Abstract: FR-PO367

Inhibition of p300/CBP-Associated Factor Attenuates Renal Tubulointerstitial Fibrosis through Modulation of NF-kB and Nrf2

Session Information

Category: Chronic Kidney Disease (Non-Dialysis)

  • 308 CKD: Mechanisms of Tubulointerstitial Fibrosis

Authors

  • Chung, Sungjin, Vanderbilt University School of Medicine, Nashville, United States
  • Li, Zhilian, Vanderbilt University School of Medicine, Nashville, United States
  • Kim, Soojeong, The Catholic University of Korea College of Medicine, Seoul, Korea (the Republic of)
  • Shin, Seok Joon, The Catholic University of Korea College of Medicine, Seoul, Korea (the Republic of)
  • Park, Cheol Whee, The Catholic University of Korea College of Medicine, Seoul, Korea (the Republic of)
  • Yang, Chul Woo, The Catholic University of Korea College of Medicine, Seoul, Korea (the Republic of)
  • Kim, Yong-Soo, The Catholic University of Korea College of Medicine, Seoul, Korea (the Republic of)
  • Koh, Eun Sil, The Catholic University of Korea College of Medicine, Seoul, Korea (the Republic of)
Background

p300/CBP-associated factor (PCAF), a histone acetyltransferase, is involved in many cellular processes such as differentiation, proliferation, apoptosis and reaction to cell damage by modulating the activities of several genes and proteins through acetylation of either histones or transcription factors. Here, we examined a pathogenic role of PCAF and its potential as a novel therapeutic target in the progression of renal tubulointerstitial fibrosis induced by unilateral ureteral obstruction.

Methods

After UUO surgery, male C57BL/6 mice were administered either the PCAF inhibitor garcinol or a vehicle by intraperitoneal injection once a day for 3 or 7 days. Renal tubular epithelial cells (HK-2) were transfected with siRNA-PCAF and analyzed for expression of pro-fibrotic factors.

Results

Administration of garcinol reversed an increase in renal expression of total PCAF and histone 3 lysine 9 acetylation, and it reduced positive areas of trichrome and α-smooth muscle actin and collagen content in UUO kidneys. The increased mRNA levels of transforming growth factor-β1, matrix metalloproteinase (MMP) 2, MMP9 and fibronectin in obstructed kidneys was significantly reduced by garcinol treatment. Furthermore, garcinol suppressed nuclear factor-κB (NF-κB) and pro-inflammatory cytokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6 whereas it elevated nuclear expression of nuclear factor erythroid-derived 2-like factor 2 (Nrf2) and levels of Nrf2-dependent antioxidants including heme oxygense-1, catalase, superoxide dismutase 1 and NAD(P)H:quinone oxidoreductase-1. In addition, garcinol treatment resulted in reduction of TUNEL-positive cells and increased ratio of Bcl-2 to Bax in obstructed kidneys. PCAF siRNA in HK-2 cells inhibited the expression of type IV collagen and fibronectin when stimulated with TNF-α.

Conclusion

Our results suggest that inhibition of the inordinately enhanced PCAF could mitigate renal fibrosis by redressing the aberrant balance between inflammatory signaling and antioxidant response through modulation of NF-κB and Nrf2.

Funding

  • Government Support - Non-U.S.