Collecting duct renin regulation of blood pressure in health and hypertension

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DESCRIPTION (provided by applicant): The intrarenal renin-angiotensin system (RAS) has been implicated in control of blood pressure (BP) under physiologic conditions and in the setting of hypertension. One component of this system, collecting duct (CD)- derived renin/prorenin, has been the subject of increasing studies in recent years. Renin production by the CD was definitively identified in 1999 and was hypothesized to hydrolyze tubule fluid angiotensinogen (AGT), ultimately leading to production of intraluminal angiotensin II (AngII). Since luminal AngII can stimulate CD Na transport, the idea developed that CD-derived renin played a role in controlling Na reabsorption and BP. Ensuing studies determined that CD-derived renin production was regulated differently than juxtaglomerular apparatus (JGA)-derived renin; in particular, AngII increased renin release by CD cells, while inhibiting renin secretion by the JGA. This suggested that CD renin might contribute to AngII-induced hypertension. In 2009, CD cells were described to express luminal prorenin receptors (PRR); since binding of renin or prorenin to PRR can increase AGT catalysis and activate intracellular signaling pathways, further support was lent to the notion that a system existed wherein CD-derived renin and/or prorenin modulated CD function to ultimately affect BP. Despite the substantial effort invested in understanding the biologic role of CD renin/prorenin, no studies to date have actually determined if CD-derived renin/prorenin can and does control Na reabsorption and BP. To address this fundamentally important question, our laboratory has developed mouse models that overexpress or delete renin/prorenin selectively within the CD. Our preliminary findings indicate that CD- derived renin/prorenin regulates BP and that this effect is evident under normal physiological conditions. These exciting data form the basis for the current proposal wherein we will analyze, for the first time, the physiological and pathophysiological relevance of CD renin/prorenin in the control of BP and renal function. The major hypotheses of this proposal are: 1) CD-derived renin/prorenin, via stimulation of luminal AngII formation and/or direct effects on the PRR, increases CD Na and water reabsorption via specific channels and raises BP; 2) CD-derived renin/prorenin contributes to the hypertension induced by high exogenous or endogenous AngII; and 3) CD renin/prorenin production is regulated by AngII via specific adenylyl cyclase (AC) isoforms, G proteins, Ca2+ signaling pathways, and protein kinase C (PKC). The proposal has three specific aims. Aim 1 will determine the effect of CD-derived renin/prorenin on blood pressure and renal function using mice with overexpressed or absent renin/prorenin in the CD. The impact of increased or absent CD renin/prorenin will be assessed with regard to BP, urinary Na and water excretion and the relevant affected channels, circulating hormones and the intrarenal RAS. Aim 2 will determine the role of CD-derived renin/prorenin in hypertension associated with excess AngII. The effect of CD renin/prorenin deficiency on hypertension due to increased exogenous (infused) or endogenous (renal artery stenosis) AngII will be assessed. Aim 3 will determine how CD renin/prorenin is regulated under basal and AngII-stimulated conditions. Using novel mouse lines with CD- specific deletion of AC isoforms, cells lines and primary cultures, the involvement of specific AC isoforms, G proteins and Ca signaling pathways in regulating CD renin/prorenin production will be examined.