title: Ang II accumulation in rat renal endosomes during Ang II-induced hypertension: role of AT(1) receptor.
abstract: Hypertension induced by long-term infusion of angiotensin II (Ang II) is associated with augmented intrarenal Ang II levels to a greater extent than can be explained on the basis of the circulating Ang II levels. Although part of this augmentation is due to AT(1) receptor-dependent internalization, the intracellular compartments involved in this Ang II accumulation remain unknown. In the present study, we sought to determine whether Ang II trafficking into renal cortical endosomes is increased during Ang II hypertension, and if so, whether the AT(1) receptor antagonist, candesartan, prevents this accumulation. Compared with controls (n=12; 114+/-2 mm Hg), Ang II-infused rats (n=12; 80 ng/kg/min, SC, for 13 days) developed hypertension with systolic blood pressure rising to 185+/-4 mm Hg by Day 12. In Ang II hypertensive rats, plasma renin activity was suppressed, whereas plasma and kidney Ang II levels were increased by 3-fold (348+/-58 versus 119+/-16 fmol/mL) and 2-fold (399+/-39 versus 186+/-26 fmol/g). Intracellular endosomal Ang II levels were increased by more than 10-fold (1100+/-283 versus 71+/-12 fmol/mg protein), whereas intermicrovillar cleft Ang II levels were increased by more than 2-fold (88+/-22 versus 37+/-7 fmol/mg protein). Flow cytometric analysis detected significant increases in AT(1A) receptor antibody binding in endosomal and intermicrovillar clefts of Ang II-infused rats. The hypertension induced by Ang II was prevented in rats treated concurrently with candesartan (2 mg/kg/d, 119+/-3 mm Hg). Candesartan treatment (n=8) also prevented increases in kidney (215+/-19 fmol/g), endosomal (96+/-29 fmol/mg protein), and intermicrovillar cleft Ang II levels (11+/-2 fmol/mg protein). These results indicate that there is substantial intracellular accumulation of angiotensin peptides in renal cortical endosomes during Ang II-dependent hypertension via an AT(1) receptor-mediated process.
authors.affiliation: Department of Physiology, Tulane University School of Medicine, Veterans Administration Medical Center , New Orleans, Louisiana 70112, USA.
authors.forename: Jia L
authors.initials: JL
authors.lastname: Zhuo
authors.forename: John D
authors.initials: JD
authors.lastname: Imig
authors.forename: Timothy G
authors.initials: TG
authors.lastname: Hammond
authors.forename: Sheyla
authors.initials: S
authors.lastname: Orengo
authors.forename: Edmund
authors.initials: E
authors.lastname: Benes
authors.forename: L Gabriel
authors.initials: LG
authors.lastname: Navar
mesh_terms: D000803:Angiotensin I / Q000097:blood; D000804:Angiotensin II / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000906:Antibodies / Q000378:metabolism; D000959:Antihypertensive Agents / Q000494:pharmacology; D001562:Benzimidazoles / Q000494:pharmacology; D001713:Biphenyl Compounds; D001794:Blood Pressure / Q000187:drug effects; D003911:Dextrans / Q000493:pharmacokinetics; D011992:Endosomes / Q000378:metabolism*; D005434:Flow Cytometry; D005452:Fluoresceins / Q000493:pharmacokinetics; D006973:Hypertension / Q000139:chemically induced / Q000378:metabolism*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D008297:Male; D008871:Microvilli / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin / Q000276:immunology / Q000378:metabolism*; D012083:Renin / Q000097:blood; D013599:Systole / Q000187:drug effects; D013777:Tetrazoles / Q000494:pharmacology
chemical_list: D057911:Angiotensin Receptor Antagonists; D000906:Antibodies; D000959:Antihypertensive Agents; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D003911:Dextrans; D005452:Fluoresceins; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin; D013777:Tetrazoles; C052526:fluorescein-dextran; D000804:Angiotensin II; D000803:Angiotensin I; D012083:Renin; C081643:candesartan