Warning: file_get_contents(https://eutils.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&id=25761881
&cmd=llinks): Failed to open stream: HTTP request failed! HTTP/1.1 429 Too Many Requests
in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 215
Feng X
; Zhang Y
; Shao N
; Wang Y
; Zhuang Z
; Wu P
; Lee MJ
; Liu Y
; Wang X
; Zhuang J
; Delpire E
; Gu D
; Cai H
Am J Physiol Renal Physiol
2015[May]; 308
(10
): F1119-27
PMID25761881
show ga
Thiazide-sensitive sodium chloride cotransporter (NCC) plays an important role in
maintaining blood pressure. Aldosterone is known to modulate NCC abundance.
Previous studies reported that dietary salts modulated NCC abundance through
either WNK4 [with no lysine (k) kinase 4]-SPAK (Ste20-related proline
alanine-rich kinase) or WNK4-extracellular signal-regulated kinase-1 and -2
(ERK1/2) signaling pathways. To exclude the influence of SPAK signaling pathway
on the role of the aldosterone-mediated ERK1/2 pathway in NCC regulation, we
investigated the effects of dietary salt changes and aldosterone on NCC abundance
in SPAK knockout (KO) mice. We found that in SPAK KO mice low-salt diet
significantly increased total NCC abundance while reducing ERK1/2
phosphorylation, whereas high-salt diet decreased total NCC while increasing
ERK1/2 phosphorylation. Importantly, exogenous aldosterone administration
increased total NCC abundance in SPAK KO mice while increasing DUSP6 expression,
an ERK1/2-specific phosphatase, and led to decreasing ERK1/2 phosphorylation
without changing the ratio of phospho-T53-NCC/total NCC. In mouse distal
convoluted tubule (mDCT) cells, aldosterone increased DUSP6 expression while
reducing ERK1/2 phosphorylation. DUSP6 Knockdown increased ERK1/2 phosphorylation
while reducing total NCC expression. Inhibition of DUSP6 by
(E)-2-benzylidene-3-(cyclohexylamino)-2,3-dihydro-1H-inden-1-one increased ERK1/2
phosphorylation and reversed the aldosterone-mediated increments of NCC partly by
increasing NCC ubiquitination. Therefore, these data suggest that aldosterone
modulates NCC abundance via altering NCC ubiquitination through a DUSP6-dependent
ERK1/2 signal pathway in SPAK KO mice and part of the effects of dietary salt
changes may be mediated by aldosterone in the DCTs.
free
free
free
