The renin-angiotensin system (RAS) plays a fundamental role in the physiological control of blood pressure and fluid homeostasis and increased activity of the system can contribute to the pathophysiology of numerous disorders including essential hypertension. A key regulator of RAS is dietary Na+; Na+ restriction activates the RAS, while Na+ loading has the opposite effect. Although extensive literature exists on the effects of dietary Na+ on renal hemodynamics in the dog, very little is known about its effects on renal dAT1 receptors. The overall goal of this project is to investigate the effects of dietary Na+ manipulation on the distribution and regulation of type-1 angiotensin II receptors in the canine kidney (dAT1) with positron emission tomography (PET) and correlate the PET findings with biochemical analysis of dAT1 protein and mRNA expression in the renal cortex and medulla. PET studies will employ a novel radioligand, [C-11]L-159,884, which is an AT1 specific receptor antagonist. This proposal is designed to test the hypothesis that alterations in dietary sodium in dogs result in regulatory changes in dAT1 renal receptors at the transcriptional and/or posttranslational level and that in vivo binding parameters of [C-11]L-159,884 in the kidney reflect these changes.
The specific aims are: To measure and quantitate binding parameters of [C-11]L-159,884 in the kidney with PET in vivo under baseline conditions (Aim 1) and to investigate the effects of low Na+ diet (Aim 2) and high Na+ diet (Aim 3) on the regulation of dAT1 receptors. In addition, dAT1 mRNA levels will be quantitated and compared with receptor binding characteristics in the renal cortex and medulla which will permit investigation of potential tissue-specific and/or post-translational regulatory mechanisms during alterations in the RAS. These experiments could provide the first in vivo evidence of tissue-specific regulatory mechanisms governing AT1 expression. In both dogs and humans, the effect of angitensin II (Ang II) action on fluid homeostasis and cardiovascular function is mediated through one AT1 gene in contrast to rodents which possess two distinct and differentially regulated AT1 receptor subtypes. Thus, the dog was chosen because the dAT1 receptor is an excellent model for the human AT1 receptor. Investigations of the regulation of AT1 receptors in the dog is a first step in using this non-invasive PET technique to examine human AT1 receptors and thus, this research may ultimately lead to a greater understanding of the regulation of human AT1 receptors under physiological and pathophysiological conditions, such as human hypertensive disorders and congestive heart failure.
Showing the most recent 10 out of 22 publications
