The effect of dexamethasone on defective nephrin transport caused by ER stress: a potential mechanism for the therapeutic action of glucocorticoids in the acquired glomerular diseases.
The mechanism by which glucocorticoids govern antiproteinuric effect in nephrotic syndrome remains unknown. Present study examined the protective role of dexamethasone (DEX) in the intracellular trafficking of nephrin under endoplasmic reticulum (ER) stress. Human embryonic kidney-293 cell line expressing a full-length human nephrin was cultured in mediums containing 5.5 or 25 mM glucose with or without DEX. The result revealed that glucose starvation evoked a rapid ER stress leading to formation of underglycosylated nephrin that was remained in the ER as a complex with calreticulin/calnexin. DEX rescued this interfered trafficking through binding to its receptor and stimulating the mitochondrial transcripts and adenosine 5' triphosphate (ATP) production, leading to synthesis of fully glycosylated nephrin. These results suggest that ER-stress in podocytes may cause alteration of nephrin N-glycosylation, which may be an underlying factor in the pathomechanism of the proteinuria in nephrotic syndrome. DEX may restore this imbalance by stimulating expression of mitochondrial genes, resulted in the production of ATP that is essential factor for proper folding machinery aided by the ER chaperones.
Department of Internal Medicine, Kyorin University School of Medicine, Mitaka, Tokyo, Japan.
Y
Y
Fujii
J
J
Khoshnoodi
H
H
Takenaka
M
M
Hosoyamada
A
A
Nakajo
F
F
Bessho
A
A
Kudo
S
S
Takahashi
Y
Y
Arimura
A
A
Yamada
T
T
Nagasawa
V
V
Ruotsalainen
K
K
Tryggvason
A S
AS
Lee
K
K
Yan
D000255:Adenosine Triphosphate / Q000032:analysis; D001692:Biological Transport; D015152:Blotting, Northern; D015153:Blotting, Western; D002460:Cell Line; D003470:Culture Media / Q000737:chemistry; D003907:Dexamethasone / Q000494:pharmacology*; D004721:Endoplasmic Reticulum / Q000187:drug effects* / Q000648:ultrastructure; D005434:Flow Cytometry; D019084:Fluorescent Antibody Technique, Indirect; D005456:Fluorescent Dyes; D005938:Glucocorticoids / Q000627:therapeutic use*; D005947:Glucose / Q000032:analysis; D006801:Humans; D006834:Hydrazines; D007674:Kidney Diseases / Q000188:drug therapy*; D008565:Membrane Proteins / Q000378:metabolism* / Q000648:ultrastructure; D018613:Microscopy, Confocal; D011233:Precipitin Tests; D011506:Proteins / Q000032:analysis; D013312:Stress, Physiological
C417561:Alexa 488 hydrazide; D003470:Culture Media; D005456:Fluorescent Dyes; D005938:Glucocorticoids; D006834:Hydrazines; D008565:Membrane Proteins; D011506:Proteins; C113267:nephrin; D003907:Dexamethasone; D000255:Adenosine Triphosphate; D005947:Glucose