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The cellular distribution of Ca(2+)-inhibitable adenylyl cyclase (AC) type 5 and type 6 mRNAs in rat outer medullary collecting duct (OMCD) was performed by in situ hybridization. Kidney sections were also stained with specific antibodies against either collecting duct intercalated cells or principal cells. The localization of type 5 AC in H(+)-ATP...
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Context 1
... Ca 2 concentrations were calculated from the maximal peak values that allowed accurate determinations of [Ca 2 ] i increases (Fig. 6A). As shown by the mean data, the [Ca 2 ] i increase obtained with the addition of both PGE 2 and carbachol was statistically higher than the response observed with each agonist (Table 2). In addition, the experimental value obtained with the superfusion of both PGE 2 and carbachol was not different from the theoretical value calculated by assuming a full additivity of the individual responses (Table 2). ...Context 2
... shown by the mean data, the [Ca 2 ] i increase obtained with the addition of both PGE 2 and carbachol was statistically higher than the response observed with each agonist (Table 2). In addition, the experimental value obtained with the superfusion of both PGE 2 and carbachol was not different from the theoretical value calculated by assuming a full additivity of the individual responses (Table 2). ...Context 3
... contrast, the superfusion of PGE 2 followed by that of carbachol, or conversely, led to successive [Ca 2 ] i increases (Fig. 6B). The simultaneous superfusion of PGE 2 and carbachol induced a response statistically higher than the individual responses, and this response was not different from the theoretical value calculated by assuming a full additivity of the increases of [Ca 2 ] i elicited by PGE 2 and carbachol ( Fig. 6B and Table 2). Altogether, these data establish that PGE 2 and carbachol release Ca 2 from different Ca 2 pools located in either the same cell or different cells of rat OMCD. ...Context 4
... bars, superfusion period of each solution. The magnitude of the responses was independent from the order of the superfusion (see Table 2). B: representative traces of [Ca 2 ] i variations elicited by different agonists added in Ca 2 -free medium. ...Context 5
... that, after the treatment with PGE 2 followed by the superfusion of carbachol, it was necessary to superfuse the tubule with 2 mM Ca 2 medium to refill the intracellular Ca 2 stores. The magnitude of the different responses was independent from the order of superfusion (see Table 2). Values are means SE obtained from different recordings (n), examples of which are given in Fig. 6. ...Similar publications
Menière's disease, clinically characterized by fluctuating, recurrent, and invalidating vertigo, hearing loss, and tinnitus, is linked to an increase in endolymph volume, the so-called endolymphatic hydrops. Since dysregulation of water transport could account for the generation of this hydrops, we investigated the role of aquaporin 3 (AQP3) in wat...
The terminal part of the inner medullary collecting duct exhibits a high degree of water permeability that is independent of increased intracellular cAMP and not accounted for by the activity of the known renal epithelial water channels CHIP28 (28-kDa channel-forming integral protein) and WCH-CD (collecting duct water channel protein). Starting wit...
Background
Arginine vasopressin dependent antidiuresis plays a key role in water‐sodium retention in heart failure. In recent years, the role of glucocorticoids in the control of body fluid homeostasis has been extensively investigated. Glucocorticoid deficiency can activate V2R (vasopressin receptor 2), increase aquaporins expression, and result i...
Introduction
Recently, there are a few moisturizers showing hydrating effects up to 24 hours after single application. Aquaporin 3 might be associated with the degree of skin hydration. We aimed to assess the effects of two brands of 24‐hour moisturizers on the skin barrier function, as well as the AQP3 gene expression.
Method
Two moisturizers wer...
To evaluate the effect of bovine oviductal fluid (OF) supplementation during in vitro culture of bovine embryos on their development and quality, in vitro-produced zygotes were cultured in synthetic oviductal fluid (SOF; negative control; C-) supplemented with OF or 5% fetal calf serum (positive control; C+). Embryo development was recorded on Days...
