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.jpg): Failed to open stream: No such file or directory in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 117 J+Am+Soc+Nephrol
2016 ; 27
(9
): 2797-808
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Serum Glucocorticoid-Regulated Kinase 1 Blocks CKD-Induced Muscle Wasting Via
Inactivation of FoxO3a and Smad2/3
#MMPMID26880799
Luo J
; Liang A
; Liang M
; Xia R
; Rizvi Y
; Wang Y
; Cheng J
J Am Soc Nephrol
2016[Sep]; 27
(9
): 2797-808
PMID26880799
show ga
Muscle proteolysis in CKD is stimulated when the ubiquitin-proteasome system is
activated. Serum glucocorticoid-regulated kinase 1 (SGK-1) is involved in
skeletal muscle homeostasis, but the role of this protein in CKD-induced muscle
wasting is unknown. We found that, compared with muscles from healthy controls,
muscles from patients and mice with CKD express low levels of SGK-1. In mice,
SGK-1-knockout (SGK-1-KO) induced muscle loss that correlated with increased
expression of ubiquitin E3 ligases known to facilitate protein degradation by the
ubiquitin-proteasome, and CKD substantially aggravated this response. SGK-1-KO
also altered the phosphorylation levels of transcription factors FoxO3a and
Smad2/3. In C2C12 muscle cells, expression of dominant negative FoxO3a or
knockdown of Smad2/3 suppressed the upregulation of E3 ligases induced by loss of
SGK-1. Additionally, SGK-1 overexpression increased the level of phosphorylated
N-myc downstream-regulated gene 1 protein, which directly interacted with and
suppressed the phosphorylation of Smad2/3. Overexpression of SGK-1 in wild-type
mice with CKD had similar effects on the phosphorylation of FoxO3a and Smad2/3
and prevented CKD-induced muscle atrophy. Finally, mechanical stretch of C2C12
muscle cells or treadmill running of wild-type mice with CKD stimulated SGK-1
production, and treadmill running inhibited proteolysis in muscle. These
protective responses were absent in SGK-1-KO mice. Thus, SGK-1 could be a
mechanical sensor that mediates exercise-induced improvement in muscle wasting
stimulated by CKD.