Expression and phosphorylation of the Na<sup>+</sup>-Cl<sup>−</sup> cotransporter NCC in vivo is regulated by dietary salt, potassium, and SGK1

Vallon, Volker; Schroth, Jana; Läng, Florian; Kuhl, Dietmar; Uchida, Shinichi

doi:10.1152/ajprenal.00030.2009

Cited by 228 publications

(225 citation statements)

References 54 publications

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“…Kidneys were harvested 1 h after application of EX4 (10 g/kg ip), ALG (10 mg/kg ip), or vehicle (0.85% NaCl, 2 l/g body wt). Renal membranes were prepared in the presence of protease and phosphatase inhibitors, as previously described (33,39). Immunoblotting was performed at 4°C overnight with the primary NHE3 Ab (Millipore, Billerica, MA), phosphorylated (S552) NHE3 Ab (Novus Biologicals, Littleton, CO), and phosphorylated (S605) NHE3 Ab (Santa Cruz Biotechnology, Santa Cruz, CA) diluted 1:1,000, 1:1,000, and 1:200, respectively.…”

Section: Methodsmentioning

confidence: 99%

Natriuretic effect by exendin-4, but not the DPP-4 inhibitor alogliptin, is mediated via the GLP-1 receptor and preserved in obese type 2 diabetic mice

Rieg

Gerasimova

Murray

et al. 2012

American Journal of Physiology-Renal Physiology

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129

111

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Activation of the glucagon-like peptide (GLP)-1 receptor (GLP-1R) and inhibition of dipeptidyl peptidase-4 (DPP-4) are new antidiabetic strategies. The GLP-1R and DPP-4 are also expressed in the renal proximal tubular brush border, where they may regulate Na ϩ reabsorption. Exendin-4 (EX4) is a naturally occurring antidiabetic polypeptide (from the saliva of the lizard Heloderma suspectum) and GLP-1R agonist; however, part of its nonglucoregulatory effects are through GLP-1R-independent mechanisms. DPP-4 cleaves and inactivates GLP-1; thus the natriuretic effect of DPP-4 inhibition may be mediated by the GLP-1R. We report that parenteral application of EX4 in wild-type mice induced a diuresis and natriuresis associated with increases in glomerular filtration rate, fractional urinary fluid and Na ϩ excretion, and renal membrane expression of the Na ϩ /H ϩ exchanger NHE3 phosphorylated at S552 and S605, established consensus sites for cAMP-dependent PKA. These effects were absent in mice lacking the GLP-1R and independent of adenylyl cyclase 6. In comparison, parenteral application of the DPP-4 inhibitor alogliptin reduced plasma DPP-4 activity by 95% and induced a diuresis and natriuresis independent of the presence of the GLP-1R or changes in phosphorylated NHE3. The inhibitory effect on renal fluid and Na ϩ reabsorption of EX4, but not alogliptin, was preserved in diabetic db/db mice and associated with a modest reduction in blood pressure. These results reveal mechanistic differences in how EX4 vs. DPP-4 inhibition induces diuresis and natriuresis under normal states, with preservation of GLP-1R-mediated, but not DPP-4 inhibitor-dependent, natriuretic mechanisms in a mouse model of obese type 2 diabetes.glucagon-like peptide-1; dipeptidyl peptidase-4; NHE3; cAMP; proximal tubule GLUCAGON-LIKE PEPTIDE -1 (GLP-1), an incretin hormone secreted from enteroendocrine L cells in the intestine, stimulates glucose-dependent insulin release and may promote preservation of beta-cell function in patients with type 2 diabetes (9, 10). As a consequence, GLP-1 has been a principal focus of clinical and basic diabetes research in recent years. After secretion, active GLP-1 is rapidly cleaved by the widely expressed enzyme dipeptidyl peptidase-4 (DPP-4, CD26), such that the half-life of bioactive GLP-1 is Ͻ3 min. Therefore, therapeutic manipulation of the GLP-1 system includes strategies that inhibit the degradation of GLP-1 by DPP-4 (i.e., DPP-4 inhibitors) or degradation-resistant GLP-1 receptor (GLP-1R) agonists with a longer half-life, such as exendin-4 (EX4) or liraglutide.In addition to its metabolic effects, GLP-1 affects kidney function. Analysis of GLP-1R expression in rats (6), pigs, and humans (34) localized the GLP-1R to the brush border microvilli of proximal tubules. Intravenous infusion of GLP-1 increased glomerular filtration rate (GFR), inhibited proximal tubular reabsorption, and increased urine flow and Na ϩ excretion in rats (6, 30). In healthy subjects, infusion of GLP-1 evoked a dose-dependent increase in...