Citations
... Moreover, de Jesus Ferreira et al. described coexpression of Ca 2+ inhibitable AC type 6 (AC6) and the Calcium Sensing Receptors (CaSR) in the cortical TAL of the kidney and further showed potent antagonism of cAMP signaling during CaSR stimulation by physiological levels of extracellular [Ca 2+ ] [31]. In addition, AC6 was found to be functionally expressed in CD and involved in the regulation of cAMP production in at this site [39]. We performed functional experiments in HEK293 cells, which endogenously express many isoforms of AC (AC1, 3, 5, 6, 7, and 9 and soluble, bicarbonate-sensitive AC; [40][41][42], of which some are inhibitable by Ca 2+ (e.g., AC5 and AC6), and which do not express Ca 2+ /calmodulin-dependent phosphodiesterases [43]. ...
Acmella oleracea is well recognized in Brazilian traditional medicine as diuretic, although few scientific data have been published to support this effect. Aim of this study was to determine the molecular effect of Acmella oleracea extract and its main alkylamide spilanthol on two major processes involved in the urine concentrating mechanism: Na-K-2Cl symporter (NKCC2) activity in the thick ascending limb and water channel aquaporin 2 accumulation at the apical plasma membrane of collecting duct cells. Phosphorylation of NKCC2 was evaluated as index of its activation by Western blotting. Rate of aquaporin 2 apical expression was analyzed by confocal laser microscopy. Spilanthol-induced intracellular signalling events were dissected by video-imaging experiments. Exposure to spilanthol reduced the basal phosphorylation level of NKCC2 both in freshly isolated mouse kidney slices and in NKCC2-expresing HEK293 cells. In addition, exposure to spilanthol strongly reduced both desmopressin and low Cl--dependent increase in NKCC2 phosphorylation in mouse kidney slices and NKCC2-expressing HEK293 cells, respectively. Similarly, spilanthol reduced both desmopressin- and forskolin-stimulated aquaporin 2 accumulation at the apical plasma membrane of collecting duct in mouse kidney slice and MCD4 cells, respectively. Of note, when orally administered, spilanthol induced a significant increase in both urine output and salt urinary excretion associated with a markedly reduced urine osmolality compared with control mice. Finally, at cellular level, spilanthol rapidly reduced or reversed basal and agonist-increased cAMP levels through a mechanism involving increases in intracellular [Ca2+]. In conclusion, spilanthol-induced inhibition of cAMP production negatively modulates urine-concentrating mechanisms thus holding great promise for its use as diuretic
... Overall, these two effects result in the production of a dilute, acidified urine, which reduces the risk of nephrolithiasis. 20-HETE, 20-hydroxyeicosatetraenoic acid; ATP2B1, plasma membrane calcium-transporting ATPase 1; AQP, aquaporin; AVP, arginine vasopressin; Cld, claudin; miRNA, microRNA; NFAT, nuclear factor of activated T cells; SLC8A1, sodium-calcium exchanger 1; SLC12A3, solute carrier family 12 member 3; PTH1R, parathyroid hormone 1 receptor; SLC4A4, sodium bicarbonate cotransporter 1. ◀ stimulation 76 ; however, several lines of evidence suggest that ADCY6 is the predominant enzyme that modulates vasopressin-regulated water reabsorption [77][78][79] . Collecting duct-specific knockout of Adcy6 in mice results in a urinary concentration defect associated with reduced vasopressin-stimulated cAMP accumulation 80 ; therefore, Ca 2+ sensing in the collecting duct by the CaSR might sensitize vasopressin to luminal Ca 2+ , which would result in an attenuation of the antidiuretic response to limit water reabsorption (FIGS 1d,2). ...
The ability to monitor changes in the ionic composition of the extracellular environment is a crucial feature that has evolved in all living organisms. The cloning and characterization of the extracellular calcium-sensing receptor (CaSR) from the mammalian parathyroid gland in the early 1990s provided the first description of a cellular, ion-sensing mechanism. This finding demonstrated how cells can detect small, physiological variations in free ionized calcium (Ca(2+)) in the extracellular fluid and subsequently evoke an appropriate biological response by altering the secretion of parathyroid hormone (PTH) that acts on PTH receptors expressed in target tissues, including the kidney, intestine, and bone. Aberrant Ca(2+) sensing by the parathyroid glands, as a result of altered CaSR expression or function, is associated with impaired divalent cation homeostasis. CaSR activators that mimic the effects of Ca(2+) (calcimimetics) have been designed to treat hyperparathyroidism, and CaSR antagonists (calcilytics) are in development for the treatment of hypercalciuric disorders. The kidney expresses a CaSR that might directly contribute to the regulation of many aspects of renal function in a PTH-independent manner. This Review discusses the roles of the renal CaSR and the potential impact of pharmacological modulation of the CaSR on renal function.
