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1 Medicine, Beth Israel Deaconess Med Ctr, Harvard Medical School, Boston, Massachusetts, United States
2 Medicine and Biochemistry, Mayo Medical School, Rochester, Minnesota, United States
3 Pathology, Univ New Mexico School of Medicine, Albuquerque, New Mexico, United States
4 Medicine/Nephrology, Indiana University Medical School, Indianapolis, Indiana, United States
* To whom correspondence should be addressed. E-mail: salper{at}bidmc.harvard.edu.
ADPKD gene products polycystin-1 (PC1) and polycystin-2 (PC2) colocalize in the apical monocilia of renal epithelial cells. Mouse and human renal cells without PC1 protein show impaired ciliary mechanosensation, and this impairment has been proposed to promote cystogenesis. However, most cyst epithelia of human ADPKD kidneys appear to express full-length PC1 and PC2 in normal or increased abundance. We show that confluent primary ADPKD cyst cells with the novel PC1 mutation 
L2433 and with normal abundance of PC1 and PC2 polypeptides lack ciliary PC1 and often lack ciliary PC2, whereas PC1 and PC2 are both present in cilia of confluent normal human kidney (NK) epithelial cells in primary culture. Confluent NK cells respond to shear stress with transient increases in [Ca2+]i dependent upon both extracellular Ca2+ and release from intracellular stores. In contrast, ADPKD cyst cells lack flow-sensitive [Ca2+]i signaling and exhibit reduced ER Ca2+ stores and store-depletion-operated Ca2+ entry, but retain near-normal Ca2+i responses to angiotensin II and to vasopressin. Expression of wildtype and mutant CD16.7-PKD1(115-226) fusion proteins reveals within the C-terminal 112 aa of PC1 a coiled-coil domain-independent ciliary localization signal. However, the coiled-coil domain is required for CD16.7-PKD1(115-226) expression to accelerate decay of the flow-induced Ca2+i signal in NK cells. These data provide evidence for ciliary dysfunction and polycystin mislocalization in human ADPKD cells with normal levels of PC1.
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