Document text
Principal Investigator: Tianxin Yang
Organization: VA SALT LAKE CITY HEALTHCARE SYSTEM
Fiscal Year: 2019
Funding agency: Veterans Affairs
DESCRIPTION (provided by applicant):
A decade ago, (pro)renin receptor (PRR) was cloned as a new component of the renin-angiotensin system (RAS) with the capability to bind prorenin and renin to increase their catalytic activity. Soluble PRR (sPRR) is derived from the extracellular domain after cleavage by furin or ADMA19. Within the kidney, PRR is predominantly expressed in the collecting duct (CD) where its expression is elevated by AngII. Preliminary studies employing a novel PRR decoy peptide PRO20 demonstrated that intramedullary antagonism of PRR in rats produced remarkable attenuation of AngII-induced hypertension, renal medullary α-ENaC expression, and kidney injury, in parallel with suppressed renal medullary renin response and urinary aldosterone excretion. Strikingly, after adrenalectomy, this treatment suppressed urinary aldosterone excretion to undetectable level in AngII-infused rats, indicating a dominant role of PRR in nonadrenal aldosterone synthesis in the kidney. In vitro studies provide strong evidence for a direct action of PRR/sPRR in regulation of ENaC activity and aldosterone release from cultured CD cells. Based on these results, we hypothesize that during AngII infusion, PRR expression is increased in the CD where it triggers the local renin/aldosterone response, leading to ENaC activation and hence hypertension. To define the functional role of PRR in the CD, we propose to produce CD-specific deletion of PRR and study its impact on AngII-induced hypertension, target organ damage, local renin/aldosterone response, and ENaC activation in vivo and in vitro. We employ intramedullary infusion and conditional gene targeting techniques to evaluate the contribution of CD ENaC to AngII-induced hypertension. Lastly, we will evaluate urinary sPRR as a biomarker and further study the functional role and mechanism of sPRR in regulation of CD Na+ transport and blood pressure. The current proposal is expected to offer new insight into the role of CD PRR in the pathogenesis of hypertension and kidney injury.
Terms: <Adrenal Gland Excision><Adrenalectomy><Affect><Aldosterone><AngII><Angiotensin II><Angiotensin-Forming Enzyme><Angiotensinogenase><Big Renin><Binding><Biological Markers><Blood Pressure><Common Rat Strains><Cryorenin><Duct><Duct (organ) structure><Ductal Cell><Ductal Epithelial Cell><ENaC><Excretory function><External Domain><Extracellular Domain><Gene Deletion><Gene Targeting><Health><Hypertension><Hypertensive Nephropathy><In Vitro><Inactive Renin><Infusion><Infusion procedures><Injury><Kidney><Kidney Diseases><Kidney Urinary System><Light><Molecular Interaction><Nephropathy><Organ><Pathogenesis><Pathogenicity><Peptides><Photoradiation><Prorenin><Rat><Rats Mammals><Rattus><Receptor Protein><Regulation><Renal Disease><Renal Hypertension><Renin><Renin-Angiotensin System><Role><System><Techniques><Testing><Vascular Hypertensive Disease><Vascular Hypertensive Disorder><Veterans><attenuation><base><bio-markers><biologic marker><biomarker><epithelial Na+ channel><epithelial sodium channel><excretion><gene deletion mutation><high blood pressure><hyperpiesia><hyperpiesis><hypertension treatment><hypertensive disease><hypertensive kidney><in vivo><insight><kidney disorder><member><novel><patient population><public health relevance><receptor><receptor expression><renal><renal disorder><response><social role><urinary>