Specific Aims This competitive renewal application is a continuation of our long-term effort to develop novel strategies for the treatment of chronic kidney disease (CKD) to prevent tubular atrophy, interstitial fibrosis, and progression to the end-stage kidney failure and the need for renal replacement therapy. Tubulointerstitial fibrosis, characterized by aberrant activation of renal fibroblasts and production and deposition of extracellular matrix components, is a key pathogenic process in progressive kidney injury. Although epigenetic regulation is critical to development of renal fibrosis, the mechanisms involved in this process remain poorly understood and the therapeutic potential of epigenetic modification in altering the progression of renal fibrosis is as yet unrealized. Studies in the previous project period of this application demonstrated that blocking class I histone deacetylases (HDACs) by MS-275 attenuated renal fibrogenesis and suppressed expression or/and phosphorylation of multiple growth factor receptors that contribute to renal fibrogenesis. These include transforming growth factor-beta receptor I (TGF-betaRI), epidermal growth factor receptor (EGFR) and platelet derived growth factor receptor (PDGFR). Further, inhibition of class I HDACs blocks epithelial G2/M cell cycle arrest and suppresses leukocyte infiltration of the fibrotic kidney. To expand these findings, we will test the hypothesis that class I HDAC inhibitors suppress progression of renal fibrosis by antagonizing production of profibrogenetic cytokines/growth factors, inactivating and downregulating multiple growth factor receptors and suppressing NF-kB signaling.
Specific Aim 1. Assess the therapeutic effect of delayed application of class 1 HDAC inhibitors on the progression of renal fibrosis in two animal models of CKD. We will assess the effect of delayed administration of the class I HDAC inhibitor on activation of renal fibroblasts, deposition of extracellular proteins, production of multiple proinflammatory cytokines/chemokines and accumulation of leukocytes in the kidney in diverse, clinically relelvant models of injuries (ischemia/reperfusion and 5/6 nephrectomy).
Specific Aim 2. Dissect the molecular mechanism by which class I HDAC inhibition suppresses expression/activation of profibrotic receptors. We will examine the effect of a class I HDAC inhibitor and of gene silencing using an isoform-specific siRNA on expression and/or activation of TGF-betaRI, EGFR, PDGFR and Notch3 in cultured renal epithelial cells and renal interstitial fibroblasts.
Specific Aim 3. Elucidate the cellular and molecular events by which class I HDAC inhibition attenuates renal inflammation. We will examine whether inhibition of class I HDACs suppresses injury-induced renal inflammation by blocking epithelial cell cycle G2/M arrest, production of proinflammatory cytokines/chemokines, and activation of NF-kB signaling pathway. Successful completion of this project will increase our understanding on the mechanism of HDAC inhibition-mediated suppression of renal fibrogenesis and may contribute to the development of novel treatments for patients with CKD.

Public Health Relevance

Chronic kidney disease (CKD) is characterized by an irreversible deterioration of renal function that gradually progresses to end-stage renal disease (ESRD). Renal tubulointerstitial fibrosis is the final common pathway of CKD to progress to ESRD. Current therapeutic options for patients with CKD are very limited and often ineffective. There is a great need in identifying the key targets essential for designing rational strategies to treat patients with fibrotic kidney disorders. Since histone deacetylase (HDAC) inhibitors have been extensively investigated as potential anticancer drugs, investigation of the functional role and mechanism of HDACs in mediating progression of renal fibrosis would be beneficial to development of HDAC inhibitors as therapeutic drugs for CKD.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Pathobiology of Kidney Disease Study Section (PBKD)
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Kimmel, Paul
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Rhode Island Hospital
United States
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