PKB/SGK-Resistant GSK3 Enhances Phosphaturia and Calciuria

Föller, Michael; Kempe, Daniela S.; Boini, Krishna M.; Pathare, Ganesh; Siraskar, Balasaheb; Capuano, Paola; Alesutan, Ioana; Sopjani, Mentor; Stange, Gerti; Mohebbi, Nilufar; Bhandaru, Madhuri; Ackermann, Teresa F.; Judenhofer, Martin S.; Pichler, Bernd J.; Biber, Jürg; Wagner, Carsten A.; Läng, Florian

doi:10.1681/asn.2010070757

Cited by 25 publications

(20 citation statements)

References 48 publications

(52 reference statements)

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“…However, gsk-3 KI mice have been shown to have phosphaturia, calciuria, and demineralized bone. These effects were in part attributed to a direct inhibitory effect of GSK3 on the main phosphate transporter of the kidney, NaPiIIa (10). Our present study suggests that the renal phosphate loss of gsk-3 KI mice is also caused by the high serum FGF23 level in these mice.…”

Section: Discussionsupporting

confidence: 49%

“…A high serum level of FGF23 is expected to induce phosphaturia, an effect already described in gsk-3 KI mice (10). Therefore, we measured serum phosphate and renal phosphate excretion before and after treatment with propranolol.…”

Section: Resultsmentioning

confidence: 88%

“…Gsk-3 KI mice have been reported to have low serum phosphate (hypophosphatemia) and 1,25(OH) 2 D 3 levels and loss of renal phosphate (phosphaturia) (10). The bone-derived hormone FGF23 induces all those effects.…”

Section: Resultsmentioning

confidence: 99%

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Enhanced FGF23 production in mice expressing PI3K‐insensitive GSK3 is normalized by β‐blocker treatment

Fajol¹,

Chen²,

Umbach³

et al. 2015

FASEB j.

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Glycogen synthase kinase (GSK)-3 is a ubiquitously expressed kinase inhibited by insulindependent Akt/PKB/SGK. Mice expressing Akt/PKB/ SGK-resistant GSK3a/GSK3b (gsk3 KI ) exhibit enhanced sympathetic nervous activity and phosphaturia with decreased bone density. Hormones participating in phosphate homeostasis include fibroblast growth factor (FGF)-23, a bone-derived hormone that inhibits 1,25-dihydroxyvitamin D 3 (1,25(OH) 2 D 3 ; calcitriol) formation and phosphate reabsorption in the kidney and counteracts vascular calcification and aging. FGF23 secretion is stimulated by the sympathetic nervous system. We studied the role of GSK3-controlled sympathetic activity in FGF23 production and phosphate metabolism. Serum FGF23, 1,25(OH) 2 D 3 , and urinary vanillylmandelic acid (VMA) were measured by ELISA, and serum and urinary phosphate and calcium were measured by photometry in gsk3 KI and gsk3 WT mice, before and after 1 wk of oral treatment with the b-blocker propranolol. Urinary VMA excretion, serum FGF23, and renal phosphate and calcium excretion were significantly higher, and serum 1,25(OH) 2 D 3 and phosphate concentrations were lower in gsk3 KI mice than in gsk3 WT mice. Propranolol treatment decreased serum FGF23 and loss of renal calcium and phosphate and increased serum phosphate concentration in gsk3 KI mice. We conclude that Akt/ PKB/SGK-sensitive GSK3 inhibition participates in the regulation of FGF23 release, 1,25(OH) 2 D 3 formation, and thus mineral metabolism, by controlling the activity of the sympathetic nervous system.-Fajol, A., Chen, H., Umbach, A. T., Quarles, L. D., Lang, F., Föller, M. Enhanced FGF23 production in mice expressing PI3K-insensitive GSK3 is normalized by b-blocker treatment. Insulin mainly regulates glucose homeostasis, but also affects renal phosphate handling (1, 2). Cellular insulin's effects are in large part mediated by activation of PI3K resulting in the stimulation of Akt/PKB and serum-and glucocorticoid-inducible kinase (SGK) isoforms (3, 4). Upon activation, Akt/PKB (5) and SGK (6, 7) isoforms can phosphorylate numerous cellular targets, including glycogen synthase kinase (GSK)-3, thereby rendering this kinase inactive. Loss of Akt2 or of SGK3 activity in mouse models results in decreased renal phosphate reabsorption and, hence, phosphate loss (8, 9). Moreover, transgenic mice expressing Akt/PKB/SGK-resistant GSK3a/b [gsk-3 knockin (gsk-3 KI )] have hypophosphatemia, phosphaturia, and decreased bone density, illustrating the significance of PI3K signaling for renal phosphate handling (10). A direct inhibitory effect of GSK3 on renal sodium-dependent phosphate transporter IIa (NaPiIIa) (10) is likely to contribute to the phosphaturia of gsk-3 KI mice, but may not fully explain it. Gsk-3 KI mice also have hypertension and a faster heart rate caused by enhanced sympathetic activity (11).Fibroblast growth factor (FGF)-23 is a bone-derived hormone that controls phosphate and calcium metabolism (12-14). Its main target is the kidney, where FGF23 inhibits tubular p...

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Section: Discussionsupporting

confidence: 49%

Section: Resultsmentioning

confidence: 88%

See 1 more Smart Citation

Enhanced FGF23 production in mice expressing PI3K‐insensitive GSK3 is normalized by β‐blocker treatment

Fajol¹,

Chen²,

Umbach³

et al. 2015

FASEB j.

