Cytosolic HDAC6 is accumulated in cystic kidneys

To the Editor: In the latest issue, Cebotaru et al. showed that histone deacetylases 6 (HDAC6) increased cyclic adenosine monophosphate (cAMP) levels and promoted cyst formation in an autosomal dominant polycystic kidney disease (ADPKD) mouse model, which highlights the important role of HDAC6 in ADPKD progression. Similarly, we found the upregulation of HDAC6 in human ADPKD kidney tissues (Figure 1a). Moreover, HDAC6 was also overexpressed in cystic kidneys of the Han:SPRD rat, which is a nonorthologous model of ADPKD, suggesting there is a common pathway regulating HDAC6 expression or stability in cystic kidneys (Figure 1b). Polycystic kidney disease is characterized by low intracellular calcium concentration and high intracellular cAMP levels. Several studies showed that the activity or transcription of histone deacetylases can be regulated by calcium or cAMP. It is intriguing to see whether the HDAC6 overexpression is caused by abnormal levels of calcium and cAMP in polycystic kidney disease. HDAC6 belongs to the class II histone deacetylases, which are localized both in the cytosol and nucleus and therefore exert different cellular functions depending on its subcellular localization. We showed that HDAC6 is accumulated in the cytosol of cyst-lining epithelial cells in Han:SPRD rats and human ADPKD, suggesting that HDAC6 stimulates cAMP and promotes cyst formation mainly through its cytosolic substrates (Figure 1c and d). Increase in cAMP levels in polycystic kidney disease is due