Targeting histone deacetylase 3 for chronic kidney disease

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PROJECT SUMMARY Chronic kidney disease (CKD) is a public health problem that affects more than 26 million Americans. The prevalence of CKD in the veteran population is 34% higher than in the general US population. A key pathologic feature of CKD is renal inflammation resulting in initiation and progression of chronic kidney disease to end-stage kidney disease. The current therapeutic options for this progressive condition are limited and often ineffective. Therefore, a better understanding of the molecular mechanisms underlying renal inflammation is essential for developing effective strategies for the treatment of CKD. We have studied the factors initiating and controlling renal inflammation and have discovered a critical role of histone deacetylase 3 (HDAC3) in the regulation of renal inflammation during the development of CKD. Our preliminary studies have demonstrated that the activation of macrophages and the production of proinflammatory cytokines are dependent upon induction of HDAC3 in the kidney. Genetic deletion or pharmacological inhibition of HDAC3 prevents macrophage activation and proinflammatory molecule production. Furthermore, the proinflammatory effect of HDAC3 appears to be mediated by regulating nuclear factor kappa B (NF-kB) signaling pathway. In this application, we plan to examine and characterize the role of HDAC3 in macrophage activation and proinflammatory molecule production to further understand the cellular and molecular mechanisms of renal inflammation. Our central hypothesis is that HDAC3 deacetylates histones resulting in chromatin remodeling, which allows NF-kB to access its DNA response elements to induce proinflammatory molecule expression. To test our hypothesis, we will pursue the following Specific Aims: Specific Aim 1 is to determine the role of HDAC3 in the macrophage activation and proinflammatory molecule production; Specific Aim 2 is to explore the molecular mechanisms by which HDAC3 promotes macrophage activation and proinflammatory molecule production; and Specific Aim 3 is to evaluate the therapeutic potential of a selective HDAC3 inhibitor for CKD. In summary, we plan to utilize molecular, cellular, pharmacological, and genetic approaches to study the role of HDAC3 in macrophage activation and development of renal injury. Results from our studies will provide a new understanding of the cellular and molecular mechanisms of renal inflammation and could lead to the development of novel therapeutic strategies for the treatment of CKD.