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Kidney Week

Abstract: TH-PO503

Selective Inhibition of Histone Deacetylase 8 Suppresses Renal Fibroblast Activation and Mitigates Renal Fibrosis

Session Information

  • CKD: Mechanisms - I
    November 07, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
    Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

  • 2103 CKD (Non-Dialysis): Mechanisms

Authors

  • Zhang, Yunhe, Rhode Island Hospital, Providence, Rhode Island, United States
  • Tolbert, Evelyn, Rhode Island Hospital, Providence, Rhode Island, United States
  • Bayliss, George P., Alpert Medical School, Brown University, Providence, Rhode Island, United States
  • Zhuang, Shougang, Rhode Island Hospital, Providence, Rhode Island, United States
Background

Histone deacetylase 8 (HDAC8), a unique class I zinc-dependent HDAC, is implicated in the pathogenesis of various rumors, however, its role in renal fibrogenesis remains poorly understood.

Methods

In this study, we examined the effect of HDAC8 inhibition on the activation of cultured renal interstitial fibroblasts and. the development of renal fibrosis in a murine model of renal fibrosis induced by unilateral ureteral obstruction (UUO).

Results

Treatment of cultured renal interstitial fibroblasts with PCI34051, a selective HDAC8 inhibitor, or small interfering RNA-mediated silencing of HDAC8, inhibited their activation as indicated by decreased expression of alpha smooth muscle actin, fibronectin and type I collagen. In a mouse model of obstructive nephropathy, HDAC8 was up-regulated in renal epithelial cells of the injured kidney. Administration of PCI34051 immediately after UUO injury reduced the deposition of extracellular matrix proteins and inhibited activation of renal fibroblasts. Moreover, HDAC8 inhibition suppressed activation of several signaling pathways associated with the progression of renal fibrosis, including Smad-3, beta-catenin, signal transducer and activator of transcription 3 (STAT3), whereas increased expression of klotho and bone morphogenetic protein 7, two renoprotecive proteins, in the injured kidney.

Conclusion

Our results indicate that selectively targeting HDAC 7 can inhibit development of renal fibrosis and activation of renal fibroblasts by inactivation multiple profibrotic molecules and increasing expression of antifibrotic proteins. Thus, HDAC8 may be a druggable target.

Funding

  • NIDDK Support