Serum- and glucocorticoid-regulated kinase 1 is upregulated following unilateral ureteral obstruction causing epithelial-mesenchymal transition.
Obstructive nephropathy leads to chronic kidney disease, characterized by a progressive epithelial-to-mesenchymal cell transition (EMT)-driven interstitial fibrosis. To identify the mechanisms causing EMT, we used the mouse model of unilateral ureteral obstruction and found a rapid and significant increase in serum- and glucocorticoid-regulated kinase-1 (SGK1) expression in the kidneys with an obstructed ureter. Knockout of SGK1 significantly suppressed obstruction-induced EMT, kidney fibrosis, increased glycogen synthase kinase-3β activity, and decreased accumulation of the transcriptional repressor Snail. This caused a reduced expression of the mesenchymal marker α-smooth muscle actin, and collagen deposition in this model. In cultured kidney epithelial cells, mechanical stretch or treatment with transforming growth factor-β not only stimulated the transcription of SGK1, but also stimulated EMT in an SGK1-dependent manner. Activated SGK1 stimulated Snail accumulation and downregulation of the epithelial marker E-cadherin. Hence, our study shows that SGK1 is involved in mediating fibrosis associated with obstructive nephropathy.
Cheng
Jizhong
J
Department of Medicine, Beijing Institute of Heart Lung and Blood Diseases, Beijing Anzhen Hospital affiliated to the Capital Medical University, Beijing, China.
Truong
Luan D
LD
Wu
Xiaoqian
X
Kuhl
Dietmar
D
Lang
Florian
F
Du
Jie
J
D000818:Animals; D015820:Cadherins / Q000235:genetics; D002478:Cells, Cultured; D058750:Epithelial-Mesenchymal Transition; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D017874:Immediate-Early Proteins / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D000071250:Snail Family Transcription Factors; D013314:Stress, Mechanical; D014157:Transcription Factors / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D014517:Ureteral Obstruction / Q000378:metabolism* / Q000473:pathology; D000099184:Serum-Glucocorticoid Regulated Kinases
D015820:Cadherins; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D017874:Immediate-Early Proteins; D017346:Protein Serine-Threonine Kinases; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D000099184:Serum-Glucocorticoid Regulated Kinases; C000605507:Gsk3b protein, mouse