Nuclear angiotensin II type 2 (AT2) receptors are functionally linked to nitric oxide production
Nuclear angiotensin II type 2 (AT2) receptors are functionally linked to nitric oxide production
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DOI：
10.1152/ajprenal.90766.2008
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发表时间：
2009-06-01
影响因子：
4.2
通讯作者：
Chappell, Mark C.
中科院分区：
文献类型：
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作者：
Gwathmey, TanYa M.;Shaltout, Hossam A.;Chappell, Mark C.
Gwathmey TM，Shaltout HA，Pendergras KD，Pirro NT，Figueroa JP，Rose JC，Diz DI，Cappell MC。核血管紧张素II(AT(2))受体在功能上与一氧化氮的产生有关。Am J Physiol Renal Physiol 296：F1484-F1493,2009。2009年2月25日首次发表；DOI：10.1152/ajprenal.90766.2008。-大鼠肾脏中核血管紧张素II(AT(1))受体的表达为细胞内肾素-血管紧张素系统的概念提供了进一步的支持。因此，我们研究了绵羊肾脏Ang II受体的细胞分布，以确定细胞内Ang受体在高级物种中的存在和功能作用。用非选择性Ang II拮抗剂I-125-[Sar(1)，Thr(8)]-Ang II(I-125-Sarthran)与AT(1)拮抗剂氯沙坦(Los artan，LOS)或AT(2)拮抗剂PD123319(PD)在分离的核(NUC)和质膜(PM)中进行受体结合。在胚胎和成年绵羊肾脏中，PD竞争大多数皮质NUC(>；=70%)和PM(>；=80%)，而LOS竞争主要存在于延髓NUC(>；=75%)和PM(>；=70%)。用AT(2)抗体进行免疫检测，在NUC和PM提取物中都发现了一条类似于42 kDa的单一条带，这表明NUC受体是一种成熟的分子形式。AT(2)定位于肾小管间质，AT(1)定位于延髓和直血管，AT(1)和AT(2)定位于肾小球。NO荧光检测器DAF负载NUC后，Ang II(1 NM)可使NUC产生NO的量增加，这种作用可被PD和N-硝基-L-精氨酸甲酯所阻断，但不能被LOS所抑制。我们的研究表明，Ang II受体亚型在绵羊肾脏中有不同的表达，而核AT(2)受体在功能上与NO的产生有关。这些发现进一步证明了肾脏细胞内肾素-血管紧张素系统的功能，这可能是调节血压的治疗靶点。
Gwathmey TM, Shaltout HA, Pendergrass KD, Pirro NT, Figueroa JP, Rose JC, Diz DI, Chappell MC. Nuclear angiotensin II type 2 (AT(2)) receptors are functionally linked to nitric oxide production. Am J Physiol Renal Physiol 296: F1484-F1493, 2009. First published February 25, 2009; doi:10.1152/ajprenal.90766.2008.-Expression of nuclear angiotensin II type 1 (AT(1)) receptors in rat kidney provides further support for the concept of an intracellular renin-angiotensin system. Thus we examined the cellular distribution of renal ANG II receptors in sheep to determine the existence and functional roles of intracellular ANG receptors in higher order species. Receptor binding was performed using the nonselective ANG II antagonist I-125-[Sar(1), Thr(8)]-ANG II (I-125- sarthran) with the AT(1) antagonist losartan (LOS) or the AT(2) antagonist PD123319 (PD) in isolated nuclei (NUC) and plasma membrane (PM) fractions obtained by differential centrifugation or density gradient separation. In both fetal and adult sheep kidney, PD competed for the majority of cortical NUC (>= 70%) and PM (>= 80%) sites while LOS competition predominated in medullary NUC (>= 75%) and PM (>= 70%). Immunodetection with an AT(2) antibody revealed a single similar to 42-kDa band in both NUC and PM extracts, suggesting a mature molecular form of the NUC receptor. Autoradiography for receptor subtypes localized AT(2) in the tubulointerstitium, AT(1) in the medulla and vasa recta, and both AT(1) and AT(2) in glomeruli. Loading of NUC with the fluorescent nitric oxide (NO) detector DAF showed increased NO production with ANG II (1 nM), which was abolished by PD and N-nitro-L-arginine methyl ester, but not LOS. Our studies demonstrate ANG II receptor subtypes are differentially expressed in ovine kidney, while nuclear AT(2) receptors are functionally linked to NO production. These findings provide further evidence of a functional intracellular renin-angiotensin system within the kidney, which may represent a therapeutic target for the regulation of blood pressure.