... Overall, these two effects result in the production of a dilute, acidified urine, which reduces the risk of nephrolithiasis. 20-HETE, 20-hydroxyeicosatetraenoic acid; ATP2B1, plasma membrane calcium-transporting ATPase 1; AQP, aquaporin; AVP, arginine vasopressin; Cld, claudin; miRNA, microRNA; NFAT, nuclear factor of activated T cells; SLC8A1, sodium-calcium exchanger 1; SLC12A3, solute carrier family 12 member 3; PTH1R, parathyroid hormone 1 receptor; SLC4A4, sodium bicarbonate cotransporter 1. ◀ stimulation 76 ; however, several lines of evidence suggest that ADCY6 is the predominant enzyme that modulates vasopressin-regulated water reabsorption [77][78][79] . Collecting duct-specific knockout of Adcy6 in mice results in a urinary concentration defect associated with reduced vasopressin-stimulated cAMP accumulation 80 ; therefore, Ca 2+ sensing in the collecting duct by the CaSR might sensitize vasopressin to luminal Ca 2+ , which would result in an attenuation of the antidiuretic response to limit water reabsorption (FIGS 1d,2). ...
Parathyroid hormone (PTH) is the major determinant of serum calcium ion (Ca 2+) levels, and serum levels of PTH are regulated by the extracellular calcium-sensing receptor (CaSR) that is located in parathyroid glands 1. The CaSR can detect minor changes in serum Ca 2+ levels, and the amount of Ca 2+ influx as a result of CaSR activation subsequently feeds back to alter the level of PTH secretion. Serum PTH levels are inversely associated with the extra-cellular Ca 2+ level. Serum Ca 2+ <1.1–1.2 mmol/l promotes PTH release, which results in reabsorption of Ca 2+ by the kidney, Ca 2+ absorption in the intestine (via 1α-hydroxyl-ation of 25(OH)D 3 into 1,25(OH) 2 D 3 by the kidney prox-imal tubule), and Ca 2+ resorption from bone 2. Serum Ca 2+ levels >1.2 mmol/l have the opposite effect; Ca 2+ binding at the CaSR elicits a G q G-protein cascade that activates the phospholipase C pathway and prevents exocytosis of PTH. This event is accompanied by an increase in cyto-solic Ca 2+ that has been released from intracellular stores 1,2. Defective Ca 2+ sensing by the parathyroid glands, due to altered CaSR expression or function, results in altered divalent cation homeostasis, which can lead to notable, long-lasting morbidity in patients if left untreated 2 .
... In the collecting duct, the calcium–inhibitable AC6 type regulates renal water excretion through control of vasopressin-stimulated cAMP accumulation (Rieg et al., 2010). AC6 is inhibited by calcium at micromolar level (Cooper et al., 1994) and is relatively abundant in collecting duct principal cells (Chabardes et al., 1996) (Helies-Toussaint et al., 2000). Although both AC3 and AC6 are expressed in principal cells and have both been suggested to contribute to the overall rise in cAMP during vasopressin stimulation (Hoffert et al., 2005), the relevance of AC6 as a major enzyme in modulating vasopressin-regulated water reabsorption is supported by the observation that collecting duct specific knockout of AC6 causes a urinary concentration defect associated with reduced vasopressin-stimulated cAMP accumulation (Roos et al., 2012). ...
We previously described that high luminal calcium in the renal collecting duct attenuates short-term vasopressin-induced aquaporin-2 (AQP2) trafficking via activation of the Calcium-Sensing Receptor (CaSR). Here we evaluated AQP2 phosphorylation and permeability in renal HEK-293 cells and in dissected inner medullary collecting duct, in response to specific activation of CaSR with NPS-R568. In CaSR transfected cells, CaSR activation drastically reduced basal AQP2-pS256 levels thus having an opposite effect with respect to vasopressin action. When forskolin stimulation was performed in the presence of NPS-R568, the increase in AQP2-pS256 and in the osmotic water permeability were prevented. In freshly isolated inner mouse medullar collecting duct stimulation with forskolin in the presence of NPS-R568 prevented the increase in AQP2-pS256 and osmotic water permeability. Our data demonstrate that the activation of CaSR in the collecting duct prevents cAMP-dependent increase in AQP2-pS256 and water permeability, counteracting short-term vasopressin response. By extension, our results bring to the attractive concept that CaSR expressed in distinct nephron segments exerts a negative feedback on hormones acting through the cAMP, conferring high sensitivity of hormone to extracellular calcium.
