Vasopressin/V2 receptor stimulates renin synthesis in the collecting duct

Abstract

Renin is synthesized in the principal cells of the collecting duct (CD), and its production is increased via cAMP in angiotensin (ANG) II-dependent hypertension, despite suppression of juxtaglomerular (JG) renin. Vasopressin, one of the effector hormones of the reninangiotensin system (RAS) via the type 2-receptor (V2R), activates the cAMP/PKA/cAMP response element-binding protein (CREB) pathway and aquaporin-2 expression in principal cells of the CD. Accordingly, we hypothesized that activation of V2R increases renin synthesis via PKA/CREB, independently of ANG II type 1 (AT1) receptor activation in CD cells. Desmopressin (DDAVP; 10 Ϫ6 M), a selective V2R agonist, increased renin mRNA (ϳ3-fold), prorenin (ϳ1.5-fold), and renin (ϳ2-fold) in cell lysates and cell culture media in the M-1 CD cell line. Cotreatment with DDAVPϩH89 (PKA inhibitor) or CREB short hairpin (sh) RNA prevented this response. H89 also blunted DDAVP-induced CREB phosphorylation and nuclear localization. In 48-h water-deprived (WD) mice, prorenin-renin protein levels were increased in the renal inner medulla (ϳ1.4-and 1.8-fold). In WD mice treated with an ACE inhibitor plus AT1 receptor blockade, renin mRNA and prorenin protein levels were still higher than controls, while renin protein content was not changed. In M-1 cells, ANG II or DDAVP increased prorenin-renin protein levels; however, there were no further increases by combined treatment. These results indicate that in the CD the activation of the V2R stimulates renin synthesis via the PKA/CREB pathway independently of RAS, suggesting a critical role for vasopressin in the regulation of renin in the CD.intrarenal renin-angiotensin system; collecting duct; water deprivation; distal tubular renin; prorenin; PKA/CREB THE RENIN-ANGIOTENSIN SYSTEM (RAS) plays a pivotal role in the regulation of blood pressure (BP) and in the maintenance of body sodium and fluid balance. There is growing evidence demonstrating the presence of the RAS in the tissues of renal and cardiovascular systems (5-7, 35), supporting the importance of the tissue RAS in the accomplishment of its functions. The kidneys generate angiotensin II (ANG II) de novo (46, 47). The luminal presence of angiotensinogen (AGT) in the proximal tubules (PT) (24), angiotensin-converting enzyme (ACE) in the collecting duct (CD) (3,15,25,39), and prorenin and renin in the distal nephron has been established (40, 41). These findings further support the formation of intratubular ANG II from sequential coordinated actions of tubular renin and ACE that act on AGT substrate delivered from the proximal segments. As evidence, ANG II, AGT, and renin contents are increased in the kidneys from ANG II-infused hypertensive rats (12), which contribute to sodium reabsorption (48). However, the mechanisms regulating renin in the CD and its physiological implications are not well understood.There is consensus evidence showing that the cAMP-PKA and cAMP response element-binding protein (CREB) pathway constitute the central pathway for renin regulation in JG ...

Prostaglandin E2 Induces Prorenin-Dependent Activation of (Pro)renin Receptor and Upregulation of Cyclooxygenase-2 in Collecting Duct Cells

“…Our data suggest that PGE 2 may be the initial stimuli to promote prorenin-renin mediated stimulation of PRR and COX-2 augmentation in CD cells. Our data suggest that this stimulation is mediated by EP1 and EP4 receptors (Figure 5), which are linked to the stimulation of PKC-Ca2+ and stimulation of cAMP formation within the cell and both mechanisms seem to be involved in renin synthesis in the CD 23 . We previously showed that during the early phase of ANG II-dependent hypertension, membrane-bound PRR and COX-2 are augmented in the renal medullary tissues 12 .…”

“…It has been shown that M-1 CD cells express EP1, EP3, and EP4 17 . We have previously demonstrated that activation of the AT1 receptor increases prorenin and renin expression via cAMP accumulation, which is dependent on PKC activity 9,23 . In the MD, the activation of EP4 receptor enhances cAMP formation and activates the cAMP-CREB pathway and renin synthesis in JG cells 29 .…”

“…The expression of renin and prorenin in the principal cells of the CD is augmented during high ANG II states 7,31,32 and is secreted in the intratubular fluid 33 . Renin and prorenin are detected in the cell culture media 9,23 suggesting that augmented prorenin and renin secretion may activate the PRR in the plasma membrane of the neighboring intercalated cell. The activation of the PRR by prorenin increases the expression of COX-2 via activation of MAPK 12,13 .…”

“…Importantly, M-1 cells are composed of principal and intercalated cells which express COX-2 21 EP1, EP3, EP4 17 prorenin-renin, and PRR constitutively 22 which make this cell line a good in vitro model to establish the role of the PRR-COX-2-PGE2 pathway on renin regulation. The M-1 cells were cultured as previously described 9,23 . As shown in Figure 1A, M-1 cells express AQP-2 and can respond to vasopressin (AVP, 10 nM, 4 h) increasing AQP-2 abundance in plasma membranes.…”

Unraveling the Physiology of (Pro)Renin Receptor in the Distal Nephron

“…AVP also stimulated release of prorenin, and sPRR in primary rat IMCD cells 56 . In M-1 CD cell line, a similar enhancement of renin mRNA, prorenin and renin is observed following desmopressin (ddAVP) treatment 57 . Together, the in vitro data demonstrates a potential role of PRR in mediating AVP-induced AQP2 expression in the CD cells.…”