It has been suggested that endoplasmic reticulum (ER) stress facilitates fibrotic remodeling. Therefore, modulation of ER stress may serve as one of the possible therapeutic approaches to renal
fibrosis. We examined whether and how activation of
AMP-activated protein kinase (AMPK) suppressed ER stress induced by chemical ER stress inducers [
tunicamycin (TM) and
thapsigargin (TG)] and also nonchemical inducers in tubular HK-2 cells. We further investigated the in vivo effects of AMPK on ER stress and renal
fibrosis. Western blot analysis, immunofluorescence, small interfering (si)
RNA experiments, and immunohistochemical staining were performed.
Metformin (the best known clinical activator of AMPK) suppressed TM- or TG-induced ER stress, as shown by the inhibition of TM- or TG-induced upregulation of
glucose-related
protein (GRP)78 and phosphorylated eukaryotic initiation factor-2α through induction of
heme oxygenase-1.
Metformin inhibited TM- or TG-induced epithelial-mesenchymal transitions as well. Compound C (AMPK inhibitor) blocked the effect of
metformin, and 5-aminoimidazole-4-carboxamide-1β riboside (another AMPK activator) exerted the same effects as
metformin. Transfection with
siRNA targeting AMPK blocked the effect of
metformin. Consistent with the results of cell culture experiments,
metformin reduced renal cortical
GRP78 expression and increased
heme oxygenase-1 expression in a mouse model of ER stress-induced
acute kidney injury by TM. Activation of AMPK also suppressed ER stress by
transforming growth factor-β, ANG II,
aldosterone, and high
glucose. Furthermore,
metformin reduced
GRP78 expression and renal
fibrosis in a mouse model of unilateral
ureteral obstruction. In conclusion, AMPK may serve as a promising therapeutic target through reducing ER stress and renal
fibrosis.