CELLULAR ION HOMEOSTASIS IN HYPERTENSION

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The goal of this project is to identify the cellular basis of a likely tubular transport abnormality (either intrinsic to the kidney or an abnormal response to regulatory humoral agents) which leads to inappropriate sodium retention in experimental animal models of hypertension. The assumption underlying this project is that the presumed membrane defect is expressed in a disturbance of the cellular homeostasis of renal cells and, therefore, should be detectable by intracellular concentration measurements. For determination of electrolyte concentrations in individual tubular cells, or even subcellular structures, we will employ the technique of electron microprobe analysis. The analyses will be performed on thin frozen-dried cryosections obtained from fresh, shock-frozen tissue samples. Initially, only short, non-perfused isolated nephron segments will be used as specimen. Later, we will attempt to obtain longer segments which can be perfused prior to freezing under in vitro conditions. For this purpose, we will develop a technique which allows rapid freezing of the tubules while being perfused. Using these methods, we will first study the cellular electrolytes composition of different tubular segments obtained from two different models of genetically fixed hypertension. Second, we will examine the effect of high and normal NaC1-containing diets in different animal models. Third, we will investigate the possibility of an abnormal responsiveness to modulators of tubular Na transport. This project will be closely integrated with the transport studies of Projects 2, 3, 4 and 8.