title: Intrarenal transfer of an intracellular fluorescent fusion of angiotensin II selectively in proximal tubules increases blood pressure in rats and mice.
abstract: The present study tested the hypothesis that intrarenal adenoviral transfer of an intracellular cyan fluorescent fusion of angiotensin II (ECFP/ANG II) selectively in proximal tubules of the kidney increases blood pressure by activating AT(1) (AT(1a)) receptors. Intrarenal transfer of ECFP/ANG II was induced in the superficial cortex of rat and mouse kidneys, and the sodium and glucose cotransporter 2 (sglt2) promoter was used to drive ECFP/ANG II expression selectively in proximal tubules. Intrarenal transfer of ECFP/ANG II induced a time-dependent, proximal tubule-selective expression of ECFP/ANG II in the cortex, which peaked at 2 wk and was sustained for 4 wk. ECFP/ANG II expression was low in the glomeruli and the entire medulla and was absent in the contralateral kidney or extrarenal tissues. At its peak of expression in proximal tubules at day 14, ANG II was increased by twofold in the kidney (P < 0.01) and more than threefold in proximal tubules (P < 0.01), but remained unchanged in plasma or urine. Systolic blood pressure was increased in ECFP/ANG II-transferred rats by 28 ± 6 mmHg (P < 0.01), whereas fractional sodium excretion was decreased by 20% (P < 0.01) and fractional lithium excretion was reduced by 24% (P < 0.01). These effects were blocked by losartan and prevented in AT(1a) knockout mice. Transfer of a scrambled ECFP/ANG IIc had no effects on blood pressure, kidney, and proximal tubule ANG II, or sodium excretion. These results provide evidence that proximal tubule-selective transfer of an intracellular ANG II fusion protein increases blood pressure by activating AT(1a) receptors and increasing sodium reabsorption in proximal tubules.
authors.affiliation: Laboratory of Receptor and Signal Transduction, Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, 39216-4505, USA.
authors.forename: Xiao C
authors.initials: XC
authors.lastname: Li
authors.forename: Julia L
authors.initials: JL
authors.lastname: Cook
authors.forename: Isabelle
authors.initials: I
authors.lastname: Rubera
authors.forename: Michel
authors.initials: M
authors.lastname: Tauc
authors.forename: Fan
authors.initials: F
authors.lastname: Zhang
authors.forename: Jia L
authors.initials: JL
authors.lastname: Zhuo
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000804:Angiotensin II / Q000096:biosynthesis* / Q000097:blood / Q000235:genetics / Q000652:urine; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D004195:Disease Models, Animal; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D049452:Green Fluorescent Proteins / Q000096:biosynthesis* / Q000097:blood / Q000235:genetics / Q000652:urine; D006973:Hypertension / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology / Q000517:prevention & control; D007687:Kidney Tubules, Proximal / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009318:Natriuresis; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1 / Q000172:deficiency / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D013997:Time Factors; D014161:Transduction, Genetic; D014162:Transfection; D015854:Up-Regulation; D014554:Urination
chemical_list: C544066:Agtr1a protein, mouse; C544067:Agtr1a protein, rat; D047228:Angiotensin II Type 1 Receptor Blockers; D044140:Receptor, Angiotensin, Type 1; D011993:Recombinant Fusion Proteins; C527701:enhanced cyan fluorescent protein; D000804:Angiotensin II; D049452:Green Fluorescent Proteins