Aberrant planar cell polarity induced by urinary tract obstruction

Abstract

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.

Aberrant Regulation of Planar Cell Polarity in Polycystic Kidney Disease

“…33 It is possible that aberrant activation of Fz3-CDC42 signaling in the distal tubular segments contributes to the different rate of cyst development. Interestingly, recent studies demonstrated Fz3 upregulation and increased apical localization in dilated tubules 3 days after urinary tract obstruction, 34 suggesting that Fz3 upregulation occurs in different cystic models. Fz3 plays a dual role in canonical and noncanonical (PCP) Wnt signaling, depending on cellular context.…”

Planar Cell Polarity Pathway in Kidney Development and Function

“…The authors concluded that Fz3 becomes activated in the absence of PKD1, leading to upregulation of Cdc42, rearrangements of actin, and loss of OCD [158]. Inappropriately elevated levels of Fz3 and randomized OCD were also detected in renal cysts induced by obstruction of the postnatal urinary tract [159].…”

“…However, the PCP-dependent mechanisms influencing cyst formation may differ according to developmental phase. During the mid-embryonic phase in mice, mutations of cilial genes may cause defective CE, whereas during early postnatal tubular elongation (or after postnatal injury such as ureteral obstruction) [159] mutant cilial genes may disturb OCD.…”

Planar cell polarity in kidney development and disease

“…Since this initial discovery, several groups have shown a correlation between defects in oriented cell division and cystogenesis. 36,42,[60][61][62] The precise role these factors play in establishing or affecting PCP is not known. However, Lokmane and colleagues found that Hnf1b directly regulates the expression of Wnt9b, potentially explaining the PCP defects observed in these mice (see below).…”

“…This is of interest, because several investigators have shown that multiple core components, including Fzds and Vangl2, are expressed in the epithelium. 21,61,62 Indeed, the ultimate readout of PCP is on the epithelium. The data of Mao and colleagues suggest that the Fat/Ds pathways may be acting in completely distinct cell types from the core determinants in the kidney and may provide further support that these two pathways act in parallel.…”