title: Intracerebroventricular infusion of the (Pro)renin receptor antagonist PRO20 attenuates deoxycorticosterone acetate-salt-induced hypertension.
abstract: We previously reported that binding of prorenin to the (pro)renin receptor (PRR) plays a major role in brain angiotensin II formation and the development of deoxycorticosterone acetate (DOCA)-salt hypertension. Here, we designed and developed an antagonistic peptide, PRO20, to block prorenin binding to the PRR. Fluorescently labeled PRO20 bound to both mouse and human brain tissues with dissociation constants of 4.4 and 1.8 nmol/L, respectively. This binding was blocked by coincubation with prorenin and was diminished in brains of neuron-specific PRR-knockout mice, indicating specificity of PRO20 for PRR. In cultured human neuroblastoma cells, PRO20 blocked prorenin-induced calcium influx in a concentration- and AT(1) receptor-dependent manner. Intracerebroventricular infusion of PRO20 dose-dependently inhibited prorenin-induced hypertension in C57Bl6/J mice. Furthermore, acute intracerebroventricular infusion of PRO20 reduced blood pressure in both DOCA-salt and genetically hypertensive mice. Chronic intracerebroventricular infusion of PRO20 attenuated the development of hypertension and the increase in brain hypothalamic angiotensin II levels induced by DOCA-salt. In addition, chronic intracerebroventricular infusion of PRO20 improved autonomic function and spontaneous baroreflex sensitivity in mice treated with DOCA-salt. In summary, PRO20 binds to both mouse and human PRRs and decreases angiotensin II formation and hypertension induced by either prorenin or DOCA-salt. Our findings highlight the value of the novel PRR antagonist, PRO20, as a lead compound for a novel class of antihypertensive agents and as a research tool to establish the validity of brain PRR antagonism as a strategy for treating hypertension.
authors.affiliation: From the Department of Biomedical Sciences, Center for Cardiovascular Research, Colorado State University, Fort Collins (W.L., M.N.S., C.J.W., Y.F.); Department of Physiology, Tulane Hypertension and Renal Center of Excellence (S.Z.), and Department of Pathology and Laboratory Medicine (Z.X.), Tulane University School of Medicine, New Orleans, LA; and Department of Pharmaceutical Sciences, College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL (R.C.S.).
authors.forename: Wencheng
authors.initials: W
authors.lastname: Li
authors.affiliation: From the Department of Biomedical Sciences, Center for Cardiovascular Research, Colorado State University, Fort Collins (W.L., M.N.S., C.J.W., Y.F.); Department of Physiology, Tulane Hypertension and Renal Center of Excellence (S.Z.), and Department of Pathology and Laboratory Medicine (Z.X.), Tulane University School of Medicine, New Orleans, LA; and Department of Pharmaceutical Sciences, College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL (R.C.S.).
authors.forename: Michelle N
authors.initials: MN
authors.lastname: Sullivan
authors.affiliation: From the Department of Biomedical Sciences, Center for Cardiovascular Research, Colorado State University, Fort Collins (W.L., M.N.S., C.J.W., Y.F.); Department of Physiology, Tulane Hypertension and Renal Center of Excellence (S.Z.), and Department of Pathology and Laboratory Medicine (Z.X.), Tulane University School of Medicine, New Orleans, LA; and Department of Pharmaceutical Sciences, College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL (R.C.S.).
authors.forename: Sheng
authors.initials: S
authors.lastname: Zhang
authors.affiliation: From the Department of Biomedical Sciences, Center for Cardiovascular Research, Colorado State University, Fort Collins (W.L., M.N.S., C.J.W., Y.F.); Department of Physiology, Tulane Hypertension and Renal Center of Excellence (S.Z.), and Department of Pathology and Laboratory Medicine (Z.X.), Tulane University School of Medicine, New Orleans, LA; and Department of Pharmaceutical Sciences, College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL (R.C.S.).
authors.forename: Caleb J
authors.initials: CJ
authors.lastname: Worker
authors.affiliation: From the Department of Biomedical Sciences, Center for Cardiovascular Research, Colorado State University, Fort Collins (W.L., M.N.S., C.J.W., Y.F.); Department of Physiology, Tulane Hypertension and Renal Center of Excellence (S.Z.), and Department of Pathology and Laboratory Medicine (Z.X.), Tulane University School of Medicine, New Orleans, LA; and Department of Pharmaceutical Sciences, College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL (R.C.S.).
authors.forename: Zhenggang
authors.initials: Z
authors.lastname: Xiong
authors.affiliation: From the Department of Biomedical Sciences, Center for Cardiovascular Research, Colorado State University, Fort Collins (W.L., M.N.S., C.J.W., Y.F.); Department of Physiology, Tulane Hypertension and Renal Center of Excellence (S.Z.), and Department of Pathology and Laboratory Medicine (Z.X.), Tulane University School of Medicine, New Orleans, LA; and Department of Pharmaceutical Sciences, College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL (R.C.S.).
authors.forename: Robert C
authors.initials: RC
authors.lastname: Speth
authors.affiliation: From the Department of Biomedical Sciences, Center for Cardiovascular Research, Colorado State University, Fort Collins (W.L., M.N.S., C.J.W., Y.F.); Department of Physiology, Tulane Hypertension and Renal Center of Excellence (S.Z.), and Department of Pathology and Laboratory Medicine (Z.X.), Tulane University School of Medicine, New Orleans, LA; and Department of Pharmaceutical Sciences, College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL (R.C.S.). Yumei.feng@colostate.edu.
authors.forename: Yumei
authors.initials: Y
authors.lastname: Feng
mesh_terms: D000804:Angiotensin II / Q000032:analysis / Q000502:physiology; D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D017704:Baroreflex / Q000187:drug effects; D001667:Binding, Competitive; D001794:Blood Pressure / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D002216:Captopril / Q000494:pharmacology; D045744:Cell Line, Tumor; D064791:Desoxycorticosterone Acetate / Q000633:toxicity; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D006973:Hypertension / Q000139:chemically induced / Q000188:drug therapy / Q000235:genetics / Q000517:prevention & control*; D007031:Hypothalamus / Q000737:chemistry / Q000187:drug effects; D057967:Infusions, Intraventricular; D017136:Ion Transport / Q000187:drug effects; D019808:Losartan / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D009447:Neuroblastoma; D010446:Peptide Fragments / Q000008:administration & dosage / Q000627:therapeutic use*; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D011956:Receptors, Cell Surface / Q000032:analysis / Q000037:antagonists & inhibitors*; D012083:Renin / Q000008:administration & dosage / Q000627:therapeutic use*; D012965:Sodium Chloride / Q000633:toxicity; D025262:Vacuolar Proton-Translocating ATPases / Q000032:analysis / Q000037:antagonists & inhibitors*; D000093342:Prorenin Receptor
chemical_list: C458319:ATP6AP2 protein, human; D000959:Antihypertensive Agents; C000595796:PRO20 peptide; D010446:Peptide Fragments; D011956:Receptors, Cell Surface; D000804:Angiotensin II; D012965:Sodium Chloride; D064791:Desoxycorticosterone Acetate; D002216:Captopril; D048049:Extracellular Signal-Regulated MAP Kinases; D012083:Renin; D025262:Vacuolar Proton-Translocating ATPases; D019808:Losartan; D002118:Calcium; D000093342:Prorenin Receptor
keywords: (pro)renin receptor; central nervous system; hypertension