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Section: Methodsmentioning

confidence: 99%

Natriuretic effect by exendin-4, but not the DPP-4 inhibitor alogliptin, is mediated via the GLP-1 receptor and preserved in obese type 2 diabetic mice

Rieg

Gerasimova

Murray

et al. 2012

American Journal of Physiology-Renal Physiology

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129

111

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“…Namely, vasopressin stimulates FL-SPAK in the DCT to phosphorylate NCC, whereas it attenuates KS-SPAK to allow FL-SPAK and OSR1 to phosphorylate NKCC2 [104]. Although SGK1 was first recognized as an activator of ENaC [127], later reports also showed effects on NCC [115]. SGK1…”

Section: Spak Deficiency However Does Not Completely Inhibit Ncc Phmentioning

confidence: 99%

“…Because SGK1 is sensitive to aldosterone, this pathway appears to be involved in the activation of NCC by aldosterone [100]. The opposite is also true, because SGK1 knockout mice failed to increase NCC activity during a low sodium diet [115].…”

Section: Spak Deficiency However Does Not Completely Inhibit Ncc Phmentioning

confidence: 99%

The sodium chloride cotransporter SLC12A3: new roles in sodium, potassium, and blood pressure regulation

Moes

Lubbe

Zietse

et al. 2013

Pflugers Arch - Eur J Physiol

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SLC12A3 encodes the thiazide-sensitive sodium chloride cotransporter (NCC), which is primarily expressed in the kidney, but also in intestine and bone. In the kidney, NCC is located in the apical plasma membrane of epithelial cells in the distal convoluted tubule. Although NCC reabsorbs only 5 to 10 % of filtered sodium, it is important for the fine-tuning of renal sodium excretion in response to various hormonal and non-hormonal stimuli. Several new roles for NCC in the regulation of sodium, potassium, and blood pressure have been unraveled recently. For example, the recent discoveries that NCC is activated by angiotensin II but inhibited by dietary potassium shed light on how the kidney handles sodium during hypovolemia (high angiotensin II) and hyperkalemia. The additive effect of angiotensin II and aldosterone maximizes sodium reabsorption during hypovolemia, whereas the inhibitory effect of potassium on NCC increases delivery of sodium to the potassium-secreting portion of the nephron. In addition, great steps have been made in unraveling the molecular machinery that controls NCC. This complex network consists of kinases and ubiquitinases, including WNKs, SGK1, SPAK, Nedd4-2, Cullin-3, and Kelch-like 3. The pathophysiological significance of this network is illustrated by the fact that modification of each individual protein in the network changes NCC activity and results in salt-dependent hypotension or hypertension. This review aims to summarize these new insights in an integrated manner while identifying unanswered questions.

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“…40,44,47,48 Proteins were transferred to ni- trocellulose membranes and immunoblotted with AQP2 (dilution 1:500; Santa Cruz Biotechnology, Santa Cruz, CA), pS256-AQP2 (1: 3000), and pS269-AQP2 (1:1000) (the latter two were generous gifts from J. Hoffert and M. Knepper, National Institutes of Health). 8,49 Chemiluminescent detection was performed with ECL Plus (Amersham, Piscataway, NJ).…”

Section: Inner Medullary Formation Of Campmentioning

confidence: 99%

Adenylate Cyclase 6 Determines cAMP Formation and Aquaporin-2 Phosphorylation and Trafficking in Inner Medulla

