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J Biol Chem
2011 Aug 26;28634:30200-10. doi: 10.1074/jbc.M111.222968.
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Activation of the bumetanide-sensitive Na+,K+,2Cl- cotransporter (NKCC2) is facilitated by Tamm-Horsfall protein in a chloride-sensitive manner.
Mutig K
,
Kahl T
,
Saritas T
,
Godes M
,
Persson P
,
Bates J
,
Raffi H
,
Rampoldi L
,
Uchida S
,
Hille C
,
Dosche C
,
Kumar S
,
Castañeda-Bueno M
,
Gamba G
,
Bachmann S
.
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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 vasopressinV2 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.
Abdallah,
Loop diuretic infusion increases thiazide-sensitive Na(+)/Cl(-)-cotransporter abundance: role of aldosterone.
2001, Pubmed
Abdallah,
Loop diuretic infusion increases thiazide-sensitive Na(+)/Cl(-)-cotransporter abundance: role of aldosterone.
2001,
Pubmed
Amlal,
Na(+)-K+(NH4+)-2Cl- cotransport in medullary thick ascending limb: control by PKA, PKC, and 20-HETE.
1996,
Pubmed
Bachmann,
Ultrastructural localization of Tamm-Horsfall glycoprotein (THP) in rat kidney as revealed by protein A-gold immunocytochemistry.
1985,
Pubmed
Bachmann,
Sodium transport-related proteins in the mammalian distal nephron - distribution, ontogeny and functional aspects.
1999,
Pubmed
Bachmann,
Renal effects of Tamm-Horsfall protein (uromodulin) deficiency in mice.
2005,
Pubmed
Bates,
Tamm-Horsfall protein knockout mice are more prone to urinary tract infection: rapid communication.
2004,
Pubmed
Chiga,
Dietary salt regulates the phosphorylation of OSR1/SPAK kinases and the sodium chloride cotransporter through aldosterone.
2008,
Pubmed
Choi,
Mutant tamm-horsfall glycoprotein accumulation in endoplasmic reticulum induces apoptosis reversed by colchicine and sodium 4-phenylbutyrate.
2005,
Pubmed
Dahan,
A cluster of mutations in the UMOD gene causes familial juvenile hyperuricemic nephropathy with abnormal expression of uromodulin.
2003,
Pubmed
Delpire,
SPAK and OSR1: STE20 kinases involved in the regulation of ion homoeostasis and volume control in mammalian cells.
2008,
Pubmed
Ellison,
Adaptation of the distal convoluted tubule of the rat. Structural and functional effects of dietary salt intake and chronic diuretic infusion.
1989,
Pubmed
Gamba,
Molecular physiology and pathophysiology of electroneutral cation-chloride cotransporters.
2005,
Pubmed
Giménez,
Short-term stimulation of the renal Na-K-Cl cotransporter (NKCC2) by vasopressin involves phosphorylation and membrane translocation of the protein.
2003,
Pubmed
Hart,
Mutations of the UMOD gene are responsible for medullary cystic kidney disease 2 and familial juvenile hyperuricaemic nephropathy.
2002,
Pubmed
Hebert,
NaCl transport in mouse medullary thick ascending limbs. I. Functional nephron heterogeneity and ADH-stimulated NaCl cotransport.
1981,
Pubmed
Hille,
Two-photon fluorescence lifetime imaging of intracellular chloride in cockroach salivary glands.
2009,
Pubmed
Kaissling,
Structural adaptation of the distal convoluted tubule to prolonged furosemide treatment.
1985,
Pubmed
Kemter,
Novel missense mutation of uromodulin in mice causes renal dysfunction with alterations in urea handling, energy, and bone metabolism.
2009,
Pubmed
Malagolini,
Intracellular transport, cell-surface exposure and release of recombinant Tamm-Horsfall glycoprotein.
1997,
Pubmed
Meade,
cAMP-dependent activation of the renal-specific Na+-K+-2Cl- cotransporter is mediated by regulation of cotransporter trafficking.
