The Role of Primary Cilia in Autosomal Dominant Polycystic Disease Revisited
Autosomal dominant polycystic kidney disease caused
by mutations in either of two genes, PKD1 or PKD2, is the 4th leading
cause of end-stage renal disease in adults, affecting approximately 12.5 million people worldwide.
ADPKD is characterized by the development of epithelial-lined cysts in the kidney,
liver, and pancreas and the presence of connective tissue abnormalities.
At the cellular level, changes in cell polarity and structural variation to
the extracellular matrix are also seen.
The protein products of PKD1 and PKD2 are transmembrane proteins
called polycystin 1 (PC1) and polycystin 2 (PC2), respectively.
The N-terminal region is located at the extra cytoplasmic domain and the C-terminal region
is at the cytoplasmic tail. When proteins bind to PC1, it is usually at the cytoplasmic tail.
However, the mechanism of Ca2+ influx and the function of PC
has come into question in recent studies.
These studies described that PC1 would turn the mechanical sensory
ciliary signal into a chemical one by binding to PC2 and causing a release
of calcium into the cilia via the opening of PC2’s calcium channels.
The mechanosensory properties of primary cilia in
kidney cells have recently come into question along with PC1’s
function as a flow sensor.
Past studies could have wrongly accounted the time for calcium influx
into the cilia since calcium could diffuse in less than 200 ms from the cytoplasm to the cilia.
Also, motion and light-path dependent artifacts could have accounted
for the error in previous studies.
The importance of intact cilia along with the presence of fully functional
polycystins to stop initiation of cysts in ADPKD points to a probable unknown
signal occurring within cilia that is termed cilia-dependent cyst activation.
Nephrol Open J. 2017; SE(1): S4-S7. doi: 10.17140/NPOJ-SE-1-102