Collecting duct-specific knockout of adenylyl cyclase type VI causes a urinary concentration defect in mice

Roos, Karl; Strait, Kevin A.; Raphael, Kalani L.; Blount, Mitsi A.; Kohan, Donald E.

doi:10.1152/ajprenal.00397.2011

Cited by 57 publications

(65 citation statements)

References 24 publications

(30 reference statements)

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“…11 Two mouse lines were used: (1) mice containing a transgene expressing Cre recombinase under the control of AQP2-Cre that express Cre selectively in renal collecting duct principal cells and (2) were bred to be doubly homozygous for the floxed Pkd1 and ADCY6 genes (the latter as previously reported 12 ). These mice were crossed with AQP2-Cre mice through a series of breedings to obtain mice that were homozygous for the floxed Pkd1 gene, heterozygous for AQP2-Cre, and either homozygous or heterozygous for the floxed ADCY6 gene.…”

Section: Transgenic Mouse Linesmentioning

confidence: 99%

“…For example, CD AC6 deficiency prevents AVP-stimulated epithelial Na channel activity in the CD 15 ; however, CD water reabsorption is only mildly impaired by CD AC6 absence. 12 Although these studies were conducted under different conditions (epithelial Na channel activity was studied in vitro, and water reabsorption was studied in vivo), they raise the possibility that AVP might exert different effects on the CD depending on which adenylyl cyclase isoforms are activated. It would seem most likely that AVP binding per se is not the determinant of which adenylyl cyclase isoforms are activated, but rather, other cellular modulatory systems are involved.…”

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confidence: 99%

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Adenylyl Cyclase 6 Deficiency Ameliorates Polycystic Kidney Disease

Rees

Kittikulsuth

Roos

et al. 2014

Journal of the American Society of Nephrology

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ABSTRACTcAMP is an important mediator of cystogenesis in polycystic kidney disease (PKD). Several adenylyl cyclase (AC) isoforms could mediate cAMP accumulation in PKD, and identification of a specific pathogenic AC isoform is of therapeutic interest. We investigated the role of AC6 in a mouse model of PKD that is homozygous for the loxP-flanked PKD1 gene and heterozygous for an aquaporin-2-Cre recombinase transgene to achieve collecting duct-specific gene targeting. Collecting duct-specific knockout of polycystin-1 caused massive renal cyst formation, kidney enlargement, and severe kidney failure, with a mean survival time of 2 months. In contrast, coincident collecting duct-specific knockout of polycystin-1 and AC6 (also homozygous for the floxed ADCY6 gene) markedly decreased kidney size and cystogenesis, improved renal function, reduced activation of the B-Raf/ERK/MEK pathway, and greatly increased survival. Absence of collecting duct AC6 did not alter urinary cAMP excretion or kidney cAMP concentration. In conclusion, AC6 is a key mediator of cyst formation and renal injury in a model of PKD.

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Section: Transgenic Mouse Linesmentioning

confidence: 99%

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confidence: 99%

Adenylyl Cyclase 6 Deficiency Ameliorates Polycystic Kidney Disease

Rees

Kittikulsuth

Roos

et al. 2014

Journal of the American Society of Nephrology

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“…25 Functional studies have shown a role of AC6 in the thick ascending limb, distal tubule, and collecting duct insofar as mice lacking AC6 have Bartter syndrome 26 and nephrogenic diabetes insipidus (NDI). 27,28 In a collecting duct-specific AC6 knockdown model, vasopressin-stimulated epithelial sodium channel open probability was abolished. 29 Based on studies indicating that vasopressin V 2 receptors use the AC6-cAMP signaling pathway [26][27][28][29][30] and the relatively high abundance of AC6 in the proximal tubule, 23,30,31 we proposed that AC6 may contribute to PTH-stimulated cAMP formation, P i excretion, and thus, P i homeostasis.…”

