Aim: To determine the time-course of collecting duct (CD) ectasia, proliferation and the expression of G1-phase cyclin partners of cyclin-dependent kinases (Cdks) 2 and 4, in a model of autosomal recessive polycystic kidney disease (ARPKD). Introduction: In ARPKD, cyst formation arises from the synchronized and fusiform dilatation of CD and distal nephron tubules. Here, we investigated the hypothesis that proliferation and cell cycle activation in CD epithelial cells occurs during the early but not the late phase of ARPKD. Methods: Kidneys from Lewis polycystic kidney disease (LPK) rats (an ARPKD model) were examined at postnatal weeks (wk) 1, 3, 6, 12, 16 and 24 and compared to control animals. Results: Kidney maturation (as shown by the persistence of comma-shaped bodies) was delayed in LPK rats at wk1. The physiological distribution of Ki-67 and cyclin D1 in medullary rays was preserved but focal areas of dilated CDs were detected in LPK rats, and epithelial cells expressed Ki-67, cyclin D1 and E. By wk 3, CD ectasia was diffuse in the outer medulla and cortex, and from wk 6 was associated with interstitial fibrosis. The mean luminal diameter of CDs increased from wks 1 to 24 (wk1: 1.16 1 0.24; wk3: 5.66 1 1.03; wk6: 5.55 1 0.82; wk16: 8.17 1 1.39; wk s24: 15.65 1 4.04 arbitrary units; P < 0.05). The proliferation index (Ki-67-positive cells) of CDs peaked between wks 3 to 6 in the cortex and outer medulla, falling to control levels by wk 24. Similarly the number of cyclin D1-positive CDs peaked at wks 3 to 6, whereas the number of cyclin E-positive CDs increased progressively, peaking at wk 24. Conclusion: These data suggest that anti-proliferative therapies are likely to be most effective in reducing CD ectasia if commenced early (before week 6) in this model. The sustained increase in cyclin E also indicates that Cdk2 may have a pathological role, independent of proliferation.
|Number of pages||1|
|Issue number||Supplement s3|
|Publication status||Published - Sept 2008|
|Event||44 Annual Scientific Meeting of the Australian and New Zealand Society of Nephrology - Newcatle, Australia|
Duration: 6 Sept 2008 → 10 Sept 2008