Polycystins and mechanosensation in renal and nodal cilia

Abstract

The external surfaces of the human body, as well as its internal organs, constantly experience different kinds of mechanical stimulations. For example, tubular epithelial cells of the kidney are continuously exposed to a variety of mechanical forces, such as fluid flow shear stress within the lumen of th nephron. The majority of epithelial cells along the nephron, except intercalated cells, possess a primary cilium, an organelle projecting from the cell's apical surface into the luminal space. Despite its discovery over 100 years ago, the primary cilium's function continued to elude researchers for many decades. However, recent studies indicate that renal cilia have a sensory function. Studies on polycystic kidney disease (PKD) have identified many of the molecular players, which should help solve the mystery of how the renal cilium senses fluid flow. In this review, we will summarize the recent breakthroughs in PKD research and discuss the role(s) of the polycystin signaling complex in mediating mechanosensory function by the primary cilium of renal epithelium as well as of the embryonic node.

Primary cilia sensitize endothelial cells for fluid shear stress

“…The ciliary involvement in endothelial shear sensing reflects the general function of primary cilia in other cell types as biosensors for mechanical forces. Kidney tubular epithelial cells, for example, present primary cilia to resolve fluid motion exerted by flowing primary urine (Nauli and Zhou, 2004). Ciliated endodermal cells on the embryonic organizing center sense nodal right-toleft flow to generate expression of Nodal on the left side of the embryonic axis (McGrath and Brueckner, 2003;Bisgrove and Yost, 2006).…”

“…It is a membrane extension with a core of 9 doublets of microtubules that are connected to the basal body of the cell. In various cell types, among them kidney and biliary epithelial cells and endodermal cells of the embryonic organizing center, cilia are involved in shear stress sensing, and are implicated in polycystic kidney diseases (Nauli and Zhou, 2004) and left-right asymmetry problems (reviewed in Nauli and Zhou, 2004;Marshall and Nonaka, 2006;Satir and Christensen, 2007). EC have also been described to possess a primary cilium (Collin and Collin, 2004) that was "shed off" by high levels of fluid flow (Iomini et al, 2004).…”

Ciliary dysfunction in polycystic kidney disease: an emerging model with polarizing potential

“…The cilium's involvement in a broad range of cellular events such as cell cycle (3,113) and cell polarity (114,115), along with differentiation and establishment of planar cell polarity has made the task of determining its primary function in vivo difficult to establish (79,116). How these functions are interconnected, if indeed they are, is an important question, as it may lead to insights into the pathogenesis of PKD.…”

“…The mechanism of cyst formation is still unknown; however, indirect evidence showing many PKD gene products localize to the primary cilium led to a ciliary hypothesis for PKD (1). The primary cilium found in many cell types (2) is considered to be a fluid-flow sensor for the epithelial cells lining the nephron (3,4). In essence, the ciliary hypothesis states that dysfunctions in proteins localized to the primary cilium cause PKD.…”

Yeast gain-of-function mutations reveal structure–function relationships conserved among different subfamilies of transient receptor potential channels

“…Such rare mutations have been recovered from screens in Escherichia coli for a mechanosensitive channel (24) or in yeast for native (25) and foreign K ϩ channel (26) after single-gene mutagenesis. Among TRP channels, disease or experimental point mutations reported to date all seem to cause reduction or loss of channel activities, including the dominant polycystic kidney disease (PKD) alleles (27) and a dominant-negative construct of TrpV1 (28). The Trp P365 mutation in the fly is an exception.…”