Increased expression of (pro)renin receptor does not cause hypertension or cardiac and renal fibrosis in mice
Increased expression of (pro)renin receptor does not cause hypertension or cardiac and renal fibrosis in mice
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DOI：
10.1038/labinvest.2014.83
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发表时间：
2014-08-01
影响因子：
5
通讯作者：
Wenzel, Ulrich
中科院分区：
文献类型：
--
作者：
Rosendahl, Alva;Niemann, Gianina;Wenzel, Ulrich
肾素和前肾素与(Pro)肾素受体(PRR)结合可提高它们的酶活性，在体外上调促纤维化基因的表达。PRR在高血压和糖尿病动物的心脏和肾脏中表达增加，但其在器官损伤中的作用尚不清楚。为了确定PRR表达增加是否足以引起心脏或肾脏损伤，我们培育了一只小鼠，在CMV立即早期增强子/鸡β-肌动蛋白启动子的控制下，通过敲入HPRT基因中的Atp6ap2/PRR基因来结构性地过度表达PRR。用C57BI/6和FVB/N品系与小鼠回交，在12个月龄时进行研究。尽管Atp6ap2/PRR的表达在肾脏增加了25到80倍，心脏增加了400倍，但我们发现野生型和PRR高表达的小鼠在收缩压或蛋白尿方面没有差异。组织学检查没有显示突变小鼠有任何肾脏或心脏纤维化。这得到了炎症标记物以及肾脏中促纤维化基因和心脏组织中胶原蛋白的实时聚合酶链式反应分析的支持。为了确定伴随的肾素增加是否会引发纤维化，我们用血管紧张素受体-1阻滞剂氯沙坦治疗PRR高表达的小鼠，为期6周。肾素在肾脏中的表达增加了8倍，但没有检测到肾脏损伤。综上所述，我们的结果表明PRR本身在器官损伤中没有主要作用，或者与其作为肾素受体的功能有关。
Binding of renin and prorenin to the (pro)renin receptor (PRR) increases their enzymatic activity and upregulates the expression of pro-fibrotic genes in vitro. Expression of PRR is increased in the heart and kidney of hypertensive and diabetic animals, but its causative role in organ damage is still unclear. To determine whether increased expression of PRR is sufficient to induce cardiac or renal injury, we generated a mouse that constitutively overexpresses PRR by knocking-in the Atp6ap2/PRR gene in the hprt locus under the control of a CMV immediate early enhancer/chicken beta-actin promoter. Mice were backcrossed in the C57BI/6 and FVB/N strain and studied at the age of 12 months. In spite of a 25- to 80-fold renal and up to 400-fold cardiac increase in Atp6ap2/PRR expression, we found no differences in systolic blood pressure or albuminuria between wild-type and PRR overexpressing littermates. Histological examination did not show any renal or cardiac fibrosis in mutant mice. This was supported by real-time PCR analysis of inflammatory markers as well as of pro-fibrotic genes in the kidney and collagen in cardiac tissue. To determine whether the concomitant increase of renin would trigger fibrosis, we treated PRR overexpressing mice with the angiotensin receptor-1 blocker losartan over a period of 6 weeks. Renin expression increased eightfold in the kidney but no renal injury could be detected. In conclusion, our results suggest no major role for PRR in organ damage per se or related to its function as a receptor of renin.