We previously reported that sodium excretion is significantly correlated to the excretion of nitrate/nitrite, cGMP, and endothelin in normotensive young adults. In rats and mice in vivo, loss of functional NOSI through both genetic and pharmacological inhibition delays the excretion of sodium and blunts nitrite/nitrate excretion following an acute salt challenge. Since the final control of sodium excretion occurs in the collecting duct, we have hypothesized that the activation of NOSI and NO production in this nephron segment facilitates sodium excretion. To directly test this hypothesis, we have recently created collecting duct specific NOSI knockout (CD NOSI KO) mice. Our preliminary data indicates that the CD NOSI KO mice have salt-dependent hypertension compared to control mice. In collaboration with Kohan's laboratory, we have demonstrated a role for collecting duct-derived endothelin in the activation of NOS under basal and high salt conditions. In vitro studies have shown that endothelin activates NOSI in renal medullary collecting duct cells. It is known that the collecting duct is a major source of endothelin. Thus, we have predicted that endothelin stimulates NOSI in the collecting duct in an autocrine manner. One of the known mechanisms that controls sodium reabsorption in the collecting duct is via subcellular trafficking of the epithelial sodium channel (ENaC) from the apical membrane via endocytosis. Recentiy, it has been shown that NO promotes endocytosis via activation of dynamin through S-nitrosylation in endothelial cells, although it is unknown whether this occurs in the collecting duct. ENaC trafficking is regulated by dynamin-dependent endocytosis. Our preliminary data demonstrates that NOSI interacts with dynamin in the renal inner medulla. Furthermore, our data indicates that dynamin is S-nitrosylated in the renal inner medulla. We have hypothesized that collecting duct N0S1 regulates dynamin-dependent endocytosis of collecting duct sodium channels. Experiments are designed based on the following aims:
Aim 1. To test the hypothesis that collecting duct-derived endothelin is a major autocrine regulator of N0S1 activation In the collecting duct during changes In dietary sodium.
Aim 2. To test the hypothesis that in the collecting duct, NOSI regulates endocytosis of sodium channels via a dynamin-dependent mechanism.
The Program Project focuses on elucidating mechanisms by which the kidney controls sodium excretion, and therefore, has direct relevance to the serious health problem of salt-dependent hypertension and kidney disease. The central hypothesis of project 3 is that endothelin facilitates sodium excretion by stimulation of NOSI and increased NO production in the collecting duct.
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