TY  - JOUR
A1  - Glosse, Philipp
A1  - Feger, Martina
A1  - Mutig, Kerim
A1  - Chen, Hong
A1  - Hirche, Frank
A1  - Hasan, Ahmed Abdallah Abdalrahman Mohamed
A1  - Gaballa, Mohamed Mahmoud Salem Ahmed
A1  - Hocher, Berthold
A1  - Lang, Florian
A1  - Föller, Michael
T1  - AMP-activated kinase is a regulator of fibroblast growth factor 23 production
JF  - Kidney international : official journal of the International Society of Nephrology
N2  - Fibroblast growth factor 23 (FGF23) is a proteohormone regulating renal phosphate transport and vitamin D metabolism as well as inducing left heart hypertrophy. FGF23-deficient mice suffer from severe tissue calcification, accelerated aging and a myriad of aging-associated diseases. Bone cells produce FGF23 upon store-operated calcium ion entry (SOCE) through the calcium selective ion channel Orai1. AMP-activated kinase (AMPK) is a powerful energy sensor helping cells survive states of energy deficiency, and AMPK down-regulates Orai1. Here we investigated the role of AMPK in FGF23 production. Fgf23 gene transcription was analyzed by qRT-PCR and SOCE by fluorescence optics in UMR106 osteoblast-like cells while the serum FGF23 concentration and phosphate metabolism were assessed in AMPKa1-knockout and wild-type mice. The AMPK activator, 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) down-regulated, whereas the AMPK inhibitor, dorsomorphin dihydrochloride (compound C) and AMPK gene silencing induced Fgf23 transcription. AICAR decreased membrane abundance of Orai1 and SOCE. SOCE inhibitors lowered Fgf23 gene expression induced by AMPK inhibition. AMPKa1-knockout mice had a higher serum FGF23 concentration compared to wild-type mice. Thus, AMPK participates in the regulation of FGF23 production in vitro and in vivo. The inhibitory effect of AMPK on FGF23 production is at least in part mediated by Orai1-involving SOCE.
KW  - calcium
KW  - FGF23
KW  - Klotho
KW  - Orai1
KW  - phosphate
KW  - parathyroid hormone
Y1  - 2018
U6  - https://doi.org/10.1016/j.kint.2018.03.006
SN  - 0085-2538
SN  - 1523-1755
VL  - 94
IS  - 3
SP  - 491
EP  - 501
PB  - Elsevier
CY  - New York
ER  - 
TY  - JOUR
A1  - Mutig, Kerim
A1  - Kahl, Thomas
A1  - Saritas, Turgay
A1  - Godes, Michael
A1  - Persson, Pontus
A1  - Bates, James
A1  - Raffi, Hajamohideen
A1  - Rampoldi, Luca
A1  - Uchida, Shinichi
A1  - Hille, Carsten
A1  - Dosche, Carsten
A1  - Kumar, Satish
A1  - Castaneda-Bueno, Maria
A1  - Gamba, Gerardo
A1  - Bachmann, Sebastian
T1  - Activation of the Bumetanide-sensitive Na+, K+,2Cl(-) Cotransporter (NKCC2) Is Facilitated by Tamm-Horsfall Protein in a Chloride-sensitive Manner
JF  - The journal of biological chemistry
N2  - Active transport of NaCl across thick ascending limb (TAL) epithelium is accomplished by Na+, K+,2Cl(-) cotransporter (NKCC2). The activity of NKCC2 is determined by vasopressin (AVP) or intracellular chloride concentration and includes its amino-terminal phosphorylation. Co-expressed Tamm-Horsfall protein (THP) has been proposed to interact with NKCC2. We hypothesized that THP modulates NKCC2 activity in TAL. THP-deficient mice (THP-/-) showed an increased abundance of intracellular NKCC2 located in subapical vesicles (+47% compared with wild type (WT) mice), whereas base-line phosphorylation of NKCC2 was significantly decreased (-49% compared with WT mice), suggesting reduced activity of the transporter in the absence of THP. Cultured TAL cells with low endogenous THP levels and low base-line phosphorylation of NKCC2 displayed sharp increases in NKCC2 phosphorylation (+38%) along with a significant change of intracellular chloride concentration upon transfection with THP. In NKCC2-expressing frog oocytes, co-injection with THP cRNA significantly enhanced the activation of NKCC2 under low chloride hypotonic stress (+112% versus +235%). Short term (30 min) stimulation of the vasopressin V2 receptor pathway by V2 receptor agonist (deamino-cis-D-Arg vasopressin) resulted in enhanced NKCC2 phosphorylation in WT mice and cultured TAL cells transfected with THP, whereas in the absence of THP, NKCC2 phosphorylation upon deamino-cis-D-Arg vasopressin was blunted in both systems. Attenuated effects of furosemide along with functional and structural adaptation of the distal convoluted tubule in THP-/- mice supported the notion that NaCl reabsorption was impaired in TAL lacking THP. In summary, these results are compatible with a permissive role for THP in the modulation of NKCC2-dependent TAL salt reabsorptive function.
Y1  - 2011
U6  - https://doi.org/10.1074/jbc.M111.222968
SN  - 0021-9258
VL  - 286
IS  - 34
SP  - 30200
EP  - 30210
PB  - American Society for Biochemistry and Molecular Biology
CY  - Bethesda
ER  -