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AMP-activated protein kinase (AMPK) activation inhibits nuclear translocation of
Smad4 in mesangial cells and diabetic kidneys.
Zhao J, Miyamoto S, You YH, Sharma K
Kumar Sharma on 2/2/2015
American journal of physiology. Renal physiology
Volume : Pages
Diabetic nephropathy is characterized by diffuse mesangial matrix expansion and
is largely dependent on the TGF-ß/Smad signaling pathway. Smad4 is required for
TGF-ß signaling however its regulation has not been well-characterized in
diabetic kidney disease. Here, we report that high glucose is sufficient to
stimulate nuclear translocation of Smad4 in mesangial cells and that stimulation
of the major energy sensor AMP-activated protein kinase (AMPK), has a potent
effect to block Smad4 nuclear translocation. Activation of AMPK by
5-aminoimidazole-4-carboxamide-1-ß-D-ribofuranoside (AICAR) inhibited high
glucose-induced and TGF-ß stimulation of nuclear Smad4. To identify which of the
catalytic alpha subunits may be involved, siRNA based inhibition of AMPKa1 or a2
subunit was employed. Inhibition of either subunit reduced overall AMPK activity
and contributed to Smad4 nuclear accumulation. In an animal model of early
diabetic kidney disease, induction of diabetes was found to markedly stimulate
Smad4 protein levels and enhance nuclear accumulation. AMPK activation with
AICAR completely prevented the up-regulation of Smad4 and reduced mesangial
matrix accumulation. We conclude that stimulation of Smad4 in cell culture and
in in vivo models of early diabetic kidney disease is dependent on AMPK.
Investigators with authorship
University of California San Diego
Neuropathy & Neurocognition
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Please acknowledge all posters, manuscripts or scientific materials that were generated in part or whole using funds from the Diabetic Complications Consortium(DiaComp) using the following text:
Financial support for this work provided by the NIDDK Diabetic Complications Consortium (RRID:SCR_001415, www.diacomp.org), grants DK076169 and DK115255
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