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“…Renal tubular phosphate reabsorption is regulated by a wide variety of parameters, such as dietary phosphate intake, acid-base status, parathyroid hormone, 1,25-(OH) 2 vitamin D 3 , FGF-23, insulin and insulin-like growth factor IGF1 [15,16,17,18,19,20,21]. Signaling involved in the regulation of NaPi-IIa includes the protein kinases A and C, ERK1/2, Klotho and the PI3K/PKB/GSK3 kinase cascade [22,23,24,25,26,27,28,29]. Nothing is known, however, about the potential regulation of NaPi-IIa by AMPK.…”

Section: Introductionmentioning

confidence: 99%

Down-Regulation of the Na<sup>+</sup>-Coupled Phosphate Transporter NaPi-IIa by AMP-Activated Protein Kinase

Dërmaku-Sopjani

Almilaji

Pakladok

et al. 2013

Kidney Blood Press Res

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Background/Aims: The Na⁺-coupled phosphate transporter NaPi-IIa is the main carrier accomplishing renal tubular phosphate reabsorption. It is driven by the electrochemical Na⁺ gradient across the apical cell membrane, which is maintained by Na⁺ extrusion across the basolateral cell membrane through the Na⁺/K⁺ ATPase. The operation of NaPi-IIa thus requires energy in order to avoid cellular Na⁺ accumulation and K⁺ loss with eventual decrease of cell membrane potential, Cl^- entry and cell swelling. Upon energy depletion, early inhibition of Na⁺-coupled transport processes may delay cell swelling and thus foster cell survival. Energy depletion is sensed by the AMP-activated protein kinase (AMPK), a serine/threonine kinase stimulating several cellular mechanisms increasing energy production and limiting energy utilization. The present study explored whether AMPK influences the activity of NAPi-IIa. Methods: cRNA encoding NAPi-IIa was injected into Xenopus oocytes with or without additional expression of wild-type AMPK (AMPK^α1-HA+AMPK^β1-Flag+AMPK^γ1-HA), of inactive AMPK^αK45R (AMPK^α1K45R+AMPK^β1-Flag+AMPK^γ1-HA) or of constitutively active AMPK^γR70Q (AMPK^α1-HA+AMPK^β1-Flag+AMPKγ1^R70Q). NaPi-IIa activity was estimated from phosphate-induced current in dual electrode voltage clamp experiments. Results: In NaPi-IIa-expressing, but not in water-injected Xenopus oocytes, the addition of phosphate (1 mM) to the extracellular bath solution generated a current (I_p), which was significantly decreased by coexpression of wild-type AMPK and of AMPK^γR70Q but not of AMPK^αK45R. The phosphate-induced current in NaPi-IIa- and AMPK-expressing Xenopus ooocytes was significantly increased by AMPK inhibitor Compound C (20 µM). Kinetic analysis revealed that AMPK significantly decreased the maximal transport rate. Conclusion: The AMP-activated protein kinase AMPK is a powerful regulator of NaPi-IIa and thus of renal tubular phosphate transport.

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“…However, gsk3 KI mice have a lower plasma corticosterone and aldosterone concentration, as well as a higher renal sodium excretion and blood pressure than gsk3 WT mice (26). Gsk3 KI mice suffer from proteinuria due to glomerular injury, which may be related to their hypertension (27), and from renal calcium and phosphate loss with demineralized bone (28). Multiple manifestations of the metabolic syndrome are counteracted by the adipose tissue-derived protein hormone adiponectin…”

mentioning

confidence: 99%

PI3K-resistant GSK3 controls adiponectin formation and protects from metabolic syndrome

Chen

Fajol

Hoene³

et al. 2016

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

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Metabolic syndrome is characterized by insulin resistance, obesity, and dyslipidemia. It is the consequence of an imbalance between caloric intake and energy consumption. Adiponectin protects against metabolic syndrome. Insulin-induced signaling includes activation of PI3 kinase and protein kinase B (PKB)/Akt. PKB/Akt in turn inactivates glycogen synthase kinase (GSK) 3, a major regulator of metabolism. Here, we studied the significance of PI3K-dependent GSK3 inactivation for adiponectin formation in diet-induced metabolic syndrome. Mice expressing PI3K-insensitive GSK3 (gsk3 KI ) and wild-type mice (gsk3 WT ) were fed a high-fat diet. Compared with gsk3 WT mice, gsk3 KI mice were protected against the development of metabolic syndrome as evident from a markedly lower weight gain, lower total body and liver fat accumulation, better glucose tolerance, stronger hepatic insulin-dependent PKB/Akt phosphorylation, lower serum insulin, cholesterol, and triglyceride levels, as well as higher energy expenditure. Serum adiponectin concentration and the activity of transcription factor C/EBPα controlling the expression of adiponectin in adipose tissue was significantly higher in gsk3 KI mice than in gsk3 WT mice. Treatment with GSK3 inhibitor lithium significantly decreased the serum adiponectin concentration of gsk3 KI mice and abrogated the difference in C/EBPα activity between the genotypes. Taken together, our data demonstrate that the expression of PI3K-insensitive GSK3 stimulates the production of adiponectin and protects from diet-induced metabolic syndrome.obesity | insulin resistance | triglycerides | leptin

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PKB/SGK-Resistant GSK3 Enhances Phosphaturia and Calciuria

Cited by 25 publications

References 48 publications

Enhanced FGF23 production in mice expressing PI3K‐insensitive GSK3 is normalized by β‐blocker treatment

Enhanced FGF23 production in mice expressing PI3K‐insensitive GSK3 is normalized by β‐blocker treatment

Down-Regulation of the Na<sup>+</sup>-Coupled Phosphate Transporter NaPi-IIa by AMP-Activated Protein Kinase

PI3K-resistant GSK3 controls adiponectin formation and protects from metabolic syndrome

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