Endothelin -1 signaling and reactive oxygen species production in hypertension and type 1 diabetes mellitus.

摘要

Nitric oxide (NO) and endothelin-1 (ET-1) play important roles in the cardiovascular system, and alterations in these pathways can have significant effects on the regulation of blood pressure and renal function. Reactive oxygen species (ROS) influence the production and actions of these two factors, and therefore modulate the biological effects of NO and ET-1. Thus, the overall goal of these studies was to determine the impact of increased ROS and ET-1 production in the development of hypertension and diabetic kidney disease. We hypothesized that (1) increased superoxide production and a dysregulation of endothelial NO synthase (NOS3) in small arteries result in reduced NO bioavailability in hypertension; and (2) enhanced ET-1 production and endothelin A (ETA) receptor activation promotes renal injury in the settings of hypertension and diabetes. We found that basal NO/cGMP signaling is diminished in small mesenteric arteries of DOCA-salt rats, and this decrease is associated with reduced NOS3 phosphorylation at two positive regulatory sites, but not superoxide production. Chronic angiotensin II (Ang) infusion combined with a high salt diet increased the renal cortical and outer medullary ET-1 content. However, high salt diet, with or without Ang infusion, reduced inner medullary ET-1 content and increased urinary excretion of ET-1. These data indicate that chronic elevations in Ang levels and sodium intake produce differential effects on ET-1 levels within the kidney. Blockade of the ETA receptor with ABT-627 reduced renal injury in the streptozotocin model of type 1 diabetes. We found that oxidative stress was increased in hyperglycemic rats; however, the production of reactive oxygen species was not attenuated by ETA receptor blockade, indicating that the increased reactive oxygen species production observed in diabetes is not due to ETA receptor activation. Additionally, we found that urinary excretion of the metabolites of prostaglandin E2 (PGE2), prostacyclin, and thromboxane are all increased in hyperglycemic rats, and ETA receptor blockade reduced the excretion of PGE2 metabolites. By obtaining a better understanding of reactive oxygen species production and ET-1 signaling pathways, we have gained a new perspective on the roles of these factors in the development of hypertension and diabetic renal disease.