© 2015. Published by The Company of Biologists Ltd.
... Although AC5 is only expressed in intercalated cells, AC6 is expressed in both intercalated and principal cells. 76 Deletion of AC6 results in a substantial improvement of cyst growth and survival in Pkd1-defi cient mice, 77 suggesting that AC6 has a central role in ADPKD. 76 Phosphodiesterases degrade cAMP and return cAMP concentrations to normal and a regulatory role for the calcium-inhibited isoform phosphodiesterase 1 in cyst growth has been reported. ...
... 76 Deletion of AC6 results in a substantial improvement of cyst growth and survival in Pkd1-defi cient mice, 77 suggesting that AC6 has a central role in ADPKD. 76 Phosphodiesterases degrade cAMP and return cAMP concentrations to normal and a regulatory role for the calcium-inhibited isoform phosphodiesterase 1 in cyst growth has been reported. 78 It is unclear which of the pathways promotes cAMP production and cAMP-mediated cyst growth (fi gure 2). ...
Autosomal dominant polycystic kidney disease is the most common inherited kidney disease and accounts for 7-10% of all patients on renal replacement therapy worldwide. Although first reported 500 years ago, this disorder is still regarded as untreatable and its pathogenesis is poorly understood despite much study. During the past 40 years, however, remarkable advances have transformed our understanding of how the disease develops and have led to rapid changes in diagnosis, prognosis, and treatment, especially during the past decade. This Review will summarise the key findings, highlight recent developments, and look ahead to the changes in clinical practice that will likely arise from the adoption of a new management framework for this major kidney disease.
Copyright © 2015 Elsevier Ltd. All rights reserved.
... This enhanced rise in [Ca 2ϩ ] i participates probably to the negative regulation of V 1a -R and apelin-R on V 2 -R effects by decreasing cAMP production. The importance of the Ca 2ϩ influx and/or extracellular Ca 2ϩ in the inhibition of cAMP accumulation was documented previously by several studies (42)(43)(44)(45). ...
Apelin receptors (ApelinR) are expressed along an increasing cortico-medullary gradient in collecting ducts (CD). We showed here, that intravenous injection of apelin 17 (K17F) in lactating rats characterized by increases in both synthesis and release of vasopressin (AVP), increased diuresis concomitantly with a significant decrease in urine osmolality and no change in Na(+) and K(+) excretion. Under these conditions, we also observed a significant decrease in apical aquaporin-2 immunolabeling in CD, with a cortico-medullary gradient, suggesting that K17F-induced diuresis could be linked to a direct action of apelin on CD. We then examined the potential crosstalk between V1a (V1aR), V2 (V2R) AVP receptors and ApelinR signaling pathways in outer (OMCD) and inner medullary (IMCD) microdissected rat CD. In OMCD, expressing the three receptors, K17F inhibited cAMP production and Ca(2+) influx induced by dDAVP, a V2R agonist. Similar effects were observed in IMCD expressing only V2R and ApelinR. In contrast in OMCD, K17F increased by 51 the Ca(2+) influx induced by the stimulation of V1aR by AVP in the presence of the V2R antagonist SR121463B, possibly enhancing the physiological antagonist effect of V1aR on V2R. Thus, the diuretic effect of apelin is not only due to a central effect by inhibiting AVP release in the blood circulation as previously shown, but also to a direct action of apelin on CD, by counteracting the antidiuretic effect of AVP occurring via V2R.
... Microdissected rat cortical CD (CCD) expressed AC2, AC4, AC5, AC6, and AC9 mRNA and protein (again, AC5 and AC6 staining could not reliably be determined) (7). AC5 and AC6, but not AC4, mRNA was observed in rat CCD (12,36). Mouse CCD contained AC3, AC4, AC5, and AC6 mRNA (79). ...
