Alteration of forkhead box O (foxo4) acetylation mediates apoptosis of podocytes
in diabetes mellitus.
Authors Chuang PY, Dai Y, Liu R, He H, Kretzler M, Jim B, Cohen CD, He JC
Submitted By Matthias Kretzler on 10/31/2012
Status Published
Journal PLoS ONE
Year 2011
Date Published 10/1/2011
Volume : Pages 6 : e23566
PubMed Reference 21858169
Abstract The number of kidney podocytes is reduced in diabetic nephropathy. Advanced
glycation end products (AGEs) accumulate in patients with diabetes and promote
the apoptosis of podocyte by activating the forkhead box O4 (Foxo4)
transcription factor to increase the expression of a pro-apoptosis gene,
Bcl2l11. Using chromatin immunoprecipitation we demonstrate that AGE-modified
bovine serum albumin (AGE-BSA) enhances Foxo4 binding to a forkhead binding
element in the promoter of Bcl2lll. AGE-BSA also increases the acetylation of
Foxo4. Lysine acetylation of Foxo4 is required for Foxo4 binding and
transcription of Bcl2l11 in podocytes treated with AGE-BSA. The expression of a
protein deacetylase that targets Foxo4 for deacetylation, sirtuin (Sirt1), is
down regulated in cultured podocytes by AGE-BSA treatment and in glomeruli of
diabetic patients. SIRT1 over expression in cultured murine podocytes prevents
AGE-induced apoptosis. Glomeruli isolated from diabetic db/db mice have
increased acetylation of Foxo4, suppressed expression of Sirt1, and increased
expression of Bcl2l11 compared to non-diabetic littermates. Together, our data
provide evidence that alteration of Foxo4 acetylation and down regulation of
Sirt1 expression in diabetes promote podocyte apoptosis. Strategies to preserve
Sirt1 expression or reduce Foxo4 acetylation could be used to prevent podocyte
loss in diabetes.

Investigators with authorship
Matthias KretzlerUniversity of Michigan