2003,
Pubmed
,
Xenbase
Mo,
Ablation of the Tamm-Horsfall protein gene increases susceptibility of mice to bladder colonization by type 1-fimbriated Escherichia coli.
2004,
Pubmed
Mutig,
Short-term stimulation of the thiazide-sensitive Na+-Cl- cotransporter by vasopressin involves phosphorylation and membrane translocation.
2010,
Pubmed
Mutig,
Vasopressin V2 receptor expression along rat, mouse, and human renal epithelia with focus on TAL.
2007,
Pubmed
Na,
Upregulation of Na+ transporter abundances in response to chronic thiazide or loop diuretic treatment in rats.
2003,
Pubmed
Nielsen,
Ultrastructural localization of Na-K-2Cl cotransporter in thick ascending limb and macula densa of rat kidney.
1998,
Pubmed
Obermüller,
Expression of the Na-K-2Cl cotransporter by macula densa and thick ascending limb cells of rat and rabbit nephron.
1996,
Pubmed
Ortiz,
cAMP increases surface expression of NKCC2 in rat thick ascending limbs: role of VAMP.
2006,
Pubmed
Pacheco-Alvarez,
The Na+:Cl- cotransporter is activated and phosphorylated at the amino-terminal domain upon intracellular chloride depletion.
2006,
Pubmed
,
Xenbase
Paladino,
Different GPI-attachment signals affect the oligomerisation of GPI-anchored proteins and their apical sorting.
2008,
Pubmed
Ponce-Coria,
Regulation of NKCC2 by a chloride-sensing mechanism involving the WNK3 and SPAK kinases.
2008,
Pubmed
,
Xenbase
Reinalter,
Pharmacotyping of hypokalaemic salt-losing tubular disorders.
2004,
Pubmed
Renigunta,
Tamm-Horsfall glycoprotein interacts with renal outer medullary potassium channel ROMK2 and regulates its function.
2011,
Pubmed
,
Xenbase
Richardson,
Activation of the thiazide-sensitive Na+-Cl- cotransporter by the WNK-regulated kinases SPAK and OSR1.
2008,
Pubmed
Rinehart,
WNK3 kinase is a positive regulator of NKCC2 and NCC, renal cation-Cl- cotransporters required for normal blood pressure homeostasis.
2005,
Pubmed
,
Xenbase
Sachs,
LC-MS/MS analysis of differential centrifugation fractions from native inner medullary collecting duct of rat.
2008,
Pubmed
Säemann,
Tamm-Horsfall glycoprotein links innate immune cell activation with adaptive immunity via a Toll-like receptor-4-dependent mechanism.
2005,
Pubmed
Sandberg,
ANG II provokes acute trafficking of distal tubule Na+-Cl(-) cotransporter to apical membrane.
2007,
Pubmed
Schaeffer,
Analysis of uromodulin polymerization provides new insights into the mechanisms regulating ZP domain-mediated protein assembly.
2009,
Pubmed
Schlatter,
cAMP increases the basolateral Cl- -conductance in the isolated perfused medullary thick ascending limb of Henle's loop of the mouse.
1985,
Pubmed
Schnermann,
Juxtaglomerular cell complex in the regulation of renal salt excretion.
1998,
Pubmed
Schröter,
Marked reduction of Tamm-Horsfall protein synthesis in hyperprostaglandin E-syndrome.
1993,
Pubmed
Takahashi,
Uncompensated polyuria in a mouse model of Bartter's syndrome.
2000,
Pubmed
Wagner,
Mouse model of type II Bartter's syndrome. II. Altered expression of renal sodium- and water-transporting proteins.
2008,
Pubmed
Welker,
Renal Na+-K+-Cl- cotransporter activity and vasopressin-induced trafficking are lipid raft-dependent.
2008,
Pubmed
,
Xenbase
Welling,
A comprehensive guide to the ROMK potassium channel: form and function in health and disease.
2009,
Pubmed
Wilson,
Markers for detergent-resistant lipid rafts occupy distinct and dynamic domains in native membranes.
2004,
Pubmed
