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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 90% (P 0.01) and inhibited FITC-labeled ANG II uptake by 50% (P 0.01). Moreover, CAV-1 siRNA attenuated ANG II-induced activation of MAPK ERK1/2 and Na/H exchanger 3 expression, respectively (P 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 50% in CAV-1 KO mice (P 0.01). Furthermore, Val5-ANG II was infused into WT and CAV-1 KO mice for 2 wk (1.5 mg·kg1·day1 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 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. [ABSTRACT FROM AUTHOR]