Physiology InFocus
From Molecules to Organisms: Approaches to Systems and Integrative Physiology
Integrating Cellular Functions: the role of the Primary Cilium in Cell Proliferation and Polycystic Kidney Disease

Half a million Americans currently suffer from autosomal dominant polycystic kidney disease (ADPKD), making it not only the most common kidney disease but also the most common cystic disease ‑ indeed, more common than cystic fibrosis. Although the PKD1 gene whose mutations are responsible for the majority of cases of ADPKD has been cloned, the pathophysiology of this disease is still poorly understood.  Unfortunately, the mouse models of polycystic disease created by inserting targeted mutations into PKD1 are not as useful as hoped since the mutations are embryonic lethal.  Development of better models and understanding the development of the disease is currently a major area of emphasis (Presentation 1 and 3).  ADPKD produces abnormal ion transport, altered cell polarity, accelerated cell growth and proliferation, protein mis-localization, and abnormal extracellular matrix composition. One of the striking new aspects of PKD is the possible involvement of the apical cilium and the possibility that the cilium acts as a flow sensor in normal cells that leads to focal calcium entry near the cilium (Presentation 2).  The conjecture is that in PKD the function of the cilium is compromised and that intracellular calcium metabolism is abnormal  Ciliary-mediated, flow-induced increases in intracellular Ca may be mediated by members of the transient receptor potential (TRP) channels (including polycystin-2)(Presentation 4).