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Kidney Week

Abstract: TH-PO790

CG200745, a Novel Histone Deacetylase Inhibitor, Attenuates Kidney Fibrosis in a Murine Model of Alport Syndrome

Session Information

Category: Genetic Diseases of the Kidneys

  • 1002 Genetic Diseases of the Kidneys: Non-Cystic

Authors

  • Suh, Sangheon, Chonnam National University Hospital, Gwangju, Korea (the Republic of)
  • Choi, Hong sang, Chonnam National University Hospital, Gwangju, Korea (the Republic of)
  • Kim, Chang Seong, Chonnam National University Hospital, Gwangju, Korea (the Republic of)
  • Ma, Seong Kwon, Chonnam National University Hospital, Gwangju, Korea (the Republic of)
  • Scholey, James W., University of Toronto, Toronto, Ontario, Canada
  • Kim, Soo Wan, Chonnam National University Hospital, Gwangju, Korea (the Republic of)
  • Bae, Eun Hui, Chonnam National University Hospital, Gwangju, Korea (the Republic of)
Background

Histone modification has been a target of therapy for progressive renal fibrosis. Here we report the protective effect of CG200745, a novel histone deacetylase inhibitor, on tubulointerstitial fibrosis in a murine model of Alport syndrome.

Methods

Col4a3–/– mice were used as a murine model of experimental AS. To examine the effects of CG200745 on the kidney of Col4a3–/– mice, CG200745 was orally administered in drinking water. To investigate the cellular mechanisms, HK-2 cells, a human proximal tubular epithelial cell line, were treated with CG200745 and/or angiotensin II (Ang II).

Results

Expression of fibrosis markers, such as αSMA, fibronectin and collagen I, significantly increased in Col4a3–/– mice at the age of 7 weeks, which was counter-regulated by CG200745 treatment, indicating attenuation of kidney fibrosis. CG200745 prevented the activation of transforming growth factor β (TGFβ) and its downstream Smad signaling in the kidney of Col4a3–/– mice. As critical upstream regulators of TGFβ signaling, Ang II, angiotensin converting enzyme (ACE), and TNFα-converting enzyme were upregulated and ACE2 and Mas receptor were downregulated, respectively, in the kidney of Col4a3–/– mice, suggesting activation of intra-renal renin-angiotensin system, with concurrent activation of inflammation and apoptosis, which were effectively suppressed by CG200745. Mechanistically, we found the positive feedback loop between RAS and TGFβ in HK-2 cells. CG200745 alleviated upregulation of TGFβ and activation of its downstream in Ang II-stimulated HK-2 cells by histone modification, preserving the protein expression of ACE2 and Mas receptor.

Conclusion

CG200745 targets TGFβ to preserve ACE2-Ang-(1-7)-Mas receptor axis and attenuates tubulointerstitial fibrosis in the kidney of Col4a3–/– mice.

Funding

  • Government Support - Non-U.S.