These observations suggest that high glucose could increase podocyte apoptosis when Sirt1 is suppressed by excess of AGE. This scenario of hyperglycemia and SIRT1 suppression likely occurs in the diabetic milieu where prolong hyperglycemia leads to AGE formation, and AGE reduces SIRT1 expression. The relatively short treatment duration with high glucose in our experiment could explain the lack of caspase 3 activation. The importance of the Sirt1-Foxo4-Bcl2l11 pathway we described here is consistent with the findings of Kume et al, where they identified a role for Sirt1 in aging-related nephropathy high content screening affecting the renal cortex. Although we were unable to detect a significant change in Sirt1 in the tubulointerstitial compartment of DN, others have reported that the expression of another member of the sirtuin family, Sirt3 is suppressed in cultured renal tubular epithelial cells by angiotensin II, a key mediator of the pathophysiology of diabetic renal disease. Efforts to increase Sirt1 activity by resveratrol treatment or to increase Sirt1 expression in transgenic mice by knockin or over expression of a bacterial artificial chromosome containing a Sirt1 transgene have been shown to improve Afatinib abmole bioscience glycemic response in murine models of diabetes mellitus. However, in order to further define the role of Sirt1 on podocyte apoptosis in DN and avoid potential confounding effects from improved glycemic control in these Sirt1 over expression models, studies that examine transgenic animals with podocyte-specific Sirt1 over expression and diabetes will need to be carried out. We demonstrated in this study that alteration in the acetylation status of a transcription factor, Foxo4, is linked to a reduction in the expression of Sirt1 and contributes to the development of podocyte loss in diabetes. These findings highlight the importance of acetylation of nuclear factors in the regulation of gene expression in an important disease process. A recent study has shown that protein lysine acetylation is not only limited to nuclear transcription regulators, but also cellular enzymes that catalyze intermediate metabolism and plays a major role in metabolic regulation. The reduction of Sirt1 and associated change in the status of lysine acetylation could have broad effects ranging from gene expression to enzymatic activity. Pharmacologic intervention to normalize Sirt1 expression or prevent acetylation of Foxo4 should be explored as potential approaches to improve the outcome of diabetic kidney disease.