title: Angiotensin II dose-dependently stimulates human renal proximal tubule transport by the nitric oxide/guanosine 3',5'-cyclic monophosphate pathway.
abstract: Stimulation of renal proximal tubule (PT) transport by angiotensin II (Ang II) is critical for regulation of BP. Notably, in rats, mice, and rabbits, the regulation of PT sodium transport by Ang II is biphasic: transport is stimulated by picomolar to nanomolar concentrations of Ang II but inhibited by nanomolar to micromolar concentrations of Ang II. However, little is known about the effects of Ang II on human PT transport. By functional analysis with isolated PTs obtained from nephrectomy surgery, we found that Ang II induces a dose-dependent profound stimulation of human PT transport by type 1 Ang II receptor (AT1)-dependent phosphorylation of extracellular signal-regulated kinase (ERK). In PTs of wild-type mice, the nitric oxide (NO) /cGMP/cGMP-dependent kinase II (cGKII) pathway mediated the inhibitory effect of Ang II. In PTs of cGKII-deficient mice, the inhibitory effect of Ang II was lost, but activation of the NO/cGMP pathway failed to phosphorylate ERK. Conversely, in human PTs, the NO/cGMP pathway mediated the stimulatory effect of Ang II by phosphorylating ERK independently of cGKII. These contrasting responses to the NO/cGMP pathway may largely explain the different modes of PT transport regulation by Ang II, and the unopposed marked stimulation of PT transport by high intrarenal concentrations of Ang II may be an important factor in the pathogenesis of human hypertension. Additionally, the previously unrecognized stimulatory effect of the NO/cGMP pathway on PT transport may represent a human-specific therapeutic target in hypertension.
authors: Departments of Internal Medicine and.
authors: Ayumi
authors: A
authors: Shirai
authors: Departments of Internal Medicine and.
authors: Osamu
authors: O
authors: Yamazaki
authors: Departments of Internal Medicine and.
authors: Shoko
authors: S
authors: Horita
authors: Departments of Internal Medicine and.
authors: Motonobu
authors: M
authors: Nakamura
authors: Departments of Internal Medicine and.
authors: Nobuhiko
authors: N
authors: Satoh
authors: Departments of Internal Medicine and.
authors: Hideomi
authors: H
authors: Yamada
authors: Departments of Internal Medicine and.
authors: Masashi
authors: M
authors: Suzuki
authors: Department of Anatomy, Kyorin University School of Medicine, Tokyo, Japan;
authors: Akihiko
authors: A
authors: Kudo
authors: Department of Anatomy, Kyorin University School of Medicine, Tokyo, Japan;
authors: Hayato
authors: H
authors: Kawakami
authors: Forschergruppe 923, Institut für Pharmakologie und Toxikologie der Technischen Universität München, München, Germany; and.
authors: Franz
authors: F
authors: Hofmann
authors: Department of Pharmacology, Kagawa University, Kagawa, Japan.
authors: Akira
authors: A
authors: Nishiyama
authors: Urology, Faculty of Medicine, The University of Tokyo, Tokyo, Japan;
authors: Haruki
authors: H
authors: Kume
authors: Urology, Faculty of Medicine, The University of Tokyo, Tokyo, Japan;
authors: Yutaka
authors: Y
authors: Enomoto
authors: Urology, Faculty of Medicine, The University of Tokyo, Tokyo, Japan;
authors: Yukio
authors: Y
authors: Homma
authors: Departments of Internal Medicine and georgeseki-tky@umin.ac.jp.
authors: George
authors: G
authors: Seki
mesh_terms: D000804:Angiotensin II / Q000008:administration & dosage* / Q000502:physiology*; D006152:Cyclic GMP / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D066298:In Vitro Techniques; D007687:Kidney Tubules, Proximal / Q000187:drug effects* / Q000378:metabolism*; D009569:Nitric Oxide / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology*
chemical_list: D000804:Angiotensin II; D009569:Nitric Oxide; D006152:Cyclic GMP