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Principal Investigator: Tianxin Yang
Organization: UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
Fiscal Year: 2019
Award: $566,573
Funding agency: National Heart Lung and Blood Institute
(Pro)renin receptor (PRR) binds prorenin/renin in vitro to increase their catalytic activity and
therefore is postulated to be a regulator of renin. Soluble PRR (sPRR) residing in the
extracellular domain of PRR is produced by furin or ADAM19-dependent cleavage process and
has been widely studied as a disease biomarker. Although PRR has an established role in
embryogenesis in both low vertebrates and mammals, the potential role of PRR/sPRR in
regulation of mammalian renal function and blood pressure largely remains elusive. Within the
kidney, PRR is predominately expressed in the distal nephron, particularly the intercalated cells
of the collecting duct (CD). In preliminary studies, we discovered a previously undescribed
paracrine action of PRR/sPRR with intercalated cell-derived sPRR acting on principal cells to
stimulate ENaC-mediated Na+ reabsorption. We presented further evidence that PRR/sPRR-
mediated paracrine control of Na+ transport contributes to pathogenesis of mineralocorticoid-salt
hypertension. This proposal will test the overall hypothesis that during mineralocorticoid excess,
the expression of PRR/sPRR is increased in the distal nephron where sPRR binds Frizzled-8 to
activate β-catenin signaling that activates adenylyl cyclase-3 (AC3)/cAMP/PKA pathway that
stimulates ENaC transcription and activity and hence hypertension and kidney injury. To test this
hypothesis, we will employ conditional gene targeting techniques to evaluate the contribution of
CD PRR and β-catenin to ENaC activation and hypertension. Moreover, we will dissect sPRR-
induced signaling mechanisms involving coordinated activation of Frizzled-8/β-catenin and
AC3/cAMP/PKA pathways in the CD cells. Lastly, we will explore a novel therapeutic potential
of inhibitors of β-catenin signaling in mineralocorticoid-salt hypertension. Overall, this proposal
is expected to offer novel insight into the function of renal PRR/sPRR in hypertension and
kidney injury.
Terms: <21+ years old><3'5'-cyclic ester of AMP><3,5 cyclic AMP synthetase><Adenosine Cyclic 3',5'-Monophosphate><Adenosine Cyclic Monophosphate><Adenosine Cyclic Monophosphate-Dependent Protein Kinases><Adenosine, cyclic 3',5'-(hydrogen phosphate)><Adenyl Cyclase><Adenylate Cyclase><Adenylyl Cyclase><Adult><Adult Human><Aldosterone><Angiotensin-Forming Enzyme><Angiotensinogenase><Anti-Hypertensive Agents><Anti-Hypertensive Drugs><Anti-Hypertensives><Antihypertensive Agents><Antihypertensive Drugs><Antihypertensives><Attenuated><BP control><BP homeostasis><BP management><BP regulation><Beta Cadherin-Associated Protein><Beta-1 Catenin><Big Renin><Binding><Biological Markers><Blood Pressure><CREB><CREB1><CREB1 gene><CUL-2><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Collecting Cell><Cryorenin><Cyclic AMP><Cyclic AMP-Dependent Protein Kinases><DOCA><Dark Cell><Disease><Disorder><Distal><Duct><Duct (organ) structure><Ductal Cell><Ductal Epithelial Cell><ENaC><Embryo Development><Embryogenesis><Embryonic Development><External Domain><Extracellular Domain><Gene Targeting><Gene Transcription><Genetic Transcription><Hypertension><Hypotensive Agent><Hypotensive Drugs><Hypotensives><In Vitro><Inactive Renin><Injury><Intercalated Cell><Intracellular Communication and Signaling><Kidney><Kidney Urinary System><Mammalia><Mammals><Mediating><Mineralocorticoids><Molecular Interaction><Nephrons><PKA><PRO2286><Pathogenesis><Pathway interactions><Process><Prorenin><Protein Kinase A><RNA Expression><Receptor Protein><Regulation><Renal function><Renin><Role><Signal Transduction><Signal Transduction Systems><Signaling><Sodium Chloride><Techniques><Testing><Transcription><United States><Uriniferous Tube><Vascular Hypertensive Disease><Vascular Hypertensive Disorder><Vertebrate Animals><Vertebrates><adenosine 3'5' monophosphate><adenylcyclase><adulthood><beta catenin><bio-markers><biologic marker><biological signal transduction><biomarker><blood pressure control><blood pressure homeostasis><blood pressure management><blood pressure regulation><cAMP><cAMP Response Element-Binding Protein 1><cAMP-Dependent Protein Kinases><epithelial Na+ channel><epithelial sodium channel><high blood pressure><hyperpiesia><hyperpiesis><hypertensive disease><inhibitor><inhibitor/antagonist><insight><kidney function><new drug treatments><new drugs><new therapeutics><new therapy><next generation therapeutics><novel><novel drug treatments><novel drugs><novel therapeutics><novel therapy><paracrine><pathway><receptor><receptor binding><receptor bound><regulate BP><regulate blood pressure><renal><salt><salt hypertension><salt induced hypertension><salt sensitive hypertension><social role><vertebrata><β-catenin>