Neuron-specific (pro)renin receptor knockout prevents the development of salt-sensitive hypertension.
The (pro)renin receptor (PRR), which binds both renin and prorenin, is a newly discovered component of the renin-angiotensin system that is highly expressed in the central nervous system. The significance of brain PRRs in mediating local angiotensin II formation and regulating blood pressure remains unclear. The current study was performed to test the hypothesis that PRR-mediated, nonproteolytic activation of prorenin is the main source of angiotensin II in the brain. Thus, PRR knockout in the brain is expected to prevent angiotensin II formation and development of deoxycorticosterone acetate-salt-induced hypertension. A neuron-specific PRR (ATP6AP2) knockout mouse model was generated using the Cre-LoxP system. Physiological parameters were recorded by telemetry. PRR expression, detected by immunostaining and reverse transcription-polymerase chain reaction, was significantly decreased in the brains of knockout mice compared with wild-type mice. Intracerebroventricular infusion of mouse prorenin increased blood pressure and angiotensin II formation in wild-type mice. This hypertensive response was abolished in PRR-knockout mice in association with a reduction in angiotensin II levels. Deoxycorticosterone acetate-salt increased PRR expression and angiotensin II formation in the brains of wild-type mice, an effect that was attenuated in PRR-knockout mice. PRR knockout in neurons prevented the development of deoxycorticosterone acetate-salt-induced hypertension as well as activation of cardiac and vasomotor sympathetic tone. In conclusion, nonproteolytic activation of prorenin through binding to the PRR mediates angiotensin II formation in the brain. Neuron-specific PRR knockout prevents the development of deoxycorticosterone acetate-salt-induced hypertension, possibly through diminished angiotensin II formation.
Department of Biomedical Science, Colorado State University, 1617 Campus Delivery, Fort Collins, CO 80523. yumei.feng@colostate.edu.
Wencheng
W
Li
Hua
H
Peng
Eamonn P
EP
Mehaffey
Christie D
CD
Kimball
Justin L
JL
Grobe
Jeanette M G
JM
van Gool
Michelle N
MN
Sullivan
Scott
S
Earley
A H Jan
AH
Danser
Atsuhiro
A
Ichihara
Yumei
Y
Feng
D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D001794:Blood Pressure / Q000502:physiology; D064791:Desoxycorticosterone Acetate / Q000494:pharmacology; D005260:Female; D006977:Hypertension, Renal / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D008901:Mineralocorticoids / Q000494:pharmacology; D009474:Neurons / Q000166:cytology / Q000502:physiology*; D006180:Proton-Translocating ATPases / Q000235:genetics* / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics* / Q000378:metabolism; D017673:Sodium Chloride, Dietary / Q000494:pharmacology*; D000093342:Prorenin Receptor
C583530:ATP6AP2 protein, mouse; D008901:Mineralocorticoids; D011956:Receptors, Cell Surface; D017673:Sodium Chloride, Dietary; D000804:Angiotensin II; D064791:Desoxycorticosterone Acetate; D006180:Proton-Translocating ATPases; D000093342:Prorenin Receptor
(pro)renin receptor; angiotensin II; central nervous system; hypertension