Hartner Andrea, Porst Markus, Klanke Bernd, Cordasic Nada, Veelken Roland, Hilgers Karl F
University Hospital for Children and Adolescents, University of Erlangen-Nuremberg, Erlangen, Germany.
Nephrol Dial Transplant. 2006 Jul;21(7):1778-85. doi: 10.1093/ndt/gfl065. Epub 2006 Mar 7.
Ren-2 transgenic hypertensive rats develop malignant hypertensive nephrosclerosis despite low to normal plasma angiotensin II and suppressed renal renin. We tested the hypothesis that local angiotensin II formation occurs at sites of renal vascular and interstitial injury in this model.
Heterozygous Ren-2 transgenic rats were compared with normotensive Sprague-Dawley-Hannover control rats and Ren-2 transgenic rats treated with a very low dose of an angiotensin II type 1 (AT1) receptor antagonist, 1 mg/kg/day losartan, for 4 weeks. Blood pressure measurements, quantifications of urinary albumin, plasma and tissue angiotensin II as well as immunohistochemical analyses were performed.
Systolic blood pressure was not affected by losartan during the study but intra-arterial recordings revealed a decrease of blood pressure. Losartan reduced albumin excretion, cell proliferation, macrophage influx, collagen I and collagen IV deposition. Plasma angiotensin II was decreased, while kidney tissue angiotensin II content was increased in Ren-2 transgenic rats compared with control rats. In Ren-2 transgenic rats, juxtaglomerular renin and angiotensin II staining were reduced, but there was a marked angiotensin II staining at foci of tubulo-interstitial fibrosis and at proliferative malignant vascular lesions.
We conclude that local angiotensin II formation is increased in proliferative or fibrotic kidney lesions in the Ren-2 transgenic rat. Local angiotensin II formation may help to explain why the AT1 receptor antagonist prevents or ameliorates this transgenic model of malignant nephrosclerosis despite low to normal plasma angiotensin II and suppressed renal renin.
尽管肾素-2转基因高血压大鼠的血浆血管紧张素II水平低至正常且肾素分泌受抑制，但仍会发生恶性高血压性肾硬化。我们检验了这样一个假设，即在该模型中，局部血管紧张素II的形成发生在肾血管和间质损伤部位。
将杂合性肾素-2转基因大鼠与正常血压的斯普拉格-道利-汉诺威对照大鼠以及用非常低剂量的1型血管紧张素II（AT1）受体拮抗剂（氯沙坦，1毫克/千克/天）治疗4周的肾素-2转基因大鼠进行比较。进行了血压测量、尿白蛋白定量、血浆和组织血管紧张素II的测定以及免疫组织化学分析。
在研究期间，氯沙坦对收缩压没有影响，但动脉内记录显示血压有所下降。氯沙坦减少了白蛋白排泄、细胞增殖、巨噬细胞浸润、I型胶原和IV型胶原沉积。与对照大鼠相比，肾素-2转基因大鼠的血浆血管紧张素II降低，而肾组织血管紧张素II含量增加。在肾素-2转基因大鼠中，肾小球旁器肾素和血管紧张素II染色减少，但在肾小管间质纤维化灶和增生性恶性血管病变处有明显的血管紧张素II染色。
我们得出结论，肾素-2转基因大鼠增殖性或纤维化肾损伤中局部血管紧张素II的形成增加。局部血管紧张素II的形成可能有助于解释为什么尽管血浆血管紧张素II水平低至正常且肾素分泌受抑制，但AT1受体拮抗剂仍能预防或改善这种恶性肾硬化的转基因模型。
