Investigation of the function of the SA gene by gene targeting

The SA gene encodes a 578 amino acid protein of unknown function. SA was first identified as a candidate gene for hypertension and blood pressure regulation due to its increased expression in the kidneys of genetically hypertensive compared with normotensive rats.;The aim of the work undertaken in this thesis was to investigate the function of the SA gene by gene targeting in the mouse and to assess any possible involvement of the SA protein in BP homeostasis. We utilised ES cell technology to generate a mouse model carrying a null mutation of the SA gene. Mice lacking the protein product of the SA gene are viable, reproductively normal and have no overt phenotype. Body weight and kidney, liver and heart weights are not affected by the absence of the SA protein.;Comparison of basal blood pressures (BP) revealed no differences between SA-null and wildtype littermate controls in either male or female mice. Exposure of male mice to a high salt diet caused an increase in BP in wildtype mice. However in SA-null mice no effect of salt intake on BP was observed. It therefore appears that absence of the SA protein may offer some protection against a sodium induced rise in BP. The mechanism for this remains to be elucidated but may include an involvement of the SA protein in sodium retention.;Administration of dihydrotestosterone (DHT) to female wildtype mice caused no increase in BP. However in SA-null mice BP was increased in response to DHT administration implying a protective effect of SA against a DHT induced rise in BP.;These findings provide for the first time direct evidence of the involvement of the SA protein in BP regulation under certain conditions.