Soluble Form of the (Pro)Renin Receptor Is Augmented in the Collecting Duct and Urine of Chronic Angiotensin II–Dependent Hypertensive Rats

González, Alexis A.; Lara, Lucienne S.; Luffman, Christina; Seth, Dale M.; Prieto, Minolfa C.

doi:10.1161/hypertensionaha.110.167957

Cited by 134 publications

(172 citation statements)

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“…Indeed, the demonstrations that ANG II and AVP can directly stimulate epithelial sodium channels in the CD (10, 33) and suggest a parallel pathway for the stimulation of synthesis and secretion of prorenin-renin, as well as of AQP-2 expression, in the principal cells. Furthermore, the binding of renin and prorenin to the (pro)renin receptor on the apical side of the CD may help prevent the losses of these proteins in the urine (11) and may also contribute to increase their catalytic activity to further increase intratubular ANG II generation (11,13). Importantly, it has been shown that plasma AVP concentrations are increased in some patients with heart failure, despite hyponatremia and low plasma osmolality (45).…”

Section: Discussionmentioning

confidence: 99%

Vasopressin/V2 receptor stimulates renin synthesis in the collecting duct

González

Cifuentes-Araneda

Ibaceta-Gonzalez

et al. 2016

American Journal of Physiology-Renal Physiology

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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 ...

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Section: Discussionmentioning

confidence: 99%

Vasopressin/V2 receptor stimulates renin synthesis in the collecting duct

González

Cifuentes-Araneda

Ibaceta-Gonzalez

et al. 2016

American Journal of Physiology-Renal Physiology

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“…Renin content in cell culture media was determined by using modified protocols from the PRA assay [GammaCoat Plasma Renin Activity 125I RIA kit (DiaSorin, Stillwater, MN)] as previously described (8).…”

Section: Methodsmentioning

confidence: 99%

PKC-α-dependent augmentation of cAMP and CREB phosphorylation mediates the angiotensin II stimulation of renin in the collecting duct

González

Liu

Lara

et al. 2015

American Journal of Physiology-Renal Physiology

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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 (AT 1R) receptor, independently of blood pressure. In vitro data indicate that CD renin is augmented by AT 1R activation through protein kinase C (PKC), but the exact mechanisms are unknown. We hypothesize that ANG II stimulates CD renin synthesis through AT 1R 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-␣ dominant negative, and by PKA inhibition. Forskolin-induced increases in cAMP and renin expression were prevented by calphostin C. PKC inhibition and Ca 2ϩ 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-␣, 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.prorenin; hypertension; protein kinase; calcium; adenylyl cyclase-6; gene expression; M-1 cells IN ANGIOTENSIN II -(ANG II) dependent hypertension, the intrarenal ANG II content is greater than can be explained from the levels found in plasma (30, 31). High intrarenal ANG II levels can be partially explained by enhanced ANG II type 1 receptor (AT 1 R)-mediated uptake of ANG II (10). Augmentation of proximal tubule angiotensinogen (AGT) synthesis and secretion is responsible for increased local intratubular ANG II generation (21). The presence of AGT in the urine indicates that AGT traverses the distal nephron segments where it may then be cleaved to ANG I, if an adequate source of renin is available.In addition to the juxtaglomerular cells (JG), renin expression has been described in the proximal tubules, connecting tubules, and cortical and medullary collecting duct (CD) cells from the mouse, rat, and human kidney (39, 44). In contrast to JG cells, in the principal cells of the CD renin is upregulated by ANG II (36), via an AT 1 R-mediated mechanism (37), which is independent of blood pressure (35). In ANG II-dependent hypertensive rats with marked plasma renin activity (PRA) suppression, increased urinary levels of renin and prorenin reflect their augmented secretion by CD cells into the luminal fluid (26). In this model of experimental hypertension, intraluminal conversion of ANG I to ANG II in the CD is supported by the local presence of angiotens...

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“…(P)RR undergoes proteolytic cleavage to generate soluble (P)RR (128,129). (P)RR is easily detected in type A intercalated cells and not in principal cells (130,131). Binding of renin and prorenin to (P)RR increases the catalytic efficiency of these enzymes in the conversion of angiotensinogen to angiotensin by 4-fold.…”

Section: Regulation Of Intercalated Cell Transport Proteins Bymentioning

confidence: 99%

Collecting Duct Intercalated Cell Function and Regulation

Roy¹,

Al‐bataineh²,

Pastor-Soler

2015

Clinical Journal of the American Society of Nephrology

211

213

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Intercalated cells are kidney tubule epithelial cells with important roles in the regulation of acid-base homeostasis. However, in recent years the understanding of the function of the intercalated cell has become greatly enhanced and has shaped a new model for how the distal segments of the kidney tubule integrate salt and water reabsorption, potassium homeostasis, and acid-base status. These cells appear in the late distal convoluted tubule or in the connecting segment, depending on the species. They are most abundant in the collecting duct, where they can be detected all the way from the cortex to the initial part of the inner medulla. Intercalated cells are interspersed among the more numerous segment-specific principal cells. There are three types of intercalated cells, each having distinct structures and expressing different ensembles of transport proteins that translate into very different functions in the processing of the urine. This review includes recent findings on how intercalated cells regulate their intracellular milieu and contribute to acid-base regulation and sodium, chloride, and potassium homeostasis, thus highlighting their potential role as targets for the treatment of hypertension. Their novel regulation by paracrine signals in the collecting duct is also discussed. Finally, this article addresses their role as part of the innate immune system of the kidney tubule.

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Soluble Form of the (Pro)Renin Receptor Is Augmented in the Collecting Duct and Urine of Chronic Angiotensin II–Dependent Hypertensive Rats

Cited by 134 publications

References 32 publications

Vasopressin/V2 receptor stimulates renin synthesis in the collecting duct

Vasopressin/V2 receptor stimulates renin synthesis in the collecting duct

PKC-α-dependent augmentation of cAMP and CREB phosphorylation mediates the angiotensin II stimulation of renin in the collecting duct

Collecting Duct Intercalated Cell Function and Regulation

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