Machura Katharina, Steppan Dominik, Neubauer Bjoern, Alenina Natalia, Coffman Thomas M, Facemire Carie S, Hilgers Karl F, Eckardt Kai-Uwe, Wagner Charlotte, Kurtz Armin
Institute of Physiology, University of Regensburg, Regensburg, Germany.
Am J Physiol Renal Physiol. 2009 Nov;297(5):F1371-80. doi: 10.1152/ajprenal.00378.2009. Epub 2009 Aug 26.
During nephrogenesis, renin expression shifts from the vessel walls of interlobular arteries to the terminal portions of afferent arterioles in a wavelike pattern. Since the mechanisms responsible for the developmental deactivation of renin expression are as yet unknown, we hypothesized that the developing renin-angiotensin system (RAS) may downregulate itself via negative feedback to prevent overactivity of renin. To test for a possible role of angiotensin II in the developmental deactivation of renin expression, we studied the development of intrarenal renin expression in mice lacking ANG II AT1a, AT1b, or AT2 receptors and in animals with abolished circulating ANG II due to deletion of the gene for angiotensin I-converting enzyme (ACE). The development of intrarenal renin expression was normal in mice lacking ANG II AT1b or AT2 receptors. In animals lacking both ANG II AT1a and AT1b receptors, ACE, or ANG II AT1a receptors, renin expression was normal early and renin disappeared from mature vessels until development of cortical interlobular and afferent arterioles began. The development of cortical vessels in these genotypes was accompanied by a markedly increased number of renin-expressing cells, many of which were ectopically located and attached in a grapelike fashion to the outer vessel perimeter. Although the number of renin-expressing cells declined during final maturation of the kidneys, the atypical distribution pattern of renin cells was maintained. These findings suggest that ANG II does not play a central role in the typical developmental shift in renin expression from the arcuate vessels to the afferent arterioles. During postnatal maturation of mouse kidneys, interruption of the RAS causes severe hyperplasia of renin cells via a mechanism that centrally involves AT(1a) receptors. However, the distribution pattern of renin cells in adult kidneys with an interrupted RAS does not mimic any normal developmental stage since renin expression is frequently found in cells outside the arteriolar vessel walls in RAS mutants.
在肾发生过程中，肾素表达以波浪状模式从叶间动脉的血管壁转移至入球小动脉的终末部分。由于肾素表达发育性失活的机制尚不清楚，我们推测发育中的肾素 - 血管紧张素系统（RAS）可能通过负反馈下调自身，以防止肾素过度激活。为了检测血管紧张素II在肾素表达发育性失活中的可能作用，我们研究了缺乏血管紧张素II AT1a、AT1b或AT2受体的小鼠以及因血管紧张素I转换酶（ACE）基因缺失而导致循环血管紧张素II缺失的动物肾内肾素表达的发育情况。缺乏血管紧张素II AT1b或AT2受体的小鼠肾内肾素表达发育正常。在同时缺乏血管紧张素II AT1a和AT1b受体、ACE或血管紧张素II AT1a受体的动物中，肾素表达早期正常，肾素从成熟血管中消失，直到皮质叶间动脉和入球小动脉开始发育。这些基因型的皮质血管发育伴随着肾素表达细胞数量的显著增加，其中许多细胞异位定位并以葡萄状方式附着于血管外周。虽然在肾脏最终成熟过程中肾素表达细胞数量减少，但肾素细胞的非典型分布模式得以维持。这些发现表明，血管紧张素II在肾素表达从弓形血管向入球小动脉的典型发育转变中不发挥核心作用。在小鼠肾脏出生后成熟过程中，RAS的中断通过一种主要涉及AT(1a)受体的机制导致肾素细胞严重增生。然而，RAS中断的成年肾脏中肾素细胞的分布模式并不模仿任何正常发育阶段，因为在RAS突变体中，肾素表达经常出现在小动脉血管壁外的细胞中。
