Aberrant planar cell polarity induced by urinary tract obstruction.
Flow sensing by primary cilia of the epithelial cells is involved in cystogenesis in polycystic kidney disease. We investigate whether a similar mechanism applies to the pathogenesis of cyst-like tubular dilatation induced by ureteral obstruction in mice. Robust proliferation occurs in the obstructed tubules when urine flow is interrupted as well as in the repairing tubules when urine flow is reestablished after relief of the obstruction, suggesting a urine flow-independent mechanism of proliferation. In the urothelium, proliferation is only detected above the obstruction, although urine flow ceased both above and below the obstruction. Our results support mechanical strain- rather than flow-mediated proliferation in obstructive uropathy. To understand the mechanism of cell proliferation leading to increased tubular diameter in cyst-like tubular dilatation, we examine planar cell polarity (PCP), which is necessary for oriented cell division and maintenance of tubular diameter. In dilated tubules, the orientation of cell division is randomized, atypical PKC (aPKC) is mislocalized, and the pattern of the expression of a core PCP protein, Frizzled3 (Fz3), is altered. In addition, the level of Fz3 expression is increased. These results indicate that aberrant PCP may contribute to cyst-like tubular dilatation in obstructive uropathy. Interestingly, the orientation of cell division, localization of aPKC, and Fz3 expression return to normal when obstruction is relieved, which suggest a role of normal PCP signaling in tubular repair.
Department of Pediatrics, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas TX 75390-9063, USA.
Ling
L
Li
Diana
D
Zepeda-Orozco
Vishal
V
Patel
Phu
P
Truong
Courtney M
CM
Karner
Thomas J
TJ
Carroll
Fangming
F
Lin
D000818:Animals; D030801:Animals, Genetically Modified; D002455:Cell Division; D016764:Cell Polarity; D049109:Cell Proliferation; D004231:Diuresis; D051157:Frizzled Receptors / Q000378:metabolism; D007684:Kidney Tubules / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D011493:Protein Kinase C / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D013314:Stress, Mechanical; D014018:Tissue Distribution; D015854:Up-Regulation; D014513:Ureter / Q000648:ultrastructure*; D014517:Ureteral Obstruction / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology
D051157:Frizzled Receptors; C486339:Fzd3 protein, mouse; D043562:Receptors, G-Protein-Coupled; C115015:PKC-3 protein; D011493:Protein Kinase C