Rapamycin-mediated suppression of renal cyst expansion in del34 Pkd1-/- mutant mouse embryos: an investigation of the feasibility of renal cyst prevention in the foetus.

AIM: Polycystic kidney disease (PKD) in humans involves kidney cyst expansion beginning in utero. Recessive PKD can result in end-stage renal disease (ESRD) within the first decade, whereas autosomal dominant PKD (ADPKD), caused by mutations in the PKD1 or PKD2 gene, typically leads to ESRD by the fifth decade of life. Inhibition of mTOR signalling was recently found to halt cyst formation in adult ADPKD mice. In contrast, no studies have investigated potential treatments to prevent cyst formation in utero in recessive PKD. Given that homozygous Pkd1 mutant mice exhibit cyst formation in utero, we decided to investigate whether mTOR inhibition in utero ameliorates kidney cyst formation in foetal Pkd1 homozygous mutant mice.
METHODS: Pregnant Pkd1(+/-) female mice (mated with Pkd1(+/-) male mice) were treated with rapamycin from E14.5 to E17.5. Foetal kidneys were dissected, genotyped and evaluated by cyst size as well as expression of the developmental marker, Pax2.
RESULTS: Numerous cysts were present in Pkd1(-/-) kidneys, which were twice the weight of wild-type kidneys. Cyst size was reduced by a third in rapamycin-treated Pkd1(-/-) kidney sections and kidney mass was reduced to near wild-type levels. However, total cyst number was not reduced compared with control embryos. Pax2 expression and kidney development were unaltered in rapamycin-treated mice but some lethality was observed in Pkd1(-/-) null embryos.
CONCLUSION: Rapamycin treatment reduces cyst formation in Pkd1(-/-) mutant mice; therefore, the prevention of kidney cyst expansion in utero by mTOR inhibition is feasible. However, selective rapamycin-associated lethality limits its usefulness as a treatment in utero.