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16:08 - 16:11
S2-12
(PP)
EPIGENETIC REGULATION BY HDAC PROTEINS PLAYS A CRITICAL ROLE IN THE
PROGRESSION OF RENAL FIBROSIS
Paul AUSTIN, Scott MANSON, Qiusha GUO and Katelynn MOORE
Washington University in St. Louis School of Medicine, Urology, Saint Louis, USA
PURPOSE
Chronic kidney disease is associated with changes in the expression of approximately 10% of the genome. The histone
deacetylases (HDACs) are a family of 10 related proteins which are among the most widely expressed and crucial
regulators of gene transcription. In this study, we examine the biologic and therapeutic importance of HDAC proteins
during disease progression.
MATERIAL AND METHODS
Chronic renal injury was modeled in vivo in mice by unilateral ureteral obstruction (UUO). The role of HDAC proteins was
assessed by using a variety of molecular techniques and treatment with the broad spectrum HDAC inhibitor Trichostatin
A (TSA).
RESULTS
UUO leads to a dramatic increase in the protein levels of 9 of the 10 HDAC isoforms. Notably, there is a 6.1-fold increase
in HDAC8 expression that localizes specifically to pericyte-derived myofibroblasts, the cell population which accounts for
the majority of matrix production during renal fibrosis. To better understand the importance of these findings, we
treated mice with the HDAC inhibitor TSA. This resulted in a 3.4-fold increase in the anti-fibrotic gene BMP7, a 41.6%
decrease in the matrix protein COLIA1, and a 61.6% decrease in the myofibroblast differentiation marker α-SMA
following UUO. These changes in gene expression culminate in a 77.9% decrease in the interstitial proliferative
response, a 43.0% decrease in myofibroblast number, 31.1% decrease in renal fibrosis, 42.8% decrease in apoptosis,
and a 43.4% decrease in the loss of renal architecture. [All results are p<0.05]
CONCLUSIONS
Chronic renal injury is associated with a dramatic increase in HDAC protein levels that stimulates pro-fibrotic gene
expression and suppresses anti-fibrotic gene expression. Importantly, treatment with HDAC inhibitors reverses these
changes in gene expression and inhibits the development of renal fibrosis. This suggests that HDAC inhibitors may serve
as effective therapies to inhibit disease progression.