Diabetic kidney disease (DKD) is the leading cause of chronic kidney disease and end-stage kidney failure in the US including the veteran population. Even with optimal therapy the incidence of DKD remains high. This is because none of the currently available therapy can reverse or completely forestall the progression of DKD. Therefore, it is extremely important to develop more effective treatment for DKD. During last funding period, we found that Advanced Glycation Endproducts (AGE) induce podocyte apoptosis through activation of a transcription factor called FOXO4. We discovered that the acetylation of FOXO4 is critical for mediating this effect. In addition to FOXO4, the acetylation of NFkB, STAT3, p53, HIF1?, and Smad3 also modulates their target gene expression and these transcription factors (TFs) are known to play the critical role in the pathogenesis of DKD. Our preliminary data suggest that the acetylation of FOXO4, NFkB, Stat3 and Smad3 are increased in diabetic kidneys. Thus, it is critical for us to understand the role of TF acetylation in DKD and targeting TF acetylation could be a new approach to treat DKD. Since acetylated lysine residues of these TFs interact with proteins containing bromodomains, we could develop bromodomain inhibitors (BrDi) to suppress the acetylation of these TFs in a more specific manner. Our preliminary data suggest that a Bromodomain-containing protein 4 (BRD4)-specific BrDi (MS417) suppresses TNF?- induced acetylation of NFkB and the expression of NFkB target genes in kidney cells in vitro. MS417 also attenuates proteinuria and glomerulosclerosis in a mouse model of HIV-associated nephropathy, in which NF-kB-mediated inflammation is a key component of the disease. MS417 also inhibits AGE- induced acetylation of NF-kB in podocytes in vitro and improves proteinuria in diabetic db/db mice. Based on these findings, we hypothesize that TF acetylation plays a key role in the progression of DKD. MS417 or other BrDi could be developed as a new class of drugs to treat patients with DKD by modulating the acetylation of these TFs. To test our hypothesis, we will first characterize acetylated lysine residues of these TFs and determine their role in the regulation of TF target gene expression in kidneys of diabetic animal models. Then, we will develop specific BrDi targeting these acetylated lysine residues. Finally, we will test whether MS417 and other BrDi improve kidney injury in animal models with DKD. The proposed studies will help us to understand how acetylation of TFs affects their target gene expression in diabetic kidneys and determine whether BrDi could be developed as a new class of drugs to treat patients with DKD.
Potential Impact on Veterans health Care: Many Veterans suffer from diabetes and diabetic complications including diabetic kidney disease (DKD). DKD is the leading cause of End-stage renal failure (ESRD) in our Veterans patient population. The Veterans on chronic dialysis have a high rate of mobility and mortality and poor quality of life. Dialysis also adds additional emotionl burden for our Veterans who have been already suffering from PTSD and other pschychological disorders such as major depression. Therefore, the research to identify the better treatment regimes for patients with DKD will help to reduce the incidence of ESRD in our Veterans and will have enormous impact on Veterans health care. We believe that our study will provide a new approach for the treatment of patients with DKD.