PKC-α-dependent augmentation of cAMP and CREB phosphorylation mediates the angiotensin II stimulation of renin in the collecting duct.
In contrast to the negative feedback of angiotensin II (ANG II) on juxtaglomerular renin, ANG II stimulates renin in the principal cells of the collecting duct (CD) in rats and mice via ANG II type 1 (AT1R) receptor, independently of blood pressure. In vitro data indicate that CD renin is augmented by AT1R activation through protein kinase C (PKC), but the exact mechanisms are unknown. We hypothesize that ANG II stimulates CD renin synthesis through AT1R via PKC and the subsequent activation of cAMP/PKA/CREB pathway. In M-1 cells, ANG II increased cAMP, renin mRNA (3.5-fold), prorenin, and renin proteins, as well as renin activity in culture media (2-fold). These effects were prevented by PKC inhibition with calphostin C, PKC-α dominant negative, and by PKA inhibition. Forskolin-induced increases in cAMP and renin expression were prevented by calphostin C. PKC inhibition and Ca2+ depletion impaired ANG II-mediated CREB phosphorylation and upregulation of renin. Adenylate cyclase 6 (AC) siRNA remarkably attenuated the ANG II-dependent upregulation of renin mRNA. Physiological activation of AC with vasopressin increased renin expression in M-1 cells. The results suggest that the ANG II-dependent upregulation of renin in the CD depends on PKC-α, which allows the augmentation of cAMP production and activation of PKA/CREB pathway via AC6. This study defines the intracellular signaling pathway involved in the ANG II-mediated stimulation of renin in the CD. This is a novel mechanism responsible for the regulation of local renin-angiotensin system in the distal nephron.
Instituto de Química, Pontificia Universidad Católica de Valparaíso, Valparaíso, Chile; Department of Physiology, Tulane University School of Medicine, New Orleans, Louisiana; and.
Alexis A
AA
Gonzalez
Department of Physiology, Tulane University School of Medicine, New Orleans, Louisiana; and.
Liu
L
Liu
Instituto de Ciencias Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil Department of Physiology, Tulane University School of Medicine, New Orleans, Louisiana; and.
Lucienne S
LS
Lara
Department of Physiology, Tulane University School of Medicine, New Orleans, Louisiana; and.
Camille R T
CR
Bourgeois
Instituto de Química, Pontificia Universidad Católica de Valparaíso, Valparaíso, Chile;
Cristobal
C
Ibaceta-Gonzalez
Instituto de Química, Pontificia Universidad Católica de Valparaíso, Valparaíso, Chile;
Nicolas
N
Salinas-Parra
Department of Physiology, Tulane University School of Medicine, New Orleans, Louisiana; and.
Venkateswara R
VR
Gogulamudi
Department of Physiology, Tulane University School of Medicine, New Orleans, Louisiana; and.
Dale M
DM
Seth
Department of Physiology, Tulane University School of Medicine, New Orleans, Louisiana; and mprieto@tulane.edu.
Minolfa C
MC
Prieto
D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D051379:Mice; D010766:Phosphorylation; D051571:Protein Kinase C-alpha / Q000378:metabolism*; D012083:Renin / Q000378:metabolism*; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D015854:Up-Regulation / Q000187:drug effects
C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D000804:Angiotensin II; C496630:Prkca protein, mouse; D051571:Protein Kinase C-alpha; D012083:Renin
M-1 cells; adenylyl cyclase-6; calcium; gene expression; hypertension; prorenin; protein kinase