ANG II is the most potent and important member of the classical renin-angiotensin system (RAS). ANG II, once considered to be an endocrine hormone, is now increasingly recognized to also play novel and important paracrine (cell-to-cell) and intracrine (intracellular) roles in cardiovascular and renal physiology and blood pressure regulation. Although an intracrine role of ANG II remains an issue of continuous debates and requires further confirmation, a great deal of research has recently been devoted to uncover the novel actions and elucidate underlying signaling mechanisms of the so-called intracellular ANG II in cardiovascular, neural, and renal systems. The purpose of this article is to provide a comprehensive review of the intracellular actions of ANG II, either administered directly into the cells or expressed as an intracellularly functional fusion protein, and its effects throughout a variety of target tissues susceptible to the impacts of an overactive ANG II, with a particular focus on the proximal tubules of the kidney. While continuously reaffirming the roles of extracellular or circulating ANG II in the proximal tubules, our review will focus on recent evidence obtained for the novel biological roles of intracellular ANG II in cultured proximal tubule cells in vitro and the potential physiological roles of intracellular ANG II in the regulation of proximal tubular reabsorption and blood pressure in rats and mice. It is our hope that the new knowledge on the roles of intracellular ANG II in proximal tubules will serve as a catalyst to stimulate further studies and debates in the field and to help us better understand how extracellular and intracellular ANG II acts independently or interacts with each other, to regulate proximal tubular transport and blood pressure in both physiological and diseased states.
Li XC, Gu V, Miguel-Qin E, Zhuo JL. Role of caveolin 1 in AT1a receptor-mediated uptake of angiotensin II in the proximal tubule of the kidney. Am J Physiol Renal Physiol 307: F949 -F961, 2014. First published August 27, 2014 doi:10.1152/ajprenal.00199.2014.-Caveolin 1 (CAV-1) functions not only as a constitutive scaffolding protein of caveolae but also as a vesicular transporter and signaling regulator. In the present study, we tested the hypothesis that CAV-1 knockout (CAV-1 KO) inhibits ANG II type 1 [AT1 (AT1a)] receptormediated uptake of ANG II in the proximal tubule and attenuates blood pressure responses in ANG II-induced hypertension. To determine the role of CAV-1 in mediating the uptake of FITC-labeled ANG II, wild-type (WT) mouse proximal convoluted tubule cells were transfected with CAV-1 small interfering (si)RNA for 48 h before AT1 receptor-mediated uptake of FITC-labeled ANG II was studied. CAV-1 siRNA knocked down CAV-1 expression by Ͼ90% (P Ͻ 0.01) and inhibited FITC-labeled ANG II uptake by Ͼ50% (P Ͻ 0.01). Moreover, CAV-1 siRNA attenuated ANG II-induced activation of MAPK ERK1/2 and Na ϩ /H ϩ exchanger 3 expression, respectively (P Ͻ 0.01). To determine whether CAV-1 regulates ANG II uptake in the proximal tubule, Alexa 488-labeled ANG II was infused into anesthetized WT and CAV-1 KO mice for 60 min (20 ng/min iv). Imaging analysis revealed that Alexa 488-labeled ANG II uptake was decreased by Ͼ50% in CAV-1 KO mice (P Ͻ 0.01). Furthermore, Val 5 -ANG II was infused into WT and CAV-1 KO mice for 2 wk (1.5 mg·kg Ϫ1 ·day Ϫ1 ip). Basal systolic pressure was higher, whereas blood pressure and renal excretory and signaling responses to ANG II were attenuated, in CAV-1 KO mice (P Ͻ 0.01). We concluded that CAV-1 plays an important role in AT1 receptor-mediated uptake of ANG II in the proximal tubule and modulates blood pressure and renal responses to ANG II. angiotensin II; angiotensin II type 1a receptor; blood pressure; caveolin 1; kidney; proximal tubule; signal transduction CAVEOLAE, the vital plasma membrane invaginations in most cell types, play important roles in intracellular vesicular transport, cancer development, G protein-coupled receptor signaling, and cholesterol homeostasis (5, 7, 34). Caveolae are formed from three major structural proteins: caveolin (CAV)-1, CAV-2, and CAV-3 (5, 34, 43). CAV-1 and CAV-2 appear to coexpress or heterooligomerize in most cell types of nonmuscular tissues, whereas the expression of CAV-3 is predominantly localized in muscles (34,43). Among the three CAV proteins, CAV-1 has been extensively studied with respect to its biology, distribution, and functions in cardiovascular and pulmonary regulation and in cancer development. Global knockout (KO) of the CAV-1 gene is associated with the absence of caveolae in all tissues (5, 9, 34), abnormal nitric oxide (NO) and Ca 2ϩ signaling, and cardiovascular disorders, including atherosclerosis, cardiac hypertrophy, and cardiomyopathy (6, 9, 43). Double CAV-1 and CAV-3 KO leads to the depletion of caveolae in both mu...
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