Expression of both a renin-angiotensin system (RAS) and a kallilrein-kinin system (KKS) in tubular lumen of the nephron must impact on circulatory homeostasis through renal handling of sodium and water. Hypotheses regarding the regulation and function of these systems will be tested using the mouse as an experimental model. They have proposed that a paracrine RAS operates along the entire nephron that involves angiotensinogen (AGT) of proximal tubule (PT) origin and renin synthesized and secreted by connecting tubule (CNT). In subsequent work, they have found that renin and tissue kallikrein are expressed by the same cells of CNT. The main hypothesis is that tubular RAS and KKS exert closely interrelated paracrine functions in the regulation of final sodium excretion; these two systems are thereafter referred to as renin- kallikrein system (RKS). They will test specific hypotheses concerning (1) the regulation of hormone precursors of the RKS by dietary sodium, (2) the genetic basis for strain-specific differences in response to dietary salt, and (3) the significance of both PT angiotensinogen expression and genetic background in arterial pressure (AP) regulation. The relationship between these hormonal components and renal handling of sodium and water will be tested through the following experiments: (1) sodium balance will be disrupted by manipulations of dietary sodium with concordant or discordant alteration of plasma volume; (2) segmental sodium and fluid delivery at various sites along the nephron will be manipulated by selective alteration of reabsorption with diuretics; (3) the significance of the tubular RKS in renal sodium handling will be probed by specific pharmacological inhibition. Concordant strain variation in the amiloride-dependance of both sodium taste and CNT renin expression suggest the hypothesis of a genetic difference among strains in one or more genes involved in or regulated by sodium entry in epithelial cells. They propose to map such genes by linkage analysis in backcrosses of select strains and to identify the causal mutations following a candidate gene strategy. To test the significance of PT angiotensinogen and genetic background for baseline AP, the response of the tubular RKS to sustained alterations of dietary sodium will be examined in transgeneic animals expressing one to three AGT genes in two distinct backgrounds.
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