese Pharmaceutical Sciences, 2021, 30(4): 319-333.

图/表 10

Figure 1. Renal clearance pathway of drugs and endogenous substances. MATE, multidrug and toxin extrusion; MRP, multidrug resistance protein; OAT, organic anion transporter; OCT, organic cation transporter.

Table 1. MRM of the transitions of compounds.

Figure 2. Body weight and biochemical parameters in adenine-induced CRF rats. *P < 0.05, **P < 0.01 Adenine (50) group were compared with the control group. #P < 0.05, ##P < 0.01 Adenine (100) group were compared with the control group (n = 6).

Figure 3. Photograph of renal tissue and H&E staining of kidney sections from rats with and without adenine treatment. (A) Photograph of renal tissue; (B) Control group; (C) Adenine (50) group; (D) Adenine (100) group.

Figure 4. Protein expression levels of renal tubular transporters in adenine-induced CRF rats. *P < 0.05, **P < 0.01 Adenine (50) group was compared with the control group. ##P < 0.01 Adenine (100) group was compared with the control group (n = 6).

Figure 5. Plasma concentration (A, B and C) (n = 6) and urinary excretion (D, E and F) (n = 5)-time curves of metformin, p-aminohippurate and furosemide in vivo, *P < 0.05, **P < 0.01 Adenine (50) group was compared with the control group. ##P < 0.01 Adenine (100) group was compared with the control group. (A) Metformin; (B) p-Aminohippurate; (C) Furosemide; (D) Metformin; (E) p-Aminohippurate; (F) Furosemide.

Table 2. The effects of adenine-induced CRF on drugs pharmacokinetic parameters (mean ± SD, n = 6).

Figure 6. Plasma concentration and renal uptake of N1-methylnicotinamide in adenine-induced CRF rats. *P < 0.05, **P < 0.01 Adenine (50) group was compared with the control group. ##P < 0.01 Adenine (100) group was compared with the control group (n = 6).

Figure 7. Plasma concentration and renal uptake of endogenous substrates in adenine-induced CRF rats. **P < 0.01 Adenine (50) group was compared with the control group. #P < 0.05, ##P < 0.01 Adenine (100) group was compared with the control group (n = 6).

Figure 8. Effect of adenine-induced CRF on the expression of renal transporters (green) and renal excretion pathways (red). GFR, glomerular filtration rate; OAT, organic anion transporter; OCT, organic cation transporter; MATE, multidrug and toxin extrusion; MRP, multidrug resistance protein.

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腺嘌呤诱导的慢性肾损伤大鼠体内肾脏排泄通道变化

Changes in renal excretion pathways in rats with adenine-induced chronic renal failure

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