scholarly journals WNK4 kinase regulates surface expression of the human sodium chloride cotransporter in mammalian cells

2006 ◽  
Vol 69 (12) ◽  
pp. 2162-2170 ◽  
Author(s):  
H. Cai ◽  
V. Cebotaru ◽  
Y-H Wang ◽  
X-M Zhang ◽  
L. Cebotaru ◽  
...  
Keyword(s):  
Sodium Chloride ◽  
Mammalian Cells ◽  
Surface Expression ◽  
Sodium Chloride Cotransporter

scholarly journals RasGRP1 stimulation enhances ubiquitination and endocytosis of the sodium-chloride cotransporter

2010 ◽  
Vol 299 (2) ◽  
pp. F300-F309 ◽  
Author(s):  
Benjamin Ko ◽  
Erik-Jan Kamsteeg ◽  
Leslie L. Cooke ◽  
Lauren N. Moddes ◽  
Peter M. T. Deen ◽  
...  
Keyword(s):  
Sodium Chloride ◽  
Cell Surface ◽  
Phorbol Ester ◽  
Phorbol Esters ◽  
Surface Expression ◽  
Dominant Negative ◽  
Cell Surface Expression ◽  
Activity Regulation ◽  
Sodium Chloride Cotransporter ◽  
Radiotracer Uptake

The sodium-chloride cotransporter (NCC) is the principal salt-absorptive pathway in the distal convoluted tubule. Recently, we described a novel pathway of NCC regulation in which phorbol esters (PE) stimulate Ras guanyl-releasing protein 1 (RasGRP1), triggering a cascade ultimately activating ERK1/2 MAPK and decreasing NCC cell surface expression (Ko B, Joshi LM, Cooke LL, Vazquez N, Musch MW, Hebert SC, Gamba G, Hoover RS. Proc Natl Acad Sci USA 104: 20120–20125, 2007). Little is known about the mechanisms which underlie these effects on NCC activity. Regulation of NCC via changes in NCC surface expression has been reported, but endocytosis of NCC has not been demonstrated. In this study, utilizing biotinylation, internalization assays, and a dynamin dominant-negative construct, we demonstrate that the regulation of NCC by PE occurs via an enhancement in internalization of NCC and is dynamin dependent. In addition, immunoprecipitation of NCC and subsequent immunoblotting for ubiquitin showed increased ubiquitination of NCC with phorbol ester treatment. MEK1/2 inhibitors and gene silencing of RasGRP1 indicated that this effect was dependent on RasGRP1 and ERK1/2 activation. Inhibition of ubiquitination prevents any PE-mediated decrease in NCC surface expression as measured by biotinylation or NCC activity as measured by radiotracer uptake. These findings confirmed that the PE effect on NCC is mediated by endocytosis of NCC. Furthermore, ubiquitination of NCC is essential for this process and this ubiquitination is dependent upon RasGRP1-mediated ERK1/2 activation.

Abstract 076: Urinary Exosomal Epithelial Sodium Channel And Sodium-chloride Cotransporter Measurement In Humans

Hypertension ◽  
2014 ◽  
Vol 64 (suppl_1) ◽  
Author(s):  
TAOPHEEQ A MUSTAPHA ◽  
VICTOR NWAZUE ◽  
KEVIN SCHEY ◽  
RAJ SATISH ◽  
JAMES M LUTHER
Keyword(s):  
Sodium Chloride ◽  
Sodium Channel ◽  
Multiple Reaction Monitoring ◽  
Epithelial Sodium Channel ◽  
Sodium Balance ◽  
Sodium Reabsorption ◽  
Dependent Manner ◽  
Creatinine Concentration ◽  
Spot Urine ◽  
Sodium Chloride Cotransporter

