Effects of ANG II type 1 and 2 receptors on oxidative stress, renal NADPH oxidase, and SOD expression

Am J Physiol Regul Integr Comp Physiol. 2003 Jul;285(1):R117-24. doi: 10.1152/ajpregu.00476.2002. Epub 2003 Feb 27.

Abstract

Oxidative stress accompanies angiotensin (ANG) II infusion, but the role of ANG type 1 vs. type 2 receptors (AT1-R and AT2-R, respectively) is unknown. We infused ANG II subcutaneously in rats for 1 wk. Excretion of 8-isoprostaglandin F2alpha (8-Iso) and malonyldialdehyde (MDA) were related to renal cortical mRNA abundance for subunits of NADPH oxidase and superoxide dismutases (SODs) using real-time PCR. Subsets of ANG II-infused rats were given the AT1-R antagonist candesartan cilexetil (Cand) or the AT2-R antagonist PD-123,319 (PD). Compared to vehicle (Veh), ANG II increased 8-Iso excretion by 41% (Veh, 5.4 +/- 0.8 vs. ANG II, 7.6 +/- 0.5 pg/24 h; P < 0.05). This was prevented by Cand (5.6 +/- 0.5 pg/24 h; P < 0.05) and increased by PD (15.8 +/- 2.0 pg/24 h; P < 0.005). There were similar changes in MDA excretion. Compared to Veh, ANG II significantly (P < 0.005) increased the renal cortical mRNA expression of p22phox (twofold), Nox-1 (2.6-fold), and Mn-SOD (1.5-fold) and decreased expression of Nox-4 (2.1-fold) and extracellular (EC)-SOD (2.1-fold). Cand prevented all of these changes except for the increase in Mn-SOD. PD accentuated changes in p22phox and Nox-1 and increased p67phox. We conclude that ANG II infusion stimulates oxidative stress via AT1-R, which increases the renal cortical mRNA expression of p22phox and Nox-1 and reduces abundance of Nox-4 and EC-SOD. This is offset by strong protective effects of AT2-R, which are accompanied by decreased expression of p22phox, Nox-1, and p67phox.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Angiotensin II / pharmacology
  • Angiotensin Receptor Antagonists
  • Animals
  • Antihypertensive Agents / pharmacology
  • Benzimidazoles / pharmacology
  • Body Weight
  • Gene Expression Regulation, Enzymologic / drug effects
  • Gene Expression Regulation, Enzymologic / physiology
  • Imidazoles / pharmacology
  • Isoprostanes / pharmacology
  • Kidney / enzymology*
  • Male
  • Malondialdehyde / metabolism
  • NADPH Oxidases / genetics
  • NADPH Oxidases / metabolism*
  • Oxidative Stress / physiology*
  • Pyridines / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, Angiotensin, Type 1
  • Receptor, Angiotensin, Type 2
  • Receptors, Angiotensin / metabolism*
  • Superoxide Dismutase / genetics
  • Superoxide Dismutase / metabolism*
  • Tetrazoles / pharmacology
  • Vasoconstrictor Agents / pharmacology

Substances

  • Angiotensin Receptor Antagonists
  • Antihypertensive Agents
  • Benzimidazoles
  • Imidazoles
  • Isoprostanes
  • Pyridines
  • Receptor, Angiotensin, Type 1
  • Receptor, Angiotensin, Type 2
  • Receptors, Angiotensin
  • Tetrazoles
  • Vasoconstrictor Agents
  • Angiotensin II
  • PD 123319
  • Malondialdehyde
  • Superoxide Dismutase
  • NADPH Oxidases
  • candesartan