There has been considerable interest in the existence of an intrarenal renin angiotensin system (RAS) and its physiological implications. The recent documentation of angiotensinogen mRNA in rat and mouse kidney provides strong evidence for the presence of an independent local RAS. This is further supported by the demonstration of tissue differential regulation (e.g. kidney vs liver) of angiotensinogen and renin mRNA expression. The purposes of this proposal are to employ biochemical and molecular biology techniques to characterize the intrarenal renin angiotensin system with focus on angiotensinogen (since renal renin is primarily secreted and changes in parallel with the circulating levels). We plan to employ in situ hybridization techniques to localize the cells which synthesize renal angiotensinogen and to compare this to the localization of renin synthesis. We expect that such localization will have strong implications for studies of angiotensinogen regulation and function. We will also examine the regulation of the expression of intrarenal angiotensinogen and its mRNA by factors known to influence the renin-angiotensin system, focusing on the role of sodium chloride. For comparison we will also examine the effects these physiological manipulations on levels of other components of the renin angiotensin system (AI, AII, renin, and renin mRNA). Selective blocking of the components of the renin angiotensin system will be used to study possible feedback regulation. Throughout these studies we will also measure blood pressure as well as parameters of renal function. Thus, this application attempts to combine molecular biology techniques with renal physiology, which may shed light on the regulation of the intrarenal renin angiotensin system and may also clarify the function of this intrarenal system.
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