Aberrant planar cell polarity induced by urinary tract obstruction

Area of Science:

• Nephrology
• Cell Biology
• Urology

Background:

• Primary cilia-mediated flow sensing is implicated in polycystic kidney disease cystogenesis.
• The role of flow sensing in obstructive uropathy-induced tubular dilatation is unclear.

Purpose of the Study:

• To investigate the mechanisms driving cyst-like tubular dilatation in obstructive uropathy.
• To determine if mechanical strain or urine flow is the primary driver of proliferation.
• To examine the role of planar cell polarity (PCP) in this process.

Main Methods:

• Induction of ureteral obstruction in mice to model obstructive uropathy.
• Analysis of tubular cell proliferation in response to urine flow interruption and reestablishment.
• Assessment of planar cell polarity (PCP) protein localization and expression (Frizzled3, atypical PKC).

Main Results:

• Tubular cell proliferation occurred independently of urine flow, both during obstruction and repair.
• Mechanical strain, rather than flow, was identified as the likely mediator of proliferation.
• Aberrant PCP, including randomized cell division orientation and mislocalization of key proteins (aPKC, Fz3), was observed in dilated tubules.
• Increased Frizzled3 expression was noted in obstructed tubules.

Conclusions:

• Mechanical strain, not urine flow, promotes tubular cell proliferation in obstructive uropathy.
• Disrupted planar cell polarity (PCP) signaling contributes to cyst-like tubular dilatation.
• Normal PCP signaling is crucial for tubular repair following obstruction relief.