sirolimus and Polycystic-Kidney--Autosomal-Recessive

Autosomal recessive polycystic kidney disease (ARPKD) is an important genetic disorder in pediatric nephrological practice. Mutation of the polycystic kidney and hepatic disease gene 1 (PKHD1) was identified as the cause of ARPKD. Rapamycin is a highly specific inhibitor of mammalian target of rapamycin (mTOR). Rapamycin exerts its biological activity by inhibiting the serine-threonine kinase mTOR, which regulates important cellular processes such as control of cell cycle, cell size, translation initiation and transcription. The ability of rapamycin to cause G1-cell cycle arrest, reduced cell growth and a reduced rate of proliferation has led to efforts to develop rapamycin and related mTOR inhibitors as anti-cystogenesis agents. Therefore, we investigated the relationship between the decreased FPC and the protein levels of mTOR and the inhibitory effects of rapamycin on the expression of mTOR, Hypoxia-inducible factor-1 alpha (HIF-1alpha) and vascular endothelial growth factor (VEGF) in the human 293T cell line. These observations should provide an important platform for determining FPC function and the pathogenesis of ARPKD, with the targeting of mTOR signaling being exploitable as a novel therapy.

Topics: Antibiotics, Antineoplastic; Cell Line; Gene Silencing; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Polycystic Kidney, Autosomal Recessive; Protein Kinases; Receptors, Cell Surface; RNA Interference; S Phase; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Vascular Endothelial Growth Factor A