AT_1 receptor activation regulates the mRNA expression of CAT1, CAT2, arginase-1, and DDAH2 in preglomerular vessels from angiotensin II hypertensive rats

摘要

Previously, we found increased expression of L-arginine metabolizing enzymes in both kidneys from two-kidney, one-clip (2K1C) hypertensive rats (Helle F, Hultstrom M, Skogstrand T, Palm F, Iversen BM. Am J Physiol Renal Physiol 296: F78-F86, 2009). In the present study, we investigate whether AT_1 receptor activation can induce the changes observed in 2K1C. Four groups of rats were infused with 80 ng/min ANG II or saline for 14 days and/or given 60 mg centre dot kg~(-1) centre dot day~(-1) losartan. Gene expression was studied in isolated preglomerular vessels by RT-PCR. Dose-responses to ANG II were studied in isolated preglomerular vessels with and without acute NOS inhibition [10~(-4)mol/l N~G-nitro-L-arginine methyl ester (L-NAME)]. Expressions of endothelial nitric oxide synthase (eNOS), caveolin-1, and arginase-2 were not changed by ANG II infusion. CAT1 (0.3 8 +- 0.07 to 0.73 +- 0.12, P < 0.05), CAT2 (1.14 +- 0.29 to 2.74 +- 0.48), DDAH2 (1.09 +- 0.27 to 2.3 +- 0.46), and arginase-1 (1.08 +- 0.17 ,to 1.82 +- 0.22) were increased in ANG II-infused rats. This was prevented by losartan treatment, which reduced the expression of eNOS (0.97 +- 0.26 to 0.37 +- 0.11 in controls; 0.8 +- 0.16 to 0.36 +- 0.1 in ANG II-infused rats) and caveolin-1 (2.49 +- 0.59 to 0.82 +- 0.24 in controls and 2.59 +- 0.61 to 1.1 +- 0.25 in ANG II-infused rats). ANG II (10~(-10) mol/l) caused vessels from ANG II-infused animals to contract to 53 +- 15% of baseline diameter and 90 +- 5% of baseline diameter in controls (P < 0.05) and was further enhanced by L-NAME to 4 +- 4% of baseline diameter (P < 0.05). In vivo losartan treatment reduced the reactivity of isolated vessels to 91 +- 2% of baseline in response to 10~(-7) mol/l ANG II compared with 82 +- 3% in controls (P < 0.05) and prevented the increased responsiveness caused by ANG II infusion. In conclusion, CAT1, CAT2, DDAH2, and arginase-1 expression in renal resistance vessels is regulated through the AT_1 receptor. This finding may be of direct importance for NOS and the regulation of preglomerular vascular function.