title: Role of caveolin 1 in AT1a receptor-mediated uptake of angiotensin II in the proximal tubule of the kidney.
abstract: 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)] receptor-mediated 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, Val(5)-ANG II was infused into WT and CAV-1 KO mice for 2 wk (1.5 mg·kg(-1)·day(-1) 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.
authors.affiliation: Laboratory of Receptor and Signal Transduction, Department of Pharmacology and Toxicology, Division of Nephrology, Department of Medicine, and Cardiovascular Renal Research Center, University of Mississippi Medical Center, Jackson, Mississippi.
authors.forename: Xiao C
authors.initials: XC
authors.lastname: Li
authors.affiliation: Laboratory of Receptor and Signal Transduction, Department of Pharmacology and Toxicology, Division of Nephrology, Department of Medicine, and Cardiovascular Renal Research Center, University of Mississippi Medical Center, Jackson, Mississippi.
authors.forename: Victor
authors.initials: V
authors.lastname: Gu
authors.affiliation: Laboratory of Receptor and Signal Transduction, Department of Pharmacology and Toxicology, Division of Nephrology, Department of Medicine, and Cardiovascular Renal Research Center, University of Mississippi Medical Center, Jackson, Mississippi.
authors.forename: Elise
authors.initials: E
authors.lastname: Miguel-Qin
authors.affiliation: Laboratory of Receptor and Signal Transduction, Department of Pharmacology and Toxicology, Division of Nephrology, Department of Medicine, and Cardiovascular Renal Research Center, University of Mississippi Medical Center, Jackson, Mississippi jzhuo@umc.edu.
authors.forename: Jia L
authors.initials: JL
authors.lastname: Zhuo
mesh_terms: D000804:Angiotensin II / Q000378:metabolism*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D051242:Caveolin 1 / Q000235:genetics / Q000502:physiology*; D002478:Cells, Cultured; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000378:metabolism*; D008297:Male; D018345:Mice, Knockout; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism*; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers / Q000096:biosynthesis
chemical_list: C495541:Cav1 protein, mouse; D051242:Caveolin 1; D034741:RNA, Small Interfering; D044140:Receptor, Angiotensin, Type 1; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers; D000804:Angiotensin II; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3
keywords: angiotensin II; angiotensin II type 1a receptor; blood pressure; caveolin 1; kidney; proximal tubule; signal transduction