Recombinant Cellular Repressor of E1A-Stimulated Genes Protects against Renal Fibrosis in Dahl Salt-Sensitive Rats
Recombinant Cellular Repressor of E1A-Stimulated Genes Protects against Renal Fibrosis in Dahl Salt-Sensitive Rats
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E1A 刺激基因的重组细胞阻遏蛋白可预防 Dahl 盐敏感大鼠的肾纤维化
DOI：
10.1159/000506411
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发表时间：
2020-05-01
影响因子：
4.2
通讯作者：
Han, Ya-ling
中科院分区：
文献类型：
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作者：
Liu, Mei-Li;Song, Hai-Xu;Han, Ya-ling
背景资料：人E1 A刺激基因的细胞阻遏物（CREG）是一种分泌性糖蛋白，可减轻血管紧张素II诱导的高血压，减轻心肌纤维化，改善心脏功能。然而，CREG在高盐（HS）饮食诱导的高血压肾病中的作用尚不清楚。研究方法：为探讨CREG在HS饮食诱导的高血压肾病中的作用及其分子机制，我们在Dahl盐敏感（SS）大鼠中建立了高血压肾病动物模型，给予HS饮食（8%NaCl，n = 20）8周。在HS负荷的第4周，通过皮下植入的泵向这些大鼠施用重组CREG（reCREG; 35 μg/kg·天，n = 5）和盐水（n = 5），并且还在饮用水中施用血管扩张剂肼苯哒嗪（20 mg/kg·天，n = 5）。我们采用苏木精-伊红染色、Masson三色染色、免疫组织化学标记、Western印迹、RT-PCR和Tunel染色来确定CREG在HS饮食诱导的高血压肾病中的信号通路。结果如下：HS摄入8周后，Dahl SS大鼠出现肾功能不全和严重的肾纤维化，分别在肾脏mRNA和蛋白质水平上与CREG表达减少78%和67%相关。给予reCREG改善了肾功能并减轻了肾纤维化。CREG的管理也抑制单核细胞浸润，减少肾细胞凋亡。CREG过表达上调叉头盒P1表达，抑制转化生长因子-β1信号通路。结论：我们的研究表明，CREG可以保护肾脏免受HS饮食诱导的肾损伤，并为肾损伤的机制提供了新的见解。
Background: Human cellular repressor of E1A-stimulated genes (CREG) is a secreted glycoprotein that attenuates angiotensin II-induced hypertension, alleviates myocardial fibrosis, and improves heart function. However, the role of CREG in high-salt (HS) diet-induced hypertensive nephropathy is unclear. Methods: To determine the effects and molecular mechanisms of CREG in HS diet-induced hypertensive nephropathy, we established a hypertensive nephropathy animal model in Dahl salt-sensitive (SS) rats fed a HS diet (8% NaCl, n = 20) for 8 weeks. At week 4 of HS loading, these rats were administered recombinant CREG (reCREG; 35 µg/kg·day, n = 5) and saline (n = 5) via subcutaneously implanted pumps and were also administered the vasodilator hydralazine (20 mg/kg·day, n = 5) in drinking water. We used hematoxylin and eosin staining, Masson’s trichrome staining, immunohistochemical labeling, western blotting, RT-PCR, and Tunel staining to determine the signaling pathways of CREG in HS diet-induced hypertensive nephropathy. Results: After 8 weeks of HS intake, the Dahl SS rats developed renal dysfunction and severe renal fibrosis associated with reductions of 78 and 67% in CREG expression, respectively, at both mRNA and protein levels in the kidney. Administration of reCREG improved renal function and relieved renal fibrosis. Administration of CREG also inhibited monocyte infiltration and reduced apoptosis in the kidney cells. CREG overexpression upregulated forkhead box P1 expression and inhibited the transforming growth factor-β1 signaling pathway. Conclusion: Our study shows that CREG protected the kidney against HS-diet-induced renal damage and provides new insights into the mechanisms underlying kidney injury.