... Soluble AC protein appears to be abundantly present in the CCD (33,54,55). The outer medullary CD (OMCD) has a similar pattern of AC isoform expression as the CCD (7,12,36,79). Further analysis of these two regions of the CD reveals a differential pattern of expression between principal and intercalated cells. ...
... Paunescu et al. (55) noted that sAC and the V-ATPase colocalized apically and subapically in type A intercalated cells, while they colocalized basolaterally in type B intercalated cells. Finally, in situ hybridization studies detected AC5 only within intercalated cells based on colocalization with V-ATPase, but not AQP2 (36). Thus, while the CCD and OMCD express several AC isoforms, AC5 is uniquely found in this region of the nephron due to selective intercalated cell expression. ...
Adenylyl cyclases (AC) catalyze formation of cAMP, a critical component of G-protein coupled receptor signaling. So far, nine distinct membrane-bound AC isoforms (AC1-9) and one soluble AC (sAC) have been identified and, except for AC8, all of them are expressed in the kidney. While the role of ACs in renal cAMP formation is well established, we are just beginning to understand the function of individual AC isoforms, particularly with regard to hormonal regulation of transporter and channel phosphorylation, membrane abundance, and trafficking. This review focuses on the role of different AC isoforms in regulating renal water and electrolyte transport in health as well as potential pathologic implications of disordered AC isoform function. In particular, we focus on modulation of transporter and channel abundance, activity and phosphorylation, with emphasis on studies employing genetically modified animals. As will be described, it is now evident that specific AC isoforms can exert unique effects in the kidney that may have important implications in our understanding of normal physiology as well as disease pathogenesis.
... These results indicated that demeclocycline directly affects AC activity. AC3 and AC6 have been shown to be expressed in collecting duct principal cells, and knockdown of AC3 and AC6 has been shown to reduce AVP-stimulated cAMP generation in primary cultured mouse inner medullary collecting duct cells (23,25,68). To test whether demeclocycline affects their expression, mpkCCD cells were incubated with dDAVP as described above and treated with demeclocycline for different periods. ...
Binding of vasopressin to its type-2 receptor in renal collecting ducts induces cAMP signaling, transcription and translocation of aquaporin-2 (AQP2) water channels to the plasma membrane and water reabsorption from the pro-urine. Demeclocycline is currently used to treat hyponatremia in patients with the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Demeclocycline's mechanism of action, which is poorly understood, is studied here. In mouse cortical collecting duct (mpkCCD) cells, which exhibit dDAVP-dependent expression of endogenous AQP2, demeclocycline decreased AQP2 abundance and gene transcription, but not its protein stability. Demeclocycline did not affect V2R localization, but decreased dDAVP-induced cAMP generation and adenylate cyclase 3 and 5/6 abundances. Addition of exogenous cAMP partially corrected the demeclocycline effect. As in patients, demeclocycline increased urine volume, decreased urine osmolality and reverted hyponatremia in an SIADH rat model. AQP2 and adenylate cyclase 5/6 abundances were reduced in the inner medulla, but increased in the cortex and outer medulla, in the absence of any sign of toxicity. In conclusion, our in vitro and in vivo data indicate that demeclocycline mainly attenuates hyponatremia in SIADH by reducing adenylate cyclase 5/6 expression, and consequently cAMP generation, AQP2 gene transcription and AQP2 abundance in the renal inner medulla, coinciding with a reduced vasopressin-escape response in the other collecting duct segments.
... These findings implicating AC6 as a key mediator of AVP-stimulated ENaC activity are particularly significant when one considers that three AC isoforms exist in the CD that might be modulated by AVP, including AC3, AC4, and AC6 17 (AC5 is also found in the CD, but is confined to intercalated cells). [23][24][25] A soluble AC isoform is expressed throughout the CD 26 ; however, it is a chemosensor that responds to intracellular pH. It is likely that two or more AC isoforms in the CD mediate AVP stimulation of water transport because mice with CD AC6 gene disruption manifest only a modest urinary concentrating defect (i.e., other AC isoforms must be involved in AVP stimulation of CD water transport). ...
