Impaired water reabsorption in mice deficient in the type VI adenylyl cyclase (AC6)

Chien, Chen-Li; Wu, Yu-Shuo; Lai, Hsing‐Lin; Chen, Yen‐Hui; Jiang, Shinn‐Jong; Shih, Chia-Ming; Lin, Sui-Shan; Chang, Chen; Chern, Yijuang

doi:10.1016/j.febslet.2010.05.004

Cited by 42 publications

(36 citation statements)

References 22 publications

(29 reference statements)

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“…cAMP is synthesized by adenylyl cyclase, which comprises a family of nine membrane-associated isoenzymes with distinct tissue distributions and subcellular localizations. Adenylyl cyclase 6 (AC6) has previously been localized in primary cilia in renal tubular cells and cholangiocytes (19,20). In Kif3a F/-renal epithelial cells, adenylyl cyclases 5 and 6 (AC5/6) colocalized with acetylated tubulin, a marker of the primary cilium ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Polycystin-2 and phosphodiesterase 4C are components of a ciliary A-kinase anchoring protein complex that is disrupted in cystic kidney diseases

Choi¹,

Suzuki²,

Hajarnis³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

117

115

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Polycystic kidney disease (PKD) is a genetic disorder that is characterized by cyst formation in kidney tubules. PKD arises from abnormalities of the primary cilium, a sensory organelle located on the cell surface. Here, we show that the primary cilium of renal epithelial cells contains a protein complex comprising adenylyl cyclase 5/6 (AC5/6), A-kinase anchoring protein 150 (AKAP150), and protein kinase A. Loss of primary cilia caused by deletion of Kif3a results in activation of AC5 and increased cAMP levels. Polycystin-2 (PC2), a ciliary calcium channel that is mutated in human PKD, interacts with AC5/6 through its C terminus. Deletion of PC2 increases cAMP levels, which can be corrected by reexpression of wild-type PC2 but not by a mutant lacking calcium channel activity. Phosphodiesterase 4C (PDE4C), which catabolizes cAMP, is also located in renal primary cilia and interacts with the AKAP150 complex. Expression of PDE4C is regulated by the transcription factor hepatocyte nuclear factor-1β (HNF-1β), mutations of which produce kidney cysts. PDE4C is down-regulated and cAMP levels are increased in HNF-1β mutant kidney cells and mice. Collectively, these findings identify PC2 and PDE4C as unique components of an AKAP complex in primary cilia and reveal a common mechanism for dysregulation of cAMP signaling in cystic kidney diseases arising from different gene mutations.

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Section: Resultsmentioning

confidence: 99%

Polycystin-2 and phosphodiesterase 4C are components of a ciliary A-kinase anchoring protein complex that is disrupted in cystic kidney diseases

Choi¹,

Suzuki²,

Hajarnis³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

117

115

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“…AC6 loxloxCre mice have greater water intake and lower urine osmolality under baseline conditions. AC6 expression is heterogeneous in the kidney tubule (21), and we have previously demonstrated roles of AC6 in cells of the proximal tubule, thick ascending limb, and distal convoluted tubule (22,23). Therefore, to isolate a potential role of AC6 in kidney and CD PCs, the main "target" cell for Li + effects (24), we generated a condition- al mouse model with AC6 deletion controlled by AQP2-dependent Cre recombinase expression (25).…”

Section: LImentioning

confidence: 99%

Role of adenylyl cyclase 6 in the development of lithium-induced nephrogenic diabetes insipidus

Poulsen¹,

Kristensen²,

Brooks³

et al. 2017

JCI Insight

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“…After 1 hour of equilibration, intravenous bolus application of vehicle (0.5 ml/g body wt of 0.85% NaCl over 1 minute) was followed by application of increasing doses of PTH (1,3,10,30, and 100 mg/kg; 1-34 Human; GenScript, Piscataway, NJ). After each bolus, allowing 5 minutes for drug distribution, urine was quantitatively collected through a bladder catheter for 15 minutes to determine urinary P i .…”

Section: Effect Of Pth On Urinary P I and Camp Excretion In Renal Clementioning

confidence: 99%

“…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. In the present study, we examined P i homeostasis, PTH-induced renal excretion of P i and cAMP, and trafficking and expression of Npt2a and Npt2c in mice lacking AC6 (AC6 2/2 ).…”

mentioning

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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Impaired water reabsorption in mice deficient in the type VI adenylyl cyclase (AC6)

Cited by 42 publications

References 22 publications

Polycystin-2 and phosphodiesterase 4C are components of a ciliary A-kinase anchoring protein complex that is disrupted in cystic kidney diseases

Polycystin-2 and phosphodiesterase 4C are components of a ciliary A-kinase anchoring protein complex that is disrupted in cystic kidney diseases

Role of adenylyl cyclase 6 in the development of lithium-induced nephrogenic diabetes insipidus

Renal Phosphate Wasting in the Absence of Adenylyl Cyclase 6

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