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慢性肾功能衰竭继发高尿酸血症促进血管钙化

宋哲, 赵阳, 王宪, 徐明江

北京大学医学部基础医学院生理学与病理生理学系，北京 100191；第三医院检验科，北京 100191

摘要

本文旨在探讨高尿酸血症对肾衰血管钙化的影响及其机制。使用腺嘌呤饮食喂养的方法建立慢性肾功能衰竭的大鼠模型。将8周龄雄性Wistar大鼠随机分为对照组(正常饮食+正常饮水)、肾衰组(腺嘌呤饮食+正常饮水)和肾衰+别嘌呤醇组(腺嘌呤饮食+别嘌呤醇饮水)，喂养6周后进行取材，用邻甲酚酞络合铜法和Von Kossa染色法检测大鼠腹主动脉钙含量，用
real-time PCR法检测大鼠腹主动脉成骨基因(Cbfα1、Msx2、Osx和Sox9)、平滑肌细胞标志物(SM22a和Acta2)和钙化抑制因子Opn和Mgp的mRNA表达水平。结果显示，肾衰组大鼠血磷、血肌酐、血清尿素氮和血尿酸水平均显著升高，别嘌呤醇治疗可显著降低肾衰大鼠血肌酐、血清尿素氮和血尿酸水平，但是不影响血磷水平。肾衰组大鼠的腹主动脉钙含量显著高于对照组(P < 0.05)，肾衰+别嘌呤醇组显著低于肾衰组(P < 0.05)；肾衰组大鼠腹主动脉Cbfα1、Msx2、Osx和Sox9的mRNA水平较对照组出现显著上调，而SM22a、Acta2、Mgp和Opn的mRNA水平出现下调，在肾衰+别嘌呤醇组Msx2、Osx、SM22a和Opn的mRNA表达变化被逆转。在高磷(3 mmol/L)诱导的血管平滑肌细胞(vascular smooth muscle cells, VSMC)钙化模型中，抗氧化剂MnTMPyP显著抑制VSMC钙化，而别嘌呤醇则无显著作用；当尿酸水平达到6和7 mg/dL时可以显著加重高磷诱导的VSMC钙化(P < 0.05)。以上结果提示，慢性肾功能衰竭继发的高尿酸血症可以促进VSMC向成骨/成软骨样细胞转分化，进而加剧血管钙化的发生。

关键词： 高尿酸血症; 血管钙化; 慢性肾功能衰竭

分类号：R33

[Secondary hyperuricemia in chronic renal failure promotes vascular calcification in rats.] [Article in Chinese]

SONG Zhe, ZHAO Yang, WANG Xian, XU Ming-Jiang

Department of Physiology and Pathophysiology, Peking University School of Basic Medical Sciences, Beijing 100191, China； The Department of Laboratory Medicine, Peking University Third Hospital, Beijing 100191, China

Abstract

The present study was aimed to explore the effects of hyperuricemia on vascular calcification in chronic renal failure (CRF) and the mechanisms. Adenine diet-induced CRF rat model was used. Twenty-three male 8-week-old Wistar rats were randomly divided into control group (Ctr, n = 5), CRF group (n = 8) and CRF plus allopurinol group (CRF + ALL, n = 10), and the rats were given standard diet plus standard drinking water, adenine diet plus standard drinking water and adenine diet plus allopurinol drinking for 6 weeks, respectively. Vascular calcification of abdominal aorta was identified by o-cresolphthalein complexone copper assay and Von Kossa staining. The mRNA expression levels of osteogenic/chondrogenic regulatory factors (Cbfα1, Msx2, Osx, and Sox9), vascular smooth muscle cell (VSMC) lineage markers (SM22a and Acta2) and calcification inhibitors (Mgp and Opn) were detected by
real-time PCR. The results showed that the levels of serum phosphorus (Pi), urea nitrogen, creatinine and uric acid were significantly increased in the CRF rats, whereas allopurinol reversed the levels of serum urea nitrogen, creatinine and uric acid, except for serum Pi. The calcium content of rat abdominal aorta in the CRF group was significantly higher than that of the Ctr group (P < 0.05), but it was partially rescued in the CRF + ALL group (P < 0.05); Compared with the Ctr group, Cbfα1, Msx2, Osx and Sox9 mRNA levels of abdominal aorta in the CRF group were significantly up-regulated, while SM22a, Acta2, Mgp and Opn mRNA levels were down-regulated. In the CRF + ALL group, the changes of Msx2, Osx, SM22a and Opn mRNA levels were reversed (P < 0.05). Allopurinol had no effect on high Pi-induced VSMC calcification, and uric acid (6 and 7 mg/dL) significantly increased high Pi-induced VSMC calcification in vitro (P < 0.05). These results suggest that hyperuricemia in CRF may promote the osteoblast/chondrocyte-like cells differentiation of VSMC and further exacerbate vascular calcification.

Key words: hyperuricemia; vascular calcification; chronic renal failure

收稿日期：2016-02-25　　录用日期：2016-10-08

通讯作者：徐明江　　E-mail: mingjiangxu@bjmu.edu.cn

引用本文：

宋哲, 赵阳, 王宪, 徐明江. 慢性肾功能衰竭继发高尿酸血症促进血管钙化[J]. 生理学报 2016; 68 (6): 709-715.

SONG Zhe, ZHAO Yang, WANG Xian, XU Ming-Jiang. [Secondary hyperuricemia in chronic renal failure promotes vascular calcification in rats.] [Article in Chinese]. Acta Physiol Sin 2016; 68 (6): 709-715 (in Chinese with English abstract).