Genetic and biochemical determinants of abnormal monovalent ion transport in primary hypertension

Data obtained during the last two decades show that spontaneously hypertens ive rats, an acceptable experimental model of primary human hypertension, p ossess increased activity of both ubiquitous and renal cell-specific isofor ms of the Na+/H+ exchanger (NHE) and Na+-K+-2Cl(-) cotransporter. Abnormali ties of these ion transporters have been found in patients suffering from e ssential hypertension. Recent genetic studies demonstrate that genes encodi ng the beta- and gamma-subunits of ENaC, a renal cell-specific isoform of t he Na+-K+-2Cl(-) cotransporter, and alpha 3-, alpha 1-, and beta 2-subunits of the Na+-K+ pump are localized within quantitative trait loci (QTL) for elevated blood pressure as well as for enhanced heart-to-body weight ratio, proteinuria, phosphate excretion, and stroke latency. On the basis of the homology of genome maps, several other genes encoding these transporters, a s well as the Na+/H+ exchanger and Na+-K+-2Cl(-) cotransporter, can be pred icted in QTL related to the pathogenesis of hypertension. However, despite their location within QTL, analysis of cDNA structure did not reveal any mu tation in the coding region of the above-listed transporters in primary hyp ertension, with the exception of G276L substitution in the alpha 1-Na+-K+ p ump from Dahl salt-sensitive rats and a higher occurrence of T594M mutation of beta-ENaC in the black population with essential hypertension. These re sults suggest that, in contrast to Mendelian forms of hypertension, the alt ered activity of monovalent ion transporters in primary hypertension is cau sed by abnormalities of systems involved in the regulation of their express ion and/or function. Further analysis of QTL in F-2 hybrids of normotensive and hypertensive rats and in affected sibling pairs will allow mapping of genes causing abnormalities of these regulatory pathways.