Mechanisms of hypertension-induced renal injury.

摘要

The first aim of this dissertation was to determine the role of elevated RPP on the production of ROS and renal damage in an Angiotensin II (AngII) + L-NAME + 0.4% NaCl model of hypertension. We hypothesized that this model of hypertension would result in elevated baseline levels of ROS and decreased NO that would result in the greatest level of susceptibility to RPP-induced renal damage. Pathways of ROS production and scavenging as well as NO production were determined in renal outer medullary and cortical tissue homogenates from AngII + L-NAME-infused rats with the left kidney servocontrolled for 14 days and in kidneys from sham operated rats. A second group of animals were studied to determine the role of elevated RPP versus circulating AngII + L-NAME on renal cortical and outer medullary damage. The results of these studies indicated that renal injury was greatest in the outer medullary region and was completely independent of elevated RPP and directly due to elevated levels of AngII and decreased NO production in this model system. Renal injury was associated with elevated ROS production and decreased NO production that was also independent of renal injury. The results of Aim 1 demonstrate that hypertension associated with a severe imbalance between intra-renal ROS and NO result in significant renal injury that is independent of elevated RPP.;The second aim of this dissertation was to determine if the susceptibility to RPP-induced renal injury is attenuated in norepinephrine (NE)-infused rats as compared to AngII-infused rats with a similar magnitude of hypertension. We had previously shown that elevated RPP was an important contributor to hypertension-induced renal injury, especially in the outer medulla, in 4.0% NaCl fed rats infused with AngII. In contrast to the AngII model of hypertension, the spontaneously hypertensive rat (SHR) does not develop significant renal injury despite severe elevations of RPP. Chronic infusion of NE has been utilized in previous studies to mimic the hypertension observed in the SHR. The results of these studies demonstrated that RPP-induced outer medullary tubular injury and fibrosis were significantly higher in AngII-infused rats as compared to NE-infused rats. Only a small, albeit significant, amount of outer medullary injury was due to the direct effects of circulating AngII, but NE showed no direct effects. These results suggest that AngII increases the susceptibility to RPP-induced outer medullary injury as compared to NE-induced hypertension.;In the third aim of this dissertation, we tested whether alterations in the intra-renal ROS-NO balance contributed to the increased susceptibility to RPP-induced outer medullary injury in AngII-infused versus NE-infused rats. RPP dependent and independent pathways of ROS and NO production were assessed in renal outer medullary and cortical tissue homogenates of AngII-infused, NE-infused, and sham operated rats. Results demonstrated that renal outer medullary superoxide production was elevated in a RPP-independent fashion in NE-infused rats. Conversely, in AngII-infused rats, both elevated RPP and circulating AngII contributed equally to outer medullary superoxide production in this model of hypertension. The magnitude of superoxide production was similar in AngII and NE-infused rats. The major source of the renal ROS production was different between these two models of hypertension with NADPH oxidase as the major source of superoxide production in AngII-infused rats while mitochondria were the primary source of superoxide production in NE-infused rats. With respect to NOS activity, AngII, but not NE, directly resulted in an increase in renal outer medullary NOS activity. These results suggest that the source of superoxide, rather than the magnitude of production, may contribute to the susceptibility to RPP-induced outer medullary injury in AngII-infused rats. The role of peroxynitrite, a reactive nitrogen species produced from the reaction of superoxide and nitric oxide, requires future investigations given the elevation in both of these molecules in AngII-infused rats, which demonstrate an increased susceptibility to RPP-induced renal injury. (Abstract shortened by UMI.)