... Although AVP is by far the best-studied regulator of CD cAMP production, a number of other factors stimulate CD cAMP accumulation, including aldosterone, 29 PGI 2 , 30 PGE 2 (via the EP4 receptor), 31 b-adrenergic agonists, 32,33 oxytocin, 34 adenosine, 35 angiotensin II, 36 and glucagon. 25,37 A number of agents also inhibit CD cAMP production; however, such analysis has been essentially confined to examination of factors that inhibit AVP actions. These include PGE 2 (via the EP3 receptor 38 ), dopamine, 39,40 ATP, 41 endothelin-1, 42 and nitric oxide. ...
Vasopressin modulates sodium reabsorption in the collecting duct through adenylyl cyclase-stimulated cyclic AMP, which exists as multiple isoforms; the specific isoform involved in vasopressin-stimulated sodium transport is unknown. To assess this, we studied mice deficient in adenylyl cyclase type VI specifically in the principal cells of the collecting duct. Knockout mice had increased urine volume and reduced urine sodium concentration, but regardless of the level of sodium intake, they did not exhibit significant alterations in urinary sodium excretion, arterial pressure, or pulse rate. Plasma renin concentration was elevated in knockout mice, however, suggesting a compensatory response. Valsartan significantly reduced arterial pressure in knockout mice but not in controls. Knockout mice had decreased renal cortical mRNA content of all three epithelial sodium channel (ENaC) isoforms, and total cell sodium channel isoforms α and γ were reduced in these animals. Patch-clamp analysis of split-open cortical collecting ducts revealed no difference in baseline activity of sodium channels, but knockout mice had abolished vasopressin-stimulated ENaC open probability and apical membrane channel number. In summary, these data suggest that adenylyl cyclase VI mediates vasopressin-stimulated ENaC activity in the kidney.
... mRNA and protein expression for almost all AC isoforms have been found in rat and mouse kidneys (2,4,26,48). AC5 and AC6 are thought to be the primary ACs that mediate the effect of AVP on intracellular cAMP in collecting ducts (6,25); however, recent studies have suggested that AVP-dependent AC activation and cAMP accumulation are regulated, in part, by CaM-stimulated ACs (26,48,51). AC3, a CaM-sensitive AC isoform, was shown to be expressed in rat and mouse medullary collecting ducts (26,48), and knockdown of either AC3 or AC6 using small interfering RNA (siRNA) in primary cultured mouse inner medullary collecting duct (IMCD) cells significantly reduced AVP-stimulated cAMP accumulation (48). ...
In ADPKD, binding of AVP to V2 receptor (V2R) increases cAMP and accelerates cyst growth by stimulating cell proliferation and Cl(-)-dependent fluid secretion. Basal cAMP is elevated in human ADPKD cells compared to normal human kidney (NHK) cells. V2R mRNA levels are elevated in ADPKD cells; however, AVP caused a greater increase in global cAMP in NHK cells, suggesting an intrinsic difference in cAMP regulation. Expression, regulatory properties, and receptor coupling of specific adenylyl cyclases (ACs) provide temporal and spatial regulation of the cAMP signal. ADPKD and NHK cells express mRNAs for all 9 ACs. Ca(2+)-inhibited ACs 5 and 6 are increased in ADPKD cells, while Ca(2+)/CaM stimulated ACs 1 and 3 are down regulated. ACs 1, 3, 5 and 6 were detected in cyst cells, in situ, and co-distribution with AQP-2 suggests that these cysts were derived from collecting ducts. To determine the contribution of CaM sensitive ACs to AVP signaling, cells were treated with W-7, a CaM inhibitor. W-7 decreased AVP-induced cAMP and Cl(-) secretion by ADPKD cells. CaMKII inhibition increased AVP-induced cAMP, suggesting that cAMP synthesis is mediated by AC3. In contrast, CaM and CaMKII inhibition in NHK cells did not affect AVP-induced cAMP production. Restriction of intracellular Ca(2+) switched the response in NHK cells, such that CaM inhibition decreased AVP-induced cAMP production. We suggest that a compensatory response to decreased Ca(2+) in ADPKD cells switches V2R coupling from Ca(2+) inhibited ACs 5/6 to Ca(2+)/CaM-stimulated AC3, to mitigate high cAMP levels in response to continuous AVP stimulation.