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confidence: 99%

Renal Phosphate Wasting in the Absence of Adenylyl Cyclase 6

Fenton

Murray

Rieg

et al. 2014

Journal of the American Society of Nephrology

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Parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF-23) enhance phosphate excretion by the proximal tubule of the kidney by retrieval of the sodium-dependent phosphate transporters (Npt2a and Npt2c) from the apical plasma membrane. PTH activates adenylyl cyclase (AC) through PTH 1 receptors and stimulates the cAMP/PKA signaling pathway. However, the precise role and isoform(s) of AC in phosphate homeostasis are not known. We report here that mice lacking AC6 (AC6 2/2 ) have increased plasma PTH and FGF-23 levels compared with wild-type (WT) mice but comparable plasma phosphate concentrations. Acute activation of the calcium-sensing receptor or feeding a zero phosphate diet almost completely suppressed plasma PTH levels in both AC6 2/2 and WT mice, indicating a secondary cause for hyperparathyroidism. Pharmacologic blockade of FGF receptors resulted in a comparable increase in plasma phosphate between genotypes, whereas urinary phosphate remained significantly higher in AC6 2/2 mice. Compared with WT mice, AC6 2/2 mice had reduced renal Npt2a and Npt2c protein abundance, with approximately 80% of Npt2a residing in lysosomes. WT mice responded to exogenous PTH with redistribution of Npt2a from proximal tubule microvilli to intracellular compartments and lysosomes alongside a PTH-induced dose-response relationship for fractional phosphate excretion and urinary cAMP excretion. These responses were absent in AC6 2/2 mice. In conclusion, AC6 in the proximal tubule modulates cAMP formation, Npt2a trafficking, and urinary phosphate excretion, which are highlighted by renal phosphate wasting in AC6 2/2 mice. 25: 282225: -283425: , 201425: . doi: 10.1681 Parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF-23) are the primary regulators of renal phosphate (P i ) excretion by the proximal tubule and critically involved in the regulation of P i balance and maintenance of plasma P i . PTH acts on the proximal tubule through the G s protein-coupled PTH 1 receptor (PTH 1 R) to stimulate adenylyl cyclase (AC) and, thus, the synthesis of cAMP and consecutive activation of protein kinase A (PKA). 1-3 After activation of PTH 1 R, the sodiumphosphate cotransporters Npt2a and Npt2c (approximately 70% and approximately 30% reabsorption of filtered P i , respectively) are retrieved from the apical plasma membrane, resulting in increased P i excretion. [4][5][6] In addition, cAMP-independent effects of PTH have been reported, 7 which may involve PTH 1 R action on phosphoinositide-specific phospholipase C (PLC) 8,9 and mitogen-activated protein kinases. 10,11 FGF-23 mediates its action in the proximal tubule through the FGF receptor/Klotho complex, which downregulates the expression of Npt2a and Npt2c. 12,13 Immunohistochemistry J Am Soc Nephrol

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“…AC6 is inhibited by Ca 2+ at the 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 (also known as ADCY3) 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 the vasopressin-regulated water reabsorption is supported by the observation that collecting-duct-specific knockout of AC6 causes a urinary concentration defect associated with reduced vasopressinstimulated cAMP accumulation (Roos et al, 2012). Taken together, our results indicate that the reduction in cAMP accumulation upon simultaneous stimulation with forskolin and activation of CaSR results from impairment of cAMP synthesis that is likely due to the inhibition of AC6 activity as a consequence of intracellular Ca 2+ rise.…”

Section: Discussionmentioning

confidence: 99%

Negative feedback from CaSR signaling to aquaporin-2 sensitizes vasopressin to extracellular Ca2+

Ranieri

Tamma

Mise

et al. 2015

Journal of Cell Science

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We previously described that high luminal Ca 2+ in the renal collecting duct attenuates short-term vasopressin-induced aquaporin-2 (AQP2) trafficking through activation of the Ca 2+ -sensing receptor (CaSR). Here, we evaluated AQP2 phosphorylation and permeability, in both renal HEK-293 cells and in the dissected inner medullary collecting duct, in response to specific activation of CaSR with NPS-R568. In CaSR-transfected cells, CaSR activation drastically reduced the basal levels of AQP2 phosphorylation at S256 (AQP2-pS256), thus having an opposite effect 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 the 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 the cAMP-dependent increase in AQP2-pS256 and water permeability, counteracting the short-term vasopressin response. By extension, our results suggest the attractive concept that CaSR expressed in distinct nephron segments exerts a negative feedback on hormones acting through cAMP, conferring high sensitivity of hormone to extracellular Ca 2+ .

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Collecting duct-specific knockout of adenylyl cyclase type VI causes a urinary concentration defect in mice

Cited by 57 publications

References 24 publications

Adenylyl Cyclase 6 Deficiency Ameliorates Polycystic Kidney Disease

Adenylyl Cyclase 6 Deficiency Ameliorates Polycystic Kidney Disease

Renal Phosphate Wasting in the Absence of Adenylyl Cyclase 6

Negative feedback from CaSR signaling to aquaporin-2 sensitizes vasopressin to extracellular Ca2+

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