Sensing, Signaling and Sorting Events in Kidney Epithelial Cell Physiology

Brown, Dennis; Breton, Sylvie; Ausiello, Dennis A.; Marshansky, Vladimir

doi:10.1111/j.1600-0854.2008.00867.x

Cited by 55 publications

(42 citation statements)

References 84 publications

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“…[3][4][5][6][7]18 We found that GPR4 mRNA is expressed in the kidney collecting duct, the nephron segment responsible for net acid excretion and final adjustments of the acid-base homeostasis. Cultured collecting duct cells (mOMCD1), which express GPR4 mRNA endogenously, exhibit pH-dependent accumulation of intra- Blood samples were obtained from the tail artery in conscious mice.…”

Section: Discussionmentioning

confidence: 99%

“…[3][4][5][6][7] Several investigators have demonstrated that GPR4 (G protein-coupled receptor 4), 4,8,9 OGR1 (ovarian cancer G protein-coupled receptor 1, GPR68), 4,10 -12 and TDAG8 (T cell death-associated gene 8, GPR65) can be stimulated by a reduction in extracellular pH to induce second messenger generation. [13][14][15][16] An elegant study by Ludwig et al 4 demonstrated that mutation of specific putative proton-accepting histidine residues in OGR1 significantly impaired acid-stimulated phosphoinositide generation.…”

mentioning

confidence: 99%

“…[3][4][5][6][7]18 This study was designed to determine the role of GPR4 in acid-base regulation. We found that GPR4 mRNA was expressed in the kidney collecting duct, where GPR4 mediated accumulation of intracellular cAMP.…”

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confidence: 99%

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Deletion of the pH Sensor GPR4 Decreases Renal Acid Excretion

Sun¹,

Yang²,

Tiegs³

et al. 2010

Journal of the American Society of Nephrology

100

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epithelial cells, and the effects of its deletion on acid-base homeostasis. We observed GPR4 expression in the kidney cortex, in the outer and inner medulla, in isolated kidney collecting ducts, and in cultured outer and inner medullary collecting duct cells (mOMCD1 and mIMCD3). Cultured mOMCD1 cells exhibited pH-dependent accumulation of intracellular cAMP, characteristic of GPR4 activation; GPR4 knockdown attenuated this accumulation. In vivo, deletion of GPR4 decreased net acid secretion by the kidney and resulted in a nongap metabolic acidosis, indicating that GPR4 is required to maintain acid-base homeostasis. Collectively, these findings suggest that GPR4 is a pH sensor with an important role in regulating acid secretion in the kidney collecting duct. Daily changes in the amount of protein in the diet produce fluctuations in metabolic net acid production. The kidneys adjust to these daily variations, ensuring tight correlation between acid production and excretion. 1,2 In humans, net acid excretion significantly correlates with changes in blood P CO2 , pH, and bicarbonate levels. 2 Physiologic changes of P CO2 , pH, and bicarbonate concentrations can therefore regulate net acid excretion, but this regulation is poorly understood.The recently discovered family of "proton-activated" G protein-coupled receptors (GPCRs) represents candidate pH sensors capable of relaying information about local and/or systemic pH to acidsecreting cells in the kidney. [3][4][5][6][7] Several investigators have demonstrated that GPR4 (G protein-coupled receptor 4), 4,8,9 OGR1 (ovarian cancer G protein-coupled receptor 1, GPR68), 4,10 -12 and TDAG8 (T cell death-associated gene 8, GPR65) can be stimulated by a reduction in extracellular pH to induce second messenger generation. [13][14][15][16] An elegant study by Ludwig et al. 4 demonstrated that mutation of specific putative proton-accepting histidine residues in OGR1 significantly impaired acid-stimulated phosphoinositide generation. Ex vivo studies from OGR1 knockouts indicate that OGR1 is the pH sensor, mediating the release of calcium from the bone during metabolic acidosis. 12 Analysis of aortic rings isolated from GPR4 knockout mice indicated that GPR4 acts as a pH sensor in blood vessels, regulating the outgrowth of new

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Deletion of the pH Sensor GPR4 Decreases Renal Acid Excretion

Sun¹,

Yang²,

Tiegs³

et al. 2010

Journal of the American Society of Nephrology

100

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“…Baf A1 has previously been shown to arrest AQP2 in the trans-Golgi network (TGN) in LLC-PK 1 cells, a porcine cell line stably expressing AQP2. 29,30 In MCD4 cells, 4AD caused an accumulation of AQP2 in perinuclear patches ( Figure 1, A and B) resembling those in LLC-PK 1 cells that represent the TGN. 17,30 In IMCD cells, 4AD did not induce the formation of patches clearly classifiable as TGN (Figure 2A).…”

