Increased expression of cyclooxygenase-2 in the renal cortex of human prorenin receptor gene-transgenic rats
Increased expression of cyclooxygenase-2 in the renal cortex of human prorenin receptor gene-transgenic rats
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DOI：
10.1038/sj.ki.5001627
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发表时间：
2006-08-01
影响因子：
19.6
通讯作者：
Inagami, T.
中科院分区：
文献类型：
--
作者：
Kaneshiro, Y.;Ichihara, A.;Inagami, T.
在糖尿病大鼠中观察到致密斑环氧合酶-2（考克斯-2）增加，并可能导致高滤过状态。然而，在糖尿病大鼠中介导增加的考克斯-2表达的信号仍然未确定。我们最近发现，非蛋白水解激活的前肾素的位点特异性结合蛋白，如前肾素受体，在糖尿病肾病的发展中起着至关重要的作用。本研究旨在探讨肾皮质考克斯-2表达与肾素原受体的关系。采用实时荧光定量聚合酶链反应（PCR）、免疫印迹和免疫组织化学方法检测6只4周龄雄性野生型大鼠和6只转人原肾素受体基因（hProRenRcTg）大鼠的考克斯-2 mRNA和蛋白水平，并进行比较。两组之间通过遥测测量的动脉压、尿钠排泄量或大鼠原肾素受体mRNA的肾脏水平无差异。hProRenRcTg大鼠的肾皮质考克斯-2 mRNA水平显著高于野生型大鼠，hProRenRcTg大鼠的肾皮质考克斯-2蛋白水平也高于野生型大鼠。免疫组织化学分析显示考克斯-2免疫染色主要存在于致密斑细胞中，并且hProRenRcTg大鼠中存在比野生型大鼠中显著更多的考克斯-2阳性细胞。此外，用NS 398抑制考克斯-2显著降低了hProRenRcTg大鼠的肾皮质血流量，但在野生型大鼠中没有。这些结果有力地表明，人原肾素受体直接或间接地参与了肾皮质考克斯-2表达的调节。
Increased macula densa cyclooxygenase-2 ( COX-2) is observed in diabetic rats and may contribute to hyperfiltration states. However, the signals mediating increased COX-2 expression in diabetic rats remain undetermined. We recently found that non-proteolytic activation of prorenin by site-specific binding proteins, such as prorenin receptor, plays a pivotal role in the development of diabetic nephropathy. The present study was designed to determine the contribution of prorenin receptor to renal cortical COX-2 expression. The COX-2 mRNA and protein levels of six 4-week-old male wild-type rats and six human prorenin receptor gene-transgenic (hProRenRcTg) rats were measured by real-time polymerase chain reaction methods, Western blotting, and immunohistochemistry, and compared. There were no differences between the two groups in arterial pressure measured by telemetry, urinary sodium excretion, or renal levels of rat prorenin receptor mRNA. The renal cortical COX-2 mRNA levels of the hProRenRcTg rats were significantly higher than those of the wild-type rats, and the renal cortical COX-2 protein levels were also higher in hProRenRcTg rats than in the wild-type rats. Immunohistochemical analysis revealed that COX-2 immunostaining was predominantly present in the macula densa cells, and significantly more COX-2-positive cells were present in the hProRenRcTg rats than in the wild-type rats. In addition, COX-2 inhibition with NS398 significantly decreased renal cortical blood flow in the hProRenRcTg rats but not in the wild-type rats. These results strongly suggest that human prorenin receptor directly or indirectly contributes to the regulation of renal cortical COX-2 expression.