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内皮素A受体阻滞剂和拟钙剂在腺嘌呤大鼠慢性肾功能不全模型中的应用

Endothelin A receptor blocker and calcimimetic in the adenine rat model of chronic renal insufficiency.

作者信息

Törmänen Suvi, Pörsti Ilkka, Lakkisto Päivi, Tikkanen Ilkka, Niemelä Onni, Paavonen Timo, Mustonen Jukka, Eräranta Arttu

机构信息

Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Finland.

Department of Internal Medicine, Tampere University Hospital, Tampere, Finland.

出版信息

BMC Nephrol. 2017 Oct 27;18(1):323. doi: 10.1186/s12882-017-0742-z.

Abstract

BACKGROUND

We studied whether endothelin receptor antagonist and calcimimetic treatments influence renal damage and kidney renin-angiotensin (RA) components in adenine-induced chronic renal insufficiency (CRI).

METHODS

Male Wistar rats (n = 80) were divided into 5 groups for 12 weeks: control (n = 12), 0.3% adenine (Ade; n = 20), Ade + 50 mg/kg/day sitaxentan (n = 16), Ade + 20 mg/kg/day cinacalcet (n = 16), and Ade + sitaxentan + cinacalcet (n = 16). Blood pressure (BP) was measured using tail-cuff, kidney histology was examined, and RA components measured using RT-qPCR.

RESULTS

Adenine caused tubulointerstitial damage with severe CRI, anemia, hyperphosphatemia, 1.8-fold increase in urinary calcium excretion, and 3.5-fold and 18-fold increases in plasma creatinine and PTH, respectively. Sitaxentan alleviated tubular atrophy, while sitaxentan + cinacalcet combination reduced interstitial inflammation, tubular dilatation and atrophy in adenine-rats. Adenine diet did not influence kidney angiotensin converting enzyme (ACE) and AT receptor mRNA, but reduced mRNA of renin, AT, AT, (pro)renin receptor and Mas to 40-60%, and suppressed ACE2 to 6% of that in controls. Sitaxentan reduced BP by 8 mmHg, creatinine, urea, and phosphate concentrations by 16-24%, and PTH by 42%. Cinacalcet did not influence BP or creatinine, but reduced PTH by 84%, and increased hemoglobin by 28% in adenine-rats. The treatments further reduced renin mRNA by 40%, while combined treatment normalized plasma PTH, urinary calcium, and increased ACE2 mRNA 2.5-fold versus the Ade group (p < 0.001).

CONCLUSIONS

In adenine-induced interstitial nephritis, sitaxentan improved renal function and tubular atrophy. Sitaxentan and cinacalcet reduced kidney renin mRNA by 40%, while their combination alleviated tubulointerstitial damage and urinary calcium loss, and increased kidney tissue ACE2 mRNA.

摘要

背景

我们研究了内皮素受体拮抗剂和拟钙剂治疗对腺嘌呤诱导的慢性肾功能不全(CRI)中肾损伤和肾脏肾素 - 血管紧张素(RA)成分的影响。

方法

将80只雄性Wistar大鼠分为5组,为期12周:对照组(n = 12)、0.3%腺嘌呤组(Ade;n = 20)、Ade + 50 mg/kg/天西他生坦组(n = 16)、Ade + 20 mg/kg/天西那卡塞组(n = 16)以及Ade + 西他生坦 + 西那卡塞组(n = 16)。使用尾套法测量血压(BP),检查肾脏组织学,并使用RT - qPCR测量RA成分。

结果

腺嘌呤导致肾小管间质损伤,并伴有严重的CRI、贫血、高磷血症、尿钙排泄增加1.8倍,以及血浆肌酐和甲状旁腺激素(PTH)分别增加3.5倍和18倍。西他生坦减轻了肾小管萎缩,而西他生坦 + 西那卡塞组合减少了腺嘌呤处理大鼠的间质炎症、肾小管扩张和萎缩。腺嘌呤饮食不影响肾脏血管紧张素转换酶(ACE)和AT受体mRNA,但使肾素、AT、AT、(前)肾素受体和Mas的mRNA降低至对照组的40 - 60%,并将ACE2抑制至对照组的6%。西他生坦使血压降低8 mmHg,肌酐、尿素和磷酸盐浓度降低16 - 24%,PTH降低42%。西那卡塞不影响血压或肌酐,但使腺嘌呤处理大鼠的PTH降低84%,血红蛋白增加28%。这些治疗使肾素mRNA进一步降低40%,而联合治疗使血浆PTH、尿钙恢复正常,并且与Ade组相比,ACE2 mRNA增加了2.5倍(p < 0.001)。

结论

在腺嘌呤诱导的间质性肾炎中,西他生坦改善了肾功能和肾小管萎缩。西他生坦和西那卡塞使肾脏肾素mRNA降低40%,而它们的组合减轻了肾小管间质损伤和尿钙流失,并增加了肾脏组织ACE2 mRNA。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f72f/5659028/0687d4d5728e/12882_2017_742_Fig1_HTML.jpg

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