Inhibition of histone deacetylase 6 activity reduces cyst growth in polycystic kidney disease

Abstract

Abnormal proliferation of cyst-lining epithelium and increased intra-cystic fluid secretion via the cystic fibrosis transmembrane conductance regulator (CFTR) are thought to contribute to cyst growth in autosomal dominant polycystic kidney disease (ADPKD). Histone deacetylase 6 (HDAC6) expression and activity are increased in certain cancers, and neurodegenerative diseases, and in Pkd1-mutant renal epithelial cells. Inhibition of HDAC6 activity with specific inhibitors slows cancer growth. Here we studied the effect of tubacin, a specific HDAC6 inhibitor, on cyst growth in polycystic kidney disease. Treatment with tubacin prevented cyst formation in MDCK cells, an in vitro model of cystogenesis. Cyclic AMP stimulates cell proliferation and activates intra-cystic CFTR-mediated chloride secretion in ADPKD. Treatment with tubacin down-regulated cyclic AMP levels, inhibited cell proliferation, and inhibited cyclic AMP-activated CFTR chloride currents in MDCK cells. We also found that tubacin reduced cyst growth by inhibiting proliferation of cyst-lining epithelial cells, down-regulated cyclic AMP levels, and improved renal function in a Pkd1-conditional mouse model of ADPKD. Thus, HDAC6 could play a role in cyst formation and could serve as a potential therapeutic target in ADPKD.

STAT5 drives abnormal proliferation in autosomal dominant polycystic kidney disease

“…Future animal studies are needed to compare the efficacy of the different STAT5 SH2 compounds in reducing cyst growth in ADPKD models. Alternatively, HDAC6 inhibition was recently shown to be effective in reducing cyst growth in murine PKD 32 ; this is particularly relevant to this study because HDAC inhibition reduces STAT5 transcriptional activity 33 , therefore use of selective HDAC inhibitors can be employed as an alternative strategy to inhibit atypical STAT5-initiated signalling.…”

Histone deacetylases 6 increases the cyclic adenosine monophosphate level and promotes renal cyst growth

“…Infusion of Escherichia coli bacteria in these animals induced hyperdynamic sepsis and rapid progression to SAKI associated with marked renal vasodilatation and increased RBF. 4 In this model, norepinephrine infusion at a dose that restored normal mean arterial pressure values significantly increased global and medullary RBF. 5 In addition, many clinical reports support the notion that norepinephrine infusion may improve, at least transiently, renal function in hyperdynamic septic shock.…”

“…Specific inhibition of HDAC6 probably confers more beneficial effects than pan-HDAC inhibitors or other specific HDAC inhibitors because no toxic effects of HDAC6 inhibition were reported in cystic animal models and HDAC6 knockout mice are viable and fertile in contrast to HDAC1, -2, -3, -4, -7, and -8 knockout mice. 5 Another important finding by Cebotaru et al 4 in the current issue is that HDAC6 inhibition decreased intracellular levels of cAMP, which is a crucial therapeutic target for ADPKD. 4 The therapeutic rationale of reducing the cAMP level in cystic kidneys has been proven clinically by using V2 receptor antagonist tolvaptan, which successfully slowed total kidney volume growth and retarded renal function decline in ADPKD patients.…”

“…5 Another important finding by Cebotaru et al 4 in the current issue is that HDAC6 inhibition decreased intracellular levels of cAMP, which is a crucial therapeutic target for ADPKD. 4 The therapeutic rationale of reducing the cAMP level in cystic kidneys has been proven clinically by using V2 receptor antagonist tolvaptan, which successfully slowed total kidney volume growth and retarded renal function decline in ADPKD patients. The intracellular cAMP ([cAMP] i ) level is elevated in ADPKD because of increased synthesis by adenylyl cyclases (ACs) and decreased degradation by phophodiesterases (PDEs).…”

Ciliotherapy–New Opportunity for Targeted Therapy in Autosomal Dominant Polycystic Kidney Disease.

“…Tubacin, the first reported HDAC6 selective inhibitor, blocks the deacetylation of α-tubulin in mammalian cells and protects cells from HDAC6-inducted ciliary disassembly without affecting histone acetylation, gene expression, or cell progression. A recent study confirmed that a pharmacological inhibition of HDAC6 led to the attenuation of the progression of renal fibrogenesis and reduction of cyst formation in polycystic kidney disease [21]. Similarly, it has been found that the inhibition of HDAC6 through tubacin leads to the decrease in differentiation of the adipocyte and may also prevent the development of obesity associated with Bardet-Biedl syndrome.…”