Section: Ad Increases Intravesicular Ph and Causesmentioning

confidence: 99%

Small-Molecule Screening Identifies Modulators of Aquaporin-2 Trafficking

Bogum

Faust

Zühlke

et al. 2013

Journal of the American Society of Nephrology

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In the principal cells of the renal collecting duct, arginine vasopressin (AVP) stimulates the synthesis of cAMP, leading to signaling events that culminate in the phosphorylation of aquaporin-2 water channels and their redistribution from intracellular domains to the plasma membrane via vesicular trafficking. The molecular mechanisms that control aquaporin-2 trafficking and the consequent water reabsorption, however, are not completely understood. Here, we used a cell-based assay and automated immunofluorescence microscopy to screen 17,700 small molecules for inhibitors of the cAMP-dependent redistribution of aquaporin-2. This approach identified 17 inhibitors, including 4-acetyldiphyllin, a selective blocker of vacuolar H + -ATPase that increases the pH of intracellular vesicles and causes accumulation of aquaporin-2 in the Golgi compartment. Although 4-acetyldiphyllin did not inhibit forskolin-induced increases in cAMP formation and downstream activation of protein kinase A (PKA), it did prevent cAMP/PKAdependent phosphorylation at serine 256 of aquaporin-2, which triggers the redistribution to the plasma membrane. It did not, however, prevent cAMP-induced changes to the phosphorylation status at serines 261 or 269. Last, we identified the fungicide fluconazole as an inhibitor of cAMP-mediated redistribution of aquaporin-2, but its target in this pathway remains unknown. In conclusion, our screening approach provides a method to begin dissecting molecular mechanisms underlying AVP-mediated water reabsorption, evidenced by our identification of 4-acetyldiphyllin as a modulator of aquaporin-2 trafficking.

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“…2 (1)(2)(3)(4)(5)(6). Mutations in the vasopressin V 2 receptor and AQP2 cause congenital nephrogenic diabetes insipidus, a disease characterized by a massive loss of water through the kidney (7,8).…”

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confidence: 99%

Phosphorylation of Aquaporin-2 Regulates Its Water Permeability

Eto

Noda

Horikawa

et al. 2010

Journal of Biological Chemistry

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Vasopressin-regulated water reabsorption through the water channel aquaporin-2 (AQP2) in renal collecting ducts maintains body water homeostasis. Vasopressin activates PKA, which phosphorylates AQP2, and this phosphorylation event is required to increase the water permeability and water reabsorption of the collecting duct cells. It has been established that the phosphorylation of AQP2 induces its apical membrane insertion, rendering the cell water-permeable. However, whether this phosphorylation regulates the water permeability of this channel still remains unclear. To clarify the role of AQP2 phosphorylation in water permeability, we expressed recombinant human AQP2 in Escherichia coli, purified it, and reconstituted it into proteoliposomes. AQP2 proteins not reconstituted into liposomes were removed by fractionating on density step gradients. AQP2-reconstituted liposomes were then extruded through polycarbonate filters to obtain unilamellar vesicles. PKA phosphorylation significantly increased the osmotic water permeability of AQP2-reconstituted liposomes. We then examined the roles of AQP2 phosphorylation at Ser-256 and Ser-261 in the regulation of water permeability using phosphorylation mutants reconstituted into proteoliposomes. The water permeability of the non-phosphorylationmimicking mutant S256A-AQP2 and non-phosphorylated WT-AQP2 was similar, and that of the phosphorylation-mimicking mutant S256D-AQP2 and phosphorylated WT-AQP2 was similar. The water permeability of S261A-AQP2 and S261D-AQP2 was similar to that of non-phosphorylated WT-AQP2. This study shows that PKA phosphorylation of AQP2 at Ser-256 enhances its water permeability.Body water homeostasis is essential for the survival of mammals and is regulated by the renal collecting duct. Key components in the regulation of collecting duct water permeability are the vasopressin receptor and the water channel aquaporin-2 (AQP2) 2 (1-6). Mutations in the vasopressin V 2 receptor and AQP2 cause congenital nephrogenic diabetes insipidus, a disease characterized by a massive loss of water through the kidney (7,8). The binding of the antidiuretic hormone vasopressin to vasopressin V 2 receptors on renal principal cells stimulates cAMP synthesis via activation of adenylate cyclase. The subsequent activation of PKA leads to phosphorylation of AQP2 at Ser-256, and this phosphorylation event is required to increase the water permeability and water reabsorption of renal principal cells. It has been established that the phosphorylation of AQP2 induces its apical membrane insertion, rendering the cell water-permeable. We showed recently that AQP2 binds to a multiprotein "motor" complex and that phosphorylation-dependent reciprocal interaction with G-actin and tropomyosin 5b directs AQP2 to the apical membrane (9 -13). However, whether this phosphorylation regulates the water permeability of individual AQP2 proteins still remains unclear. Kuwahara et al. (14) showed that cAMP stimulation increased the water permeability of AQP2 expressed in Xenopus oocytes, alt...

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Sensing, Signaling and Sorting Events in Kidney Epithelial Cell Physiology

Cited by 55 publications

References 84 publications

Deletion of the pH Sensor GPR4 Decreases Renal Acid Excretion

Deletion of the pH Sensor GPR4 Decreases Renal Acid Excretion

Small-Molecule Screening Identifies Modulators of Aquaporin-2 Trafficking

Phosphorylation of Aquaporin-2 Regulates Its Water Permeability

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