Sodium reabsorption in the distal nephron is tightly regulated in part by epithelial sodium channel (ENaC) and sodium chloride cotransporter (NCC), although non-invasive measure of these proteins in humans has not previously been feasible. We recently analyzed the urinary exosomal proteome and identified candidate targets for quantification of ENaC and NCC using targeted mass spectrometry. To test the hypothesis that urinary exosomal ENaC and NCC are altered during renin-angiotensin-aldosterone system activation, we activated the endogenous RAAS using a low sodium diet (LS) in two separate studies. We provided 8 subjects LS diet (10mmol/day for 7days) to assess urinary protein excretion at 7 days (study 1) and longitudinally over the course of 1 week (study 2). Daily 24-hour urine was collected to monitor sodium balance, and spot urine samples were obtained each morning on days 0, 2, 4, and 6 of LS diet. Urinary exosomal ENaC-α, ENaC-γ, and NCC peptides were analyzed using targeted multiple-reaction-monitoring analysis quantified with stable-isotope peptide standards, and results were normalized to urine creatinine concentration. In study 1, urinary ENaCγ increased after 8 days of LS diet (Figure A). In study 2, urinary exosomal ENaCγ (Figure B) and NCC peptides (Figure C) increased in a time-dependent manner during LS diet. These measures of urinary sodium channel expression may provide further insight into distal sodium reabsorption in human hypertension.

scholarly journals IRE1α kinase–mediated unconventional protein secretion rescues misfolded CFTR and pendrin

2020 ◽  
Vol 6 (8) ◽  
pp. eaax9914
Author(s):  
Hak Park ◽  
Dong Hoon Shin ◽  
Ju-Ri Sim ◽  
Sowon Aum ◽  
Min Goo Lee
Keyword(s):  
Cell Surface ◽  
Protein Secretion ◽  
Protein Misfolding ◽  
Mammalian Cells ◽  
Surface Expression ◽  
Cell Surface Expression ◽  
Downstream Effector ◽  
Mouse Colon ◽  
Δf508 Cftr ◽  
Kinase Pathway

The most prevalent pathogenic mutations in the CFTR (ΔF508) and SLC26A4/pendrin (p.H723R), which cause cystic fibrosis and congenital hearing loss, respectively, evoke protein misfolding and subsequent defects in their cell surface trafficking. Here, we report that activation of the IRE1α kinase pathway can rescue the cell surface expression of ΔF508-CFTR and p.H723R-pendrin through a Golgi-independent unconventional protein secretion (UPS) route. In mammalian cells, inhibition of IRE1α kinase, but not inhibition of IRE1α endonuclease and the downstream effector XBP1, inhibited CFTR UPS. Treatment with the IRE1α kinase activator, (E)-2-(2-chlorostyryl)-3,5,6-trimethyl-pyrazine (CSTMP), rescued cell surface expression and functional activity of ΔF508-CFTR and p.H723R-pendrin. Treatment with a nontoxic dose of CSTMP to ΔF508-CFTR mice restored CFTR surface expression and CFTR-mediated anion transport in the mouse colon. These findings suggest that UPS activation via IRE1α kinase is a strategy to treat diseases caused by defective cell surface trafficking of membrane proteins, including ΔF508-CFTR and p.H723R-pendrin.

Vasopressin regulation of sodium transport in the distal nephron and collecting duct

2015 ◽  
Vol 309 (4) ◽  
pp. F280-F299 ◽  
Author(s):  
M. L. A. Kortenoeven ◽  
N. B. Pedersen ◽  
L. L. Rosenbaek ◽  
R. A. Fenton
Keyword(s):  
Sodium Transport ◽  
Driving Forces ◽  
Collecting Duct ◽  
Peptide Hormone ◽  
Surface Expression ◽  
Cell Surface Expression ◽  
Thick Ascending Limb ◽  
Distal Nephron ◽  
Sodium Chloride Cotransporter ◽  
Posterior Pituitary Gland

Arginine vasopressin (AVP) is released from the posterior pituitary gland during states of hyperosmolality or hypovolemia. AVP is a peptide hormone, with antidiuretic and antinatriuretic properties. It allows the kidneys to increase body water retention predominantly by increasing the cell surface expression of aquaporin water channels in the collecting duct alongside increasing the osmotic driving forces for water reabsorption. The antinatriuretic effects of AVP are mediated by the regulation of sodium transport throughout the distal nephron, from the thick ascending limb through to the collecting duct, which in turn partially facilitates osmotic movement of water. In this review, we will discuss the regulatory role of AVP in sodium transport and summarize the effects of AVP on various molecular targets, including the sodium-potassium-chloride cotransporter NKCC2, the thiazide-sensitive sodium-chloride cotransporter NCC, and the epithelial sodium channel ENaC.

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