Polycystic kidney diseases (PKDs) are characterised by the presence of numerous fluid-filled cysts in the kidney that are produced by the unregulated expansion of renal epithelial cells. A leading cause of end-stage renal failure, autosomal dominant PKD is caused by mutations in PKD1 and PKD2, which encode polycystin 1 and 2. These large transmembrane proteins form a cation channel complex that is involved in mechanosensation-triggered Ca2+ influx into cells. In this issue, two papers investigate the regulation and function of the polycystins.
On p. , Oliver Wessely and colleagues report that the RNA-binding protein bicaudal C (Bicc1) is a post-transcriptional regulator of polycystin 2. Bicc1-null mice develop severe PKD, they report, and Bicc1 is normally expressed in the mouse meso- and metanephric kidney. The authors also demonstrate that Bicc1 regulates the stability of Pkd2 mRNA and its translation efficiency by antagonising the repressive activity of the microRNA miR-17 on the 3′UTR of Pkd2 mRNA. To confirm this result, they show that the kidney defects caused by bicc1 knockdown in Xenopus are rescued by miR-17 knockdown. Finally, they report that Bicc1 is localised to cytoplasmic foci that contain proteins involved in post-transcriptional regulation of mRNAs. Together, these results reveal the important role played by a microRNA-based translational control mechanism in PKD and in normal kidney development.
On p. , Rong Li and colleagues describe how the mechanosensory function of polycystins prevents the development of renal cysts. Using expression microarray analysis, they show that myocyte enhancer factor 2 (MEF2C) and histone deacetylase 5 (HDAC5) are targets of polycystin-dependent stress sensing in polarised mouse renal epithelial cells. Fluid flow stimulation of polarised epithelial monolayers, they report, induces the phosphorylation and nuclear export of HDAC5. This, in turn, leads to the activation of MEF2C target genes, including missing in metastasis (MIM), which encodes a regulator of the actin cytoskeleton. Finally, the researchers show that kidney-specific knockout of Mef2C or the inactivation of MIM in mice causes renal tubule dilation. By contrast, treatment with an HDAC inhibitor reduces cyst formation in Pkd2−/− mouse embryos. They suggest, therefore, that HDAC inhibition might be a potential treatment for autosomal dominant PKD.
