Implications of Dysfunction of Mechanosensory Cilia in Polycystic Kidney Disease

Abstract

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a multisystemic disorder characterized by numerous fluid-filled renal cysts that eventually destroy the kidney architecture and lead to end-stage kidney disease (ESKD). Although the formation of bilateral cystic kidneys is the hallmark of the disease, patients with ADPKD also suffer from extra-renal manifestations and cardiovascular complications. ADPKD is considered a ciliopathy disease due to defects in mechanosensory polycystins, localized to primary cilia, which have been recognized as mechanosensory organelles due to their involvement in ADPKD only within the past decade. Our recent studies focus on the fluid mechanosensory functions of primary cilia using cultured cells, animal models, and tissue from ADPKD patients. Growing evidence from these studies suggests that aberrant expression or localization of polycystins to cilia could promote high blood pressure due to the inability to synthesize nitric oxide in response to an increase in shear stress, and alteration of function of cilia could contribute to vascular and renal abnormalities in ADPKD. Our results have led us to propose that drugs targeting primary ciliary function could to be a novel therapeutic approach to slow the progression of pathogenesis in ADPKD. In this chapter, in order to explain the involvement of primary cilia in ADPKD, the structure of primary cilia and their mechanosensory function will be described and their contribution to diseases of the kidney and cardiovascular system will be discussed in regards to ADPKD.