One of the most consistent abnormalities in ion transport found in patients with essential hypertension and their first degree relatives is overactivity of the red cell Na+-Li+ countertransporter. Given the fact that this transporter normally mediates Na+-Na+ exchange in red cells under physiologic conditions, its pathophysiologic role in hypertension has remained obscure. The principal goal of this project is to identify both the protein mediating Na+-Li+ countertransport and the gene that encodes it. It will then be possible to characterize the kinetic properties of this transporter, to determine in what other tissues it may be expressed, and thereby to gain new insight into its possible pathophysiologic role in hypertension. Moreover, once the gene encoding the Na+-Li+ countertransporter is identified, we will be able to test directly whether mutations leading to increased transport activity are associated with human hypertension. Our experimental approach will be guided by the hypothesis that the Na+-Li+ countertransporter is an isoform of the NHE (Na+-H+ exchanger) family of monovalent cation exchangers. In addition to characterizing the Na+-Li+ countertransporter and its role in hypertension, we will test whether mutations in NHE isoforms mediating Na+ reabsorption in the kidney (eg. NHE3) are associated with human hypertension. We will pursue the following sequence of studies. First, we will generate suitable antibodies to determine whether NHE4, the only one of the known NHE isoforms for which data have not rendered a role in mediating red cell Na+-Li+ countertransport unlikely, is expressed in red cells of human and rabbit, the latter a species with high countertransporter activity. If NHE4 is expressed in human and rabbit red cells, we will perform functional expression studies to test whether this isoform is capable of mediating amiloride-insensitive Na+-Li+ countertransport, and to evaluate transport properties of more physiologic relevance, such as the ability to mediate Na+-H+ exchange. In parallel with these studies, we will screen human bone marrow libraries to clone cDNAs encoding novel NHE isoform(s). For any novel NHE isoform that is identified, we will generate isoform- specific antisera to confirm its expression in red cells, and to determine the cellular and subcellular sites of its expression in other organs and tissues. In addition, functional expression studies will be performed to test the novel isoform for its ability to mediate Na+-Li+ countertransport, and to characterize its physiologically relevant transport properties. For NHE isoforms found to mediate red cell Na+-Li+ countertransport or to mediate apical Na+ entry into renal tubular cells (eg. NHE3), we will test for linkage to hypertension and will screen for mutations. Functional expression studies will be performed to compare the kinetic properties of wild-type and mutant NHE proteins. We will thereby be able to directly test the hypothesis that NHE mutations causing increased transport activity are associated with hypertension.
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