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10.1681/ASN.2015080867

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suck abstract from ncbi


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pmid26880799
      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.
  • |Animals [MESH]
  • |Forkhead Box Protein O3/*physiology [MESH]
  • |Immediate-Early Proteins/*physiology [MESH]
  • |Mice [MESH]
  • |Muscular Atrophy/*enzymology/*etiology [MESH]
  • |Protein Serine-Threonine Kinases/*physiology [MESH]
  • |Renal Insufficiency, Chronic/*complications/*enzymology [MESH]
  • |Smad2 Protein/*physiology [MESH]


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