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Abstract: FR-PO322

Histone Acetyltransferase p300 Inhibition Attenuates Kidney Fibrosis Under Diabetic Conditions

Session Information

Category: Diabetic Kidney Disease

  • 701 Diabetic Kidney Disease: Basic

Authors

  • Kim, Gyu Ri, Department of Internal Medicine, College of Medicine, Yonsei University, Seoul, Korea (the Republic of)
  • Nam, Boyoung, Department of Internal Medicine, College of Medicine, Yonsei University, Seoul, Korea (the Republic of)
  • Ryu, Jaejin, Department of Internal Medicine, College of Medicine, Yonsei University, Seoul, Korea (the Republic of)
  • Ko, Ye Eun, Department of Internal Medicine, College of Medicine, Yonsei University, Seoul, Korea (the Republic of)
  • Kim, Hyung Woo, Department of Internal Medicine, College of Medicine, Yonsei University, Seoul, Korea (the Republic of)
  • Han, Seung Hyeok, Department of Internal Medicine, College of Medicine, Yonsei University, Seoul, Korea (the Republic of)
  • Yoo, Tae-Hyun, Department of Internal Medicine, College of Medicine, Yonsei University, Seoul, Korea (the Republic of)
  • Kang, Shin-Wook, Department of Internal Medicine, College of Medicine, Yonsei University, Seoul, Korea (the Republic of)
  • Park, Jung Tak, Department of Internal Medicine, College of Medicine, Yonsei University, Seoul, Korea (the Republic of)
Background

Diabetic nephropathy, the major cause of chronic kidney disease, is associated with progressive renal fibrosis. Transforming growth factor (TGF)-β1 plays important roles in extracellular matrix accumulation in diabetic nephropathy. Recently, acetyltransferase p300 has been shown to mediate intracellular TGF-β1 activity through facilitating Smad function. Therefore, in this study, the effect of p300 inhibition on kidney fibrosis under diabetic conditions was investigated to assess the therapeutic potential of p300 modulation.

Methods

Primary tubular epithelial cells (TECs) from C57BL/6 mice were treated with TGF-β1 with or without histone acetyltransferase p300 siRNA transfection of A485, a selective inhibitor for p300. For in vivo experiments, kidney samples were obtained from streptozotocin induced diabetic mice were administered with A485 (1mg/kg) oral gavage for 6 weeks.

Results

In vitro, TGF-β1 (5ng/ml) treatment significantly upregulated p300, PAI-1, connective tissue growth factor (CTGF), fibronectin, and type I collagen mRNA and protein expressions in TECs. These increases were attenuated significantly when TECs were transfected with p300 siRNA. Similar findings were found when the cells were treated with p300 specific inhibitor A485 (100nM). In vivo, the mRNA and protein expression of p300, PAI-1, connective tissue growth factor (CTGF), fibronectin, and type I collagen were significantly increased in kidney samples form DM mice compared to non-diabetic control mice. Oral A485 administration abrogated these increases significantly. In addition, the increased blood urea nitrogen and albuminuria levels were significantly attenuated with oral A485 treatment in the diabetic mice. Immunohistochemistry and Sirius Red staining also revealed that fibronectin expression was significantly higher and tubulointersititial fibrosis was significantly worse in diabetic mice kidneys compared with control mice. These changes were ameliorated by A485 treatment.

Conclusion

These findings suggest that inhibition of histone acetyltransferase p300 could improve diabetic-induced tubular fibrosis and may be a potential therapeutic strategy for diabetic nephropathy.