Abstract
Although solitary or sensory cilia are present in most cells of the body and their existence has been known since the sixties, very little is been known about their functions. One suspected function is fluid flow sensing- physical bending of cilia produces an influx of Ca++, which can then result in a variety of activated signaling pathways. Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a progressive disease, typically appearing in the 5th decade of life and is one of the most common monogenetic inherited human diseases, affecting approximately 600,000 people in the United States. Because ADPKD is a slowly progressing disease, I asked how fluid flow may act, via the primary cilium, to alter epithelial physiology during the course of cell turnover. I performed an experiment to determine under what conditions fluid flow can result in a change of function of renal epithelial tissue. A wildtype epithelial cell line derived the cortical collecting duct of a heterozygous offspring of the Immortomouse (Charles River Laboratory) was selected as our model system. Gentle orbital shaking was used to induce physiologically relevant fluid flow, and periodic measurements of the transepithelial Sodium current were performed. At the conclusion of the experiment, mechanosensitive proteins of interest were visualized by immunostaining. I found that fluid flow, in itself, modifies the transepithelial sodium current, cell proliferation, and the actin cytoskeleton. These results significantly impact the understanding of both the mechanosensation function of primary cilia as well as the understanding of ADPKD disease progression.
Highlights
Cilia are microtubule-based projections from the cell body
Several observations have illustrated the importance of the solitary cilium: 1) Smell, taste, and vision occurs via modified cilia: olfactory or gustatory sensory cilia and outer segments of rod cell, respectively Some receptors are located on neurocilia [4]. 3) mutations that occur in proteins resulting in mislocation of normal ciliary proteins or malfunction of solitary cilia itself in the renal epithelium produces a polycystic kidney disease phenotype, which is characterized by the transformation of an absorptive epithelium into a secretory one with formation of cysts [5,6,7,8]. 5) Defects in solitary cilia present during development result in inversion of the normal left-right axis of internal organs, e.g., the heart forms on the right side [9,10]
Cohort 3 did not exhibit a graded response: differentiated cells exposed to fluid flow (3B, 3C) showed a significant decrease in transepithelial sodium current as compared to 3A, but there was no significant difference in response to either slow or fast shaking
Summary
Cilia are microtubule-based projections from the cell body (general references http://www.ifcbiol.org/Primaryciliumweb/ index.html). Solitary or sensory cilia are present in most cells of the body and their functions are only beginning to be defined. Their existence has been known from morphological studies since the sixties [2]; because very little has been known about their functions, not much attention has been paid to this particular organelle until recently. 3) mutations that occur in proteins resulting in mislocation of normal ciliary proteins or malfunction of solitary cilia itself in the renal epithelium produces a polycystic kidney disease phenotype, which is characterized by the transformation of an absorptive epithelium into a secretory one with formation of cysts [5,6,7,8]. A second common motif is the demonstration that physical bending of cilia produces influx of Ca++, which can lead through Ca++-induced Ca++ release to a Ca++ wave spreading through several cells [16,17,18]
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