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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.

Alteration of Forkhead Box O (Foxo4) Acetylation Mediates Apoptosis of Podocytes in Diabetes Mellitus