Autosomal Dominant Polycystic Kidney Disease Induced by Ciliary Defects

Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is a common genetic renal disease, which is caused by pathogenic mutations of either PKD1 (85%) or PKD2 (15%) genes, encoding for polycystin-1 (PC1) or polycystin-2 (PC2), respectively. These two proteins hetero-dimerize in renal primary cilia to act as a calcium channel. Primary cilia that protrude from cell membranes have a microtubule-based finger-like structure and are found on most mammalian cells. Primary cilia in the kidney have no motility but act as mechanosensors to sense fluid flow through renal tubules. In addition, various signaling proteins related to Hedgehog (Hh) and platelet-derived growth factor receptor alpha (PDGFRα) are localized to the cilia to detect changes in the extracellular environment. Recent studies have demonstrated that many ADPKD animal models have defective cilia in the epithelial cells that line the cysts. Also, animal models targeting ciliary genes show abnormal phenotypes such as polycystic kidneys and developmental defects. These findings reveal that ciliary malfunction is sufficient to cause ADPKD. In this chapter, we will review the putative roles of cilia in cyst formation and development in ADPKD.