Novel involvement of nuclear hormone receptors in autosomal dominant polycystic kidney disease

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a systemic disorder that affects approximately 1 in 1000 individuals. It is caused by mutations of PKD1 and PKD2. Murine gene targeting studies have shown that these genes have an essential role in development, with homozygous inactivation resulting in pre-natal lethality. Among the noted abnormalities seen in Pkd1-/- mice are a variety of cardiovascular defects, diffuse renal cysts, and placental abnormalities, which are responsible for Pkd1-/- fetal demise. In these studies, our goal was to better understand the underlying transcriptional alterations that result in these developmental abnormalities. This was done by conducting microarray analysis of these affected tissues at multiple timepoints in development. Microarray analysis of Pkd1-/- tissues showed upregulation of a set of apolipoproteins and apolipoprotein-related transcripts. These transcriptional changes were validated using a variety of independent methods and were found to be associated with increased amounts of apolipoproteins in amniotic fluid. Similar abnormalities were observed in Pkd2-/- placentae and in kidneys of Pkd1cond/-; Meox2cre/+ mice. Increased HNF-4alpha activity and decreased transcription of COUP-TFII were also observed. These findings suggest a role for polycystin-1 and -2 in the regulation of nuclear hormone receptors and implicate the latter in the pathogenesis of disease.