Cao Z, Kelly D J, Cox A, Casley D, Forbes J M, Martinello P, Dean R, Gilbert R E, Cooper M E
Department of Medicine, University of Melbourne, Austin and Repatriation Medical Center (Repatriation Campus),Heidelberg West, Victoria, Australia.
Kidney Int. 2000 Dec;58(6):2437-51. doi: 10.1046/j.1523-1755.2000.00427.x.
Angiotensin II (Ang II) is associated with cell proliferation and apoptosis. The role of the angiotensin type 2 receptor (AT2R) in these processes remains controversial. Conventional radioligand binding of 125I-Sar1, Ile8 Ang II in adult kidney has failed to demonstrate the binding for the AT2R.
The presence of the AT2R was explored in adult rat kidney by in vitro and in vivo autoradiography using the selective AT2R radioligand 125I-CGP 42112B. The roles of the angiotensin type 1 receptor (AT1R) and the AT2R in mediating cellular proliferation and apoptosis were assessed using selective AT1R or AT2R antagonists in Ang II-infused Sprague-Dawley (SD) rats.
125I-CGP 42112B binding was demonstrated by in vitro and in vivo autoradiography techniques in the glomeruli and proximal tubules of SD rats. This binding could be displaced by Ang II and the AT2R antagonist PD123319 but not by the AT1R antagonist valsartan. Subcutaneous infusion of Ang II for 14 days in eight-week-old SD rats induced proliferation of proximal tubular epithelial cells, as assessed by a twofold increase in proliferating cell nuclear antigen (PCNA)-positive cells and apoptosis, as assessed by a threefold increase in terminal dUTP nick end labeling (TUNEL)-positive cells. The administration of the AT2R antagonist PD123319 or the AT1R antagonist valsartan was associated with attenuation of the increases in both PCNA- and TUNEL-positive cells following Ang II infusion. Ang II infusion was associated with increased osteopontin gene and protein expression, which could be reduced by treatment with either valsartan or PD123319.
These findings indicate that there is significant expression of the AT2R in the adult kidney, and that the AT2R has a role in mediating Ang II-induced proliferation and apoptosis in proximal tubular epithelial cells and expression of osteopontin.
血管紧张素II（Ang II）与细胞增殖和凋亡相关。2型血管紧张素受体（AT2R）在这些过程中的作用仍存在争议。在成年肾脏中，使用125I-Sar1、Ile8 Ang II进行的传统放射性配体结合未能证明AT2R的结合。
使用选择性AT2R放射性配体125I-CGP 42112B，通过体外和体内放射自显影技术在成年大鼠肾脏中探索AT2R的存在。在经Ang II灌注的Sprague-Dawley（SD）大鼠中，使用选择性AT1R或AT2R拮抗剂评估1型血管紧张素受体（AT1R）和AT2R在介导细胞增殖和凋亡中的作用。
体外和体内放射自显影技术证明125I-CGP 42112B在SD大鼠的肾小球和近端小管中有结合。这种结合可被Ang II和AT2R拮抗剂PD123319取代，但不能被AT1R拮抗剂缬沙坦取代。对8周龄SD大鼠皮下输注Ang II 14天，可诱导近端肾小管上皮细胞增殖，通过增殖细胞核抗原（PCNA）阳性细胞增加两倍来评估；同时可诱导细胞凋亡，通过末端脱氧核苷酸转移酶介导的缺口末端标记（TUNEL）阳性细胞增加三倍来评估。给予AT2R拮抗剂PD123319或AT1R拮抗剂缬沙坦与Ang II输注后PCNA和TUNEL阳性细胞增加的减弱有关。Ang II输注与骨桥蛋白基因和蛋白表达增加有关，用缬沙坦或PD123319治疗可使其降低。
这些发现表明，成年肾脏中存在显著的AT2R表达，并且AT2R在介导Ang II诱导的近端肾小管上皮细胞增殖、凋亡以及骨桥蛋白表达中发挥作用。
