Activation of FoxO1/PGC-1α prevents mitochondrial dysfunction and ameliorates mesangial cell injury in diabetic rats

L Wu, Q Wang, F Guo, Y Zhou, H Ji, F Liu, X Ma… - Molecular and Cellular …, 2015 - Elsevier
L Wu, Q Wang, F Guo, Y Zhou, H Ji, F Liu, X Ma, Y Zhao, G Qin
Molecular and Cellular Endocrinology, 2015Elsevier
The generation of hyperglycemia-induced mitochondrial reactive oxygen species (ROS) is a
key event in diabetic nephropathy development. The forkhead-box class O1 (FoxO1) and
peroxisome proliferator-activated receptor γ co-activator 1α (PGC-1α) proteins are
implicated in oxidative stress. We investigated the in vivo association of FoxO1 and PGC-1α
in renal cortices from streptozotocin-induced diabetic rats and in rat kidney mesangial cells
(MCs) treated with high glucose, in vitro. High-glucose induced FoxO1 inhibition was …
Abstract
The generation of hyperglycemia-induced mitochondrial reactive oxygen species (ROS) is a key event in diabetic nephropathy development. The forkhead-box class O1 (FoxO1) and peroxisome proliferator-activated receptor γ co-activator 1α (PGC-1α) proteins are implicated in oxidative stress. We investigated the in vivo association of FoxO1 and PGC-1α in renal cortices from streptozotocin-induced diabetic rats and in rat kidney mesangial cells (MCs) treated with high glucose, in vitro. High-glucose induced FoxO1 inhibition was associated with decreased PGC-1α expression in MCs. These changes were accompanied by mitochondrial dysfunction and increased ROS generation. However, constitutive FoxO1 activation increased PGC-1α expression and partially reversed these changes, which were significantly decreased by the treatment of PGC-1α-small interfering RNA. We identified PGC-1α as a direct FoxO1 transcriptional target by chromatin immunoprecipitation. In addition, lentiviral-mediated FoxO1 overexpression in diabetic-rat kidneys significantly increased PGC-1α, NRF-1, and Mfn2 expression, and decreased malondialdehyde production and proteinuria. These data suggest that FoxO1/PGC-1α activation protected rats against high-glucose-induced MC injury by attenuating mitochondrial dysfunction and cellular ROS production.
Elsevier