Date of Degree
PhD (Doctor of Philosophy)
Curt D. Sigmund
Renin is an enzyme that catalyzes the rate-limiting step in the production of angiotensin peptides, and is thus a key regulator of processes controlled by angiotensin such as blood pressure, hydromineral balance, and metabolism. Our laboratory and others have previously identified a novel isoform of renin (icRen) which, as a result of the utilization of an alternate first exon, lacks the signal peptide and first third of the pro-segment of classical secreted renin (sRen). This alternate icRen isoform thus remains within the cytoplasm of the cell, but is constitutively active. Here, we report that while sRen is the predominant form of renin expressed in most tissues during development, icRen is the predominant form of renin within the adult brain. Thus, we hypothesized that sRen and icRen play distinct physiological roles in adult mice. To examine this hypothesis, we have utilized the Cre-LoxP system to selectively delete either isoform globally or within selected cell types such as neurons and glia. We have successfully developed a "sRen-flox" model, in which endogenous mouse sRen isoform can be selectively deleted, while not affecting endogenous icRen production. Breeding these mice against the E2A-Cre, Nestin-Cre, and GFAP-Cre mouse lines resulted in global-, neuronal-, and glial-specific knockouts of sRen, respectively. Physiological characterization of resulting mice has uncovered postnatal lethality, hypotension, renal atrophy, vascular dysfunction and decreased body weight and white adipose in the global knockouts. Depletion of sRen from only neuronal or glial cells does not appear to alter any of these phenotypes at baseline. From these data, we conclude that while peripheral sRen is of primary importance to blood pressure regulation, hydromineral balance, and metabolism, central expression of this isoform is unimportant. Further, comparison of our results to published findings from global total renin knockout models indirectly supports a role for icRen in the brain. We are currently in the process of generating icRen-flox and subsequent knockout mice, which will be useful models to directly analyze the physiological role(s) of icRen.
Blood Pressure, Brain, Isoform, Mouse Model, Renin
xiv, 226 pages
Includes bibliographical references (pages 210-226).
Copyright 2010 Di Xu