Rieg

Tang²,

Murray³

et al. 2010

Journal of the American Society of Nephrology

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Arginine vasopressin (AVP) enhances water reabsorption in the renal collecting duct by vasopressin V 2 receptor (V 2 R)-mediated activation of adenylyl cyclase (AC), cAMP-promoted phosphorylation of aquaporin-2 (AQP2), and increased abundance of AQP2 on the apical membrane. Multiple isoforms of adenylate cyclase exist, and the roles of individual AC isoforms in water homeostasis are not well understood. Here, we found that levels of AC6 mRNA, the most highly expressed AC isoform in the inner medulla, inversely correlate with fluid intake. Moreover, mice lacking AC6 had lower levels of inner medullary cAMP, reduced abundance of phosphorylated AQP2 (at both serine-256 and serine-269), and lower urine osmolality than wild-type mice. Water deprivation or administration of the V 2 R agonist dDAVP did not increase urine osmolality of AC6-deficient mice to the levels of wild-type mice. Furthermore, AC6-deficient mice lacked dDAVP-promoted inner medullary cAMP formation and phosphorylation of serine-269 and had attenuated increases in both phosphorylation of serine-256 and apical membrane AQP2 trafficking. In summary, AC6 expression determines inner medullary cAMP formation and AQP2 phosphorylation and trafficking, the absence of which causes nephrogenic diabetes insipidus. The anti-diuretic hormone arginine-vasopressin (AVP) is the primary regulator of water reabsorption in the renal collecting duct (CD) and is critically involved in the regulation of water balance and maintenance of plasma osmolality. 1 AVP acts on the CD through the G s protein-coupled vasopressin V 2 receptor (V 2 R) to stimulate adenylyl cyclase (AC) and thus the synthesis of cAMP. 2 cAMP activates protein kinase A (PKA), which phosphorylates the water channel aquaporin-2 (AQP2) in its COOH-terminal tail on serine residue 256 (S256), thereby resulting in apical plasma membrane accumulation of AQP2. [3][4][5][6] In addition, cAMP-independent activation of AQP2 has been reported, which may involve V 2 R action of phosphoinositide-specific phospholipase C. 7 Other non-PKA-targeted AQP2 phosphorylation sites include S261, S264, and S269. 8 Phosphorylation of AQP2 at S264 and S269 requires prior phosphorylation of S256. 9 Immunohistochemistry showed that pS269-AQP2 localizes exclusively in the apical plasma

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Expression and phosphorylation of the Na⁺-Cl⁻ cotransporter NCC in vivo is regulated by dietary salt, potassium, and SGK1

Abstract: Vallon V, Schroth J, Lang F, Kuhl D, Uchida S. Expression and phosphorylation of the Na ϩ -Cl Ϫ cotransporter NCC in vivo is regulated by dietary salt, potassium, and SGK1.

Cited by 228 publications

References 54 publications

Natriuretic effect by exendin-4, but not the DPP-4 inhibitor alogliptin, is mediated via the GLP-1 receptor and preserved in obese type 2 diabetic mice

Natriuretic effect by exendin-4, but not the DPP-4 inhibitor alogliptin, is mediated via the GLP-1 receptor and preserved in obese type 2 diabetic mice

The sodium chloride cotransporter SLC12A3: new roles in sodium, potassium, and blood pressure regulation

Adenylate Cyclase 6 Determines cAMP Formation and Aquaporin-2 Phosphorylation and Trafficking in Inner Medulla

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Expression and phosphorylation of the Na+-Cl− cotransporter NCC in vivo is regulated by dietary salt, potassium, and SGK1

Abstract: Vallon V, Schroth J, Lang F, Kuhl D, Uchida S. Expression and phosphorylation of the Na ϩ -Cl Ϫ cotransporter NCC in vivo is regulated by dietary salt, potassium, and SGK1.

Cited by 228 publications

References 54 publications

Natriuretic effect by exendin-4, but not the DPP-4 inhibitor alogliptin, is mediated via the GLP-1 receptor and preserved in obese type 2 diabetic mice

Natriuretic effect by exendin-4, but not the DPP-4 inhibitor alogliptin, is mediated via the GLP-1 receptor and preserved in obese type 2 diabetic mice

The sodium chloride cotransporter SLC12A3: new roles in sodium, potassium, and blood pressure regulation

Adenylate Cyclase 6 Determines cAMP Formation and Aquaporin-2 Phosphorylation and Trafficking in Inner Medulla

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Expression and phosphorylation of the Na⁺-Cl⁻ cotransporter NCC in vivo is regulated by dietary salt, potassium, and SGK1