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Kidney Week

Abstract: TH-PO501

Lysine Deacetylase Inhibition Attenuates Tubulointerstitial Injury and Fibrosis in a Model of Proteinuric CKD

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

  • Williams, Vanessa R., University of Toronto, Toronto, Ontario, Canada
  • Konvalinka, Ana, University Health Network, Toronto, Ontario, Canada
  • John, Rohan, University Health Network, Toronto, Ontario, Canada
  • Pei, York P., University Health Network, Toronto, Ontario, Canada
  • Scholey, James W., University of Toronto, Toronto, Ontario, Canada
Background

There is a paucity of effective treatments for tubulointerstitial fibrosis associated with progressive CKD. Previously, we derived a CKD progression signature composed of differentially expressed genes based on aging and disease in Col4a3–/– mice, a model associated with proteinuria and progressive loss of kidney function. Through drug repurposing with the progression signature and the Connectivity Map we identified vorinostat, a lysine deacetylase (KDAC) inhibitor, as a potential therapy for CKD progression. Here, we examine effects of vorinostat treatment on tissue fibrosis in Col4a3–/– mice.

Methods

Male Col4a3–/– mice on a congenic 129/SvJ background were treated with vorinostat (50 mg/kg/day) or vehicle from 4 to 7 weeks of age by oral gavage. Mice were euthanized at 7 weeks of age. Plasma, urine, and kidney samples were collected. Kidney histological, function, inflammation, and fibrosis analyses were performed. Separate groups were followed for survival assessment. Finally, albumin-stimulated human proximal tubule epithelial (HK-2) cells were treated with vorinostat (5 μM) and used to assess mechanisms.

Results

Vorinostat treatment did not improve kidney function and had no effect on glomerulosclerosis scores, but significantly reduced tubular injury markers, KIM-1 and NGAL. This was associated with a significant increase in the lifespan of Col4a3–/– mice. Col1a1, Fn1, Serpine1, and Tnf mRNA levels were reduced in the kidneys of vorinostat-treated mice. Vorinostat administration lowered TGF-β1 and α-SMA protein levels in kidneys and urine, respectively. Treatment attenuated JNK phosphorylation in Col4a3–/– mouse kidneys. In vitro, vorinostat reduced albumin-induced activation of JNK, p38, and ERK in HK-2 cells. Vorinostat also attenuated the activation of activator protein 1 transcription factor in vitro.

Conclusion

Our findings suggest that KDAC inhibition and blockade of MAPKs may be effective treatment approaches to CKD associated with proteinuria and progressive tubulointerstitial injury.