These investigators propose to examine the role of the endothelin-B receptor (ETB) in renal sodium handling and regulation of blood pressure. They have preliminary data indicating that genetically ETB-deficient rats exhibit salt-sensitive hypertension due to removal of ETB-mediated inhibition of apical epithelial sodium channels (ENaC) in the distal nephron. They hypothesize that in the distal nephron the endothelin system (via epithelial ETB) acts as a counterbalance to the renin-angiotensin-aldosterone system (RAS) in the regulation of the collecting duct ENaC, that is, activation of epithelial ETB downregulates the ENaC channel under high oral salt intake and thus promotes natriuresis. For this they propose four specific aims.
In Specific Aim 1 they hypothesize that ETB activation is essential for normal renal adjustment to increased salt intake. They will a) examine whether ETB-deficient rats exhibit abnormal sodium retention when challenged with a high-sodium diet, and to what extent this abnormality is affected by other systems involved in sodium homeostasis such as the RAS, atrial natriuretic peptide (ANP) and the sympathetic nervous system; b) attempt to reproduce this phenotype in wild-type rats through chronic ETB blockade and investigate the role of ETA activation in development of the phenotype; and c) test whether abnormal sodium retention can be corrected by ENaC inhibition.
In Specific Aim 2 they hypothesize that the relevant site of ETB action in blood pressure and fluid-volume regulation in rats is intrinsic to the kidney. They will conduct renal cross-transplantation experiments to determine whether the salt-sensitive hypertension in ETB-deficient rats is the result of an abnormality intrinsic to the kidney.
In Specific Aim 3 they hypothesize that normal rats respond to increased salt intake with increased activation of renal cortical collecting tubule ETB. They will use a variety of biochemical and histological techniques to examine the expression of ETB and its ligands, ET1 and ET3, in the normal kidney during high and low salt intake and also determine which cells within the kidney are responsible for increased ligand and/or receptor expression in rats challenged with an acute increase in sodium intake.
| Berti-Mattera, Liliana N; Gariepy, Cheryl E; Burke, Rebecca M et al. (2006) Reduced expression of endothelin B receptors and mechanical hyperalgesia in experimental chronic diabetes. Exp Neurol 201:399-406 |
| Ohkita, Mamoru; Wang, Yuqin; Nguyen, Ngoc Diep T et al. (2005) Extrarenal ETB plays a significant role in controlling cardiovascular responses to high dietary sodium in rats. Hypertension 45:940-6 |
| Gariepy, C E (2001) Intestinal motility disorders and development of the enteric nervous system. Pediatr Res 49:605-13 |
