Angiotensin II induces carbon monoxide production in the perfused kidney: relationship to protein kinase C activation.

Abstract

Heme oxygenase (HO)-derived carbon monoxide (CO) attenuates vascular reactivity to constrictor stimuli. ANG II produces vasoconstriction and induces HO-1 isoform expression. However, direct evidence that ANG II promotes HO product generation is lacking. Therefore, we examined the effects of ANG II on CO release and HO isoform expression in isolated rat kidneys. Kidneys were perfused with oxygenated Krebs buffer. ANG II (1 micromol/l) increased (P < 0.05) perfusion pressure from 97 +/- 9 to 150 +/- 14 mmHg; it also increased (P < 0.05) the concentration of CO in the venous effluent (from 27.1 +/- 11.9 to 45.6 +/- 11.7, 62.5 +/- 16.7, 94.8 +/- 20.7, and 101.9 +/- 13.1 nmol/l after 30, 60, 90, and 120 min, respectively). The pressor effect of ANG II was blunted (P < 0.05) in kidneys perfused with buffer containing losartan (10 micromol/l) or PKC inhibitors staurosporine (0.1 micromol/l) or calphostin C (1 micromol/l). Kidneys perfused with buffer containing ANG II for 120 min also displayed increased (P < 0.05) HO-1 expression. Stannous mesoporphyrin (30 micromol/l) decreased CO release (P < 0.05) in preparations perfused with and without ANG II; the HO inhibitor also increased (P < 0.05) perfusion pressure, more so in kidneys perfused with that without ANG II. We conclude that ANG II stimulates CO production and release in isolated, perfused rat kidneys. This action of ANG II is linked to the activation of AT(1) receptors and involves PKC activation and upregulation of renal HO-1 but not of HO-2 protein expression. The study suggests upregulation of renal HO-1 and CO release are protagonic events in a counterregulatory mechanism that attenuates ANG II-induced